View source for Hemoglobin

{{Short description|Metalloprotein that binds with oxygen}}
{{Use American English|date=August 2024}}
{{Infobox heteropolypeptide
| heteropolymer = Hemoglobin
| polymer_type = heterotetramer, (<span style="color:red;">'''α'''</span><span style="color:blue;">'''β'''</span>)<sub>2</sub>
| protein_type = [[metalloprotein]], [[chromoprotein]], [[globulin]]
| function = [[oxygen]]-transport
| cofactors = [[heme]] (4)
| image = 1GZX Haemoglobin.png
| image_source = Structure of human hemoglobin. <span style="color:red;">'''α'''</span> and <span style="color:blue;">'''β'''</span> [[globin]] subunits are in red and blue, respectively, and the iron-containing [[heme]] groups in green. From {{PDB|1GZX}} {{Proteopedia|Hemoglobin}}
| SubunitCount = 3
| subunit1 = Hb-α1
| gene1 = [[HBA1]]
| locus1 = [[Chromosome 16|Chr. 16]] [https://omim.org/search?index=geneMap&search=16p13.3 p13.3]
| subunit2 = Hb-α2
| gene2 = [[HBA2]]
| locus2 = [[Chromosome 16|Chr. 16]] [https://omim.org/search?index=geneMap&search=16p13.3 p13.3]
| subunit3 = Hb-β
| gene3 = [[HBB]]
| locus3 = [[Chromosome 11|Chr. 11]] [https://omim.org/search?index=geneMap&search=11p15.5 p15.5]
| Formula= C2952 H 4664 O 832 N812 S8 Fe 4
}}

'''Hemoglobin''' ('''haemoglobin''',{{efn|from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globule'' 'ball, sphere' + ''-in''; {{IPAc-en|ˌ|h|iː|m|ə|ˈ|ɡ|l|oʊ|b|ᵻ|n|,_|ˈ|h|ɛ|m|oʊ|ˌ|-}}<ref>{{cite LPD |3}}</ref><ref>{{cite EPD |18}}</ref>}} '''Hb''' or '''Hgb''') is a [[protein]] containing [[iron]] that facilitates the transportation of [[oxygen]] in [[red blood cell]]s. Almost all [[vertebrate]]s contain hemoglobin,<ref>{{cite book
|last1=Maton |first1=Anthea
|author2=Jean Hopkins
|author3=Charles William McLaughlin
|author4=Susan Johnson
|author5=Maryanna Quon Warner
|author6=David LaHart
|author7=Jill D. Wright
|title=Human Biology and Health
|publisher=Prentice Hall
|year=1993
|location=Englewood Cliffs, New Jersey, US
|isbn=978-0-13-981176-0
|url=https://archive.org/details/humanbiologyheal00scho
}}</ref> with the sole exception of the fish family [[Channichthyidae]].<ref name="Sidell-2006">{{cite journal
|last=Sidell |first=Bruce
|author2=Kristin O'Brien
|year=2006
|title=When bad things happen to good fish: the loss of hemoglobin and myoglobin expression in Antarctic icefishes
|periodical=[[The Journal of Experimental Biology]]
|volume=209
|issue=Pt 10 |pages=1791–802
|pmid=16651546 |doi=10.1242/jeb.02091
|s2cid=29978182
}}</ref> Hemoglobin in the [[blood]] carries oxygen from the respiratory organs ([[lung]]s or [[gill]]s) to the other tissues of the body, where it releases the oxygen to enable [[aerobic respiration]] which powers an animal's [[metabolism]]. A healthy human has 12{{spaces}}to 20{{spaces}}grams of hemoglobin in every 100{{spaces}}mL of blood. Hemoglobin is a [[metalloprotein]], a [[chromoprotein]], and a [[globulin]].

In [[mammal]]s, hemoglobin makes up about 96% of a red blood cell's [[dry matter|dry weight]] (excluding water), and around 35% of the total weight (including water).<ref>{{cite journal |author1=Weed, Robert I. |author2=Reed, Claude F. |author3=Berg, George |title=Is hemoglobin an essential structural component of human erythrocyte membranes? |journal=J Clin Invest |volume=42 |issue=4 |pages=581–88 |year=1963 |pmid=13999462 |doi=10.1172/JCI104747 |pmc=289318}}</ref> Hemoglobin has an oxygen-binding capacity of 1.34{{spaces}}mL of O<sub>2</sub> per gram,<ref>{{cite journal |vauthors=Dominguez de Villota ED, Ruiz Carmona MT, Rubio JJ, de Andrés S |title=Equality of the in vivo and in vitro oxygen-binding capacity of hemoglobin in patients with severe respiratory disease |journal=Br J Anaesth |volume=53 |issue=12 |pages=1325–28 |year=1981 |pmid=7317251 |doi=10.1093/bja/53.12.1325 |doi-access=free |s2cid=10029560}}</ref> which increases the total [[blood oxygen capacity]] seventy-fold compared to dissolved oxygen in blood plasma alone.<ref>{{cite book |last1=Rhodes |first1=Carl E. |last2=Denault |first2=Deanna |last3=Varacallo |first3=Matthew |title=Physiology, Oxygen Transport |date=2019-03-04 |publisher=StatPearls Publishing |place=Treasure Island (FL) |pmid=30855920 |via=NCBI Bookshelf |url=https://www.ncbi.nlm.nih.gov/books/NBK538336/ |access-date=2019-05-04 |url-status=live |archive-url=https://web.archive.org/web/20210827215723/https://www.ncbi.nlm.nih.gov/books/NBK538336/ |archive-date=2021-08-27}}</ref> The mammalian hemoglobin molecule can bind and transport up to four oxygen molecules.<ref name="Costanzo-2007">{{cite book |author=Costanzo, Linda S. |title=Physiology |publisher=Lippincott Williams & Wilkins |location=Hagerstwon, MD |year=2007 |isbn=978-0-7817-7311-9 |url=https://archive.org/details/physiology00cost_0}}</ref>

Hemoglobin also transports other gases. It carries off some of the body's respiratory [[carbon dioxide]] (about 20–25% of the total)<ref>{{cite book |title=Anatomy and Physiology |publisher=Elsevier Health Sciences |date=2015-02-10 |isbn=978-0-323-31687-3 |last=Patton |first=Kevin T. 
|url=https://books.google.com/books?id=Ko2bBgAAQBAJ |access-date=2016-01-09 |url-status=live |archive-url=https://web.archive.org/web/20160426205246/https://books.google.com/books?id=Ko2bBgAAQBAJ |archive-date=2016-04-26}}</ref> as [[carbaminohemoglobin]], in which CO<sub>2</sub> binds to the [[heme protein]]. The molecule also carries the important regulatory molecule [[nitric oxide]] bound to a [[thiol]] group in the globin protein, releasing it at the same time as oxygen.<ref name="Epstein-1998">{{cite journal
|last1=Epstein |first1=F. H.
|last2=Hsia |first2=C. C. W.
|title=Respiratory Function of Hemoglobin
|journal=New England Journal of Medicine
|volume=338
|issue=4
|pages=239–47
|year=1998
|pmid=9435331
|doi=10.1056/NEJM199801223380407
}}</ref>

Hemoglobin is also found in other cells, including in the [[dopaminergic cell group A9|A9 dopaminergic neurons]] of the [[substantia nigra]], [[macrophage]]s, [[alveolar cell]]s, lungs, retinal pigment epithelium, hepatocytes, [[mesangial cell]]s of the kidney, endometrial cells, cervical cells, and vaginal epithelial cells.<ref name="Saha-2014">{{cite journal |last1=Saha |first1=D. |last2=Reddy |first2=K. V. R. |last3=Patgaonkar |first3=M. |last4=Ayyar |first4=K. |last5=Bashir |first5=T. |last6=Shroff |first6=A. |title=Hemoglobin Expression in Nonerythroid Cells: Novel or Ubiquitous? |journal=[[International Journal of Inflammation]] |volume=2014 |issue=803237 |pages=1–8 |year=2014 |pmid=25431740 |doi=10.1155/2014/803237 |doi-access=free |pmc=4241286}}</ref> In these tissues, hemoglobin absorbs unneeded oxygen as an [[antioxidant]], and regulates [[iron metabolism]].<ref name="Biagioli-2009">{{cite journal |vauthors=Biagioli M, Pinto M, Cesselli D, etal |title=Unexpected expression of alpha- and beta-globin in mesencephalic dopaminergic neurons and glial cells |journal=[[Proceedings of the National Academy of Sciences of the United States of America]] |volume=106 |issue=36 |pages=15454–59 |year=2009 |bibcode=2009PNAS..10615454B |pmid=19717439 |doi=10.1073/pnas.0813216106 |doi-access=free |pmc=2732704}}</ref> Excessive glucose in the blood can attach to hemoglobin and raise the level of hemoglobin A1c.<ref name="NIH-NHLBI">{{cite web |title=Blood Tests |website=National Heart, Lung, and Blood Institute (NHLBI) |url=https://www.nhlbi.nih.gov/health/blood-tests |access-date=2019-04-27 |url-status=live |archive-url=https://web.archive.org/web/20190409050700/https://www.nhlbi.nih.gov/health-topics/blood-tests |archive-date=2019-04-09}}</ref>

Hemoglobin and hemoglobin-like molecules are also found in many invertebrates, fungi, and plants.<ref name="Weber-2001"/> In these organisms, hemoglobins may carry oxygen, or they may transport and regulate other small molecules and ions such as carbon dioxide, nitric oxide, hydrogen sulfide and sulfide. A variant called [[leghemoglobin]] serves to scavenge oxygen away from [[wikt:anaerobic|anaerobic]] systems such as the nitrogen-fixing nodules of [[legume|leguminous]] plants, preventing oxygen poisoning.

The medical condition [[hemoglobinemia]], a form of [[anemia]], is caused by [[intravascular hemolysis]], in which hemoglobin leaks from red blood cells into the [[blood plasma]].

==Research history==
[[File:Max Perutz.jpg|thumb|upright|[[Max Perutz]] won the [[Nobel Prize for chemistry]] for his work determining the molecular structure of hemoglobin and [[myoglobin]]<ref>{{cite news |title=Max Perutz, Father of Molecular Biology, Dies at 87 |website=The New York Times |date=2002-02-08 |url=https://www.nytimes.com/2002/02/08/world/max-perutz-father-of-molecular-biology-dies-at-87.html |archive-url=https://web.archive.org/web/20160423072418/https://www.nytimes.com/2002/02/08/world/max-perutz-father-of-molecular-biology-dies-at-87.html |archive-date=2016-04-23}}</ref>]]

Although blood had been known to carry oxygen since at least 1794,<ref>{{cite book |last=Parry |first=CH |title=Letters from Dr. Withering, ... Dr. Ewart, ... Dr. Thorton ... and Dr. Biggs ... together with some other papers, supplementary to two publications on asthma, consumption, fever, and other diseases, by T. Beddoes |date=1794 |page=43 |language=en |url=https://books.google.com/books?id=XkxpAAAAcAAJ&q=factitious |access-date=2021-11-30 |url-status=live |archive-url=https://web.archive.org/web/20220131131255/https://books.google.com/books?id=XkxpAAAAcAAJ&q=factitious |archive-date=2022-01-31}}</ref><ref>{{cite book |last=Beddoes |first=T. |title=Considerations on the Medicinal Use, and on the Production of Factitious Airs: Part I. By Thomas Beddoes, M.D. Part II. By James Watt, Engineer; "Part 1, section 2, "Of the breathing of man and familiar animals" |date=1796 |publisher=Bulgin and Rosser |at=Part 1, p. 9–13 |language=en |url=https://books.google.com/books?id=iAg2AQAAMAAJ&dq=cavendish&pg=PA31 |access-date=2021-11-30 |url-status=live |archive-url=https://web.archive.org/web/20220131131252/https://books.google.com/books?id=iAg2AQAAMAAJ&dq=cavendish&pg=PA31 |archive-date=2022-01-31}}</ref> the oxygen-carrying property of hemoglobin was described by Hünefeld in 1840.<ref>{{cite book |last1=Hünefeld |first1=Friedrich Ludwig |title=Der Chemismus in der thierischen Organisation |date=1840 |publisher=F. A. Brockhaus |location=Leipzig |language=de |url=https://www.digitale-sammlungen.de/de/view/bsb10368567?page=7 |access-date=26 February 2021 |url-status=live |archive-url=https://web.archive.org/web/20210414105616/https://reader.digitale-sammlungen.de/de/fs1/object/display/bsb10368567_00007.html |archive-date=14 April 2021}}</ref> In 1851, German physiologist [[Otto Funke]] published a series of articles in which he described growing hemoglobin crystals by successively diluting red blood cells with a solvent such as pure water, alcohol or ether, followed by slow evaporation of the solvent from the resulting protein solution.<ref name="Funke-1851">{{cite journal |author=Funke O |title=Über das milzvenenblut |journal=Z Rat Med |volume=1 |pages=172–218 |year=1851}}</ref><ref>{{cite web |title=A NASA Recipe For Protein Crystallography |website=Educational Brief |publisher=National Aeronautics and Space Administration |url=https://www.okcareertech.org/cimc/special/nochild/downloads/science/Protein.Crystallography.pdf |access-date=2008-10-12 |archive-url=https://web.archive.org/web/20080410161517/https://www.okcareertech.org/cimc/special/nochild/downloads/science/Protein.Crystallography.pdf |archive-date=2008-04-10}}</ref> Hemoglobin's reversible oxygenation was described a few years later by [[Felix Hoppe-Seyler]].<ref name="Hoppe-Seyler-1866">{{cite journal |author=Hoppe-Seyler F |title=Über die oxydation in lebendem blute |journal=Med-chem Untersuch Lab |volume=1 |pages=133–40 |year=1866}}</ref>

In 1825, Johann Friedrich Engelhart discovered that the ratio of iron to protein is identical in the hemoglobins of several species.<ref name="Engelhart-1825">{{cite book |last=Engelhart |first=Johann Friedrich |title=Commentatio de vera materia sanguini purpureum colorem impertientis natura |year=1825 |publisher=Dietrich |location=Göttingen |language=la |url=https://opacplus.bsb-muenchen.de/Vta2/bsb10972513/bsb:BV006399484?page=1 |access-date=2020-06-16 |url-status=live |archive-url=https://web.archive.org/web/20200616114253/https://opacplus.bsb-muenchen.de/Vta2/bsb10972513/bsb:BV006399484?page=1 |archive-date=2020-06-16}}</ref><ref name="Edinburgh Medical and Surgical Journal-1827">{{cite journal |title=Engelhard & Rose on the Colouring Matter of the Blood |journal=Edinburgh Medical and Surgical Journal |volume=27 |number=90 |pages=95–102 |date=1827 |pmid=30330061 |pmc=5763191}}</ref> From the known atomic mass of iron, he calculated the molecular mass of hemoglobin to ''n'' × 16000 (''n''=number of iron atoms per hemoglobin molecule, now known to be 4), the first determination of a protein's molecular mass. This "hasty conclusion" drew ridicule from colleagues who could not believe that any molecule could be so large. However, [[Gilbert Smithson Adair]] confirmed Engelhart's results in 1925 by measuring the osmotic pressure of hemoglobin solutions.<ref>{{cite journal |last=Adair |first=Gilbert Smithson |title=A critical study of the direct method of measuring the osmotic pressure of hǣmoglobin |journal=Proc. R. Soc. Lond. |year=1925 |volume=108 |issue=750 |pages=292–300 |bibcode=1925RSPSA.109..292A |doi=10.1098/rspa.1925.0126 |doi-access=free}}</ref>

With the development of [[X-ray crystallography]], it became possible to solve protein structures.<ref name="Stoddart-2022">{{cite journal |last1=Stoddart |first1=Charlotte |title=Structural biology: How proteins got their close-up |journal=Knowable Magazine |date=1 March 2022 |doi=10.1146/knowable-022822-1 |doi-access=free |url=https://knowablemagazine.org/article/living-world/2022/structural-biology-how-proteins-got-their-closeup |access-date=25 March 2022|url-access=subscription }}</ref> In 1959, [[Max Perutz]] determined the molecular structure of hemoglobin.<ref name="Perutz-1960a">{{cite journal |last1=Perutz |first1=M.F. |last2=Rossmann |first2=M.G. |last3=Cullis |first3=A.F. |last4=Muirhead |first4=H. |last5=Will |first5=G. |last6=North |first6=A.C.T. |year=1960 |title=Structure of haemoglobin: a three-dimensional Fourier synthesis at 5.5-A. resolution, obtained by X-ray analysis |journal=Nature |volume=185 |issue=4711 |pages=416–22 |bibcode=1960Natur.185..416P |pmid=18990801 |doi=10.1038/185416a0 |s2cid=4208282}}</ref><ref name="Perutz-1960b">{{cite journal |author=Perutz MF |title=Structure of haemoglobin |journal=Brookhaven Symposia in Biology |volume=13 |pages=165–83 |year=1960 |pmid=13734651}}</ref> For this work he shared the 1962 [[Nobel Prize in Chemistry]] with [[John Kendrew]], who sequenced the globular protein [[myoglobin]].<ref name="Stoddart-2022"/><ref name="de Chadarevian-2018">{{cite journal |last1=de Chadarevian |first1=Soraya |title=John Kendrew and myoglobin: Protein structure determination in the 1950s: John Kendrew and Myoglobin |journal=Protein Science |date=June 2018 |volume=27 |issue=6 |pages=1136–1143 |pmid=29607556 |doi=10.1002/pro.3417 |pmc=5980623}}</ref>

The role of hemoglobin in the blood was elucidated by French [[physiologist]] [[Claude Bernard]].

The name ''hemoglobin'' (or ''haemoglobin'') is derived from the words ''[[heme]]'' (or ''[[heme|haem]]'') and ''[[globin]]'', reflecting the fact that each [[protein subunit|subunit]] of hemoglobin is a [[globular protein]] with an embedded [[heme]] group. Each heme group contains one iron atom, that can bind one oxygen molecule through ion-induced dipole forces. The most common type of hemoglobin in mammals contains four such subunits.<ref>{{Cite journal |last1=Nishi |first1=Hiroshi |last2=Inagi |first2=Reiko |last3=Kato |first3=Hideki |last4=Tanemoto |first4=Masayuki |last5=Kojima |first5=Ichiro |last6=Son |first6=Daisuke |last7=Fujita |first7=Toshiro |last8=Nangaku |first8=Masaomi |date=August 2008 |title=Hemoglobin Is Expressed by Mesangial Cells and Reduces Oxidant Stress |journal=Journal of the American Society of Nephrology |volume=19 |issue=8 |pages=1500–1508 |doi=10.1681/ASN.2007101085 |issn=1046-6673 |pmc=2488266 |pmid=18448584}}</ref>

== Genetics ==
Hemoglobin consists of [[protein subunit]]s ([[globin]] molecules), which are [[polypeptide]]s, long folded chains of specific [[amino acid]]s which determine the protein's chemical properties and function. The amino acid sequence of any polypeptide is [[translation (biology)|translated]] from a segment of DNA, the corresponding [[gene]].

There is more than one hemoglobin gene. In humans, [[hemoglobin A]] (the main form of hemoglobin in adults) is coded by genes ''[[HBA1]]'', ''[[HBA2]]'', and ''[[HBB]]''.<ref name="Hardison-2012">{{cite journal |last=Hardison |first=Ross C. |date=2012-12-01 |title=Evolution of hemoglobin and its genes |journal=Cold Spring Harbor Perspectives in Medicine |volume=2 |issue=12 |article-number=a011627 |doi=10.1101/cshperspect.a011627 |issn=2157-1422 |pmc=3543078 |pmid=23209182}}</ref> Alpha 1 and alpha 2 subunits are respectively coded by genes ''HBA1'' and ''HBA2'' close together on chromosome 16, while the beta subunit is coded by gene ''HBB'' on chromosome 11. The amino acid sequences of the globin subunits usually differ between species, with the difference growing with evolutionary distance. For example, the most common hemoglobin sequences in humans, bonobos and chimpanzees are completely identical, with exactly the same alpha and beta globin protein chains.<ref>{{cite journal |last=Offner |first=Susan |date=2010-04-01 |title=Using the NCBI Genome Databases to Compare the Genes for Human & Chimpanzee Beta Hemoglobin |journal=The American Biology Teacher |language=en |volume=72 |issue=4 |pages=252–56 |issn=0002-7685 |doi=10.1525/abt.2010.72.4.10 |s2cid=84499907 |url=https://abt.ucpress.edu/content/72/4/252 |access-date=2019-12-26 |url-status=live |archive-url=https://web.archive.org/web/20191226155117/https://abt.ucpress.edu/content/72/4/252 |archive-date=2019-12-26|url-access=subscription }}</ref><ref>{{cite web |title=HBB – Hemoglobin subunit beta – Pan paniscus (Pygmy chimpanzee) – HBB gene & protein |website=uniprot.org |url=https://www.uniprot.org/uniprot/P68872 |access-date=2020-03-10 |url-status=live |archive-url=https://web.archive.org/web/20200801122023/https://www.uniprot.org/uniprot/P68872 |archive-date=2020-08-01}}</ref><ref>{{cite web |title=HBA1 – Hemoglobin subunit alpha – Pan troglodytes (Chimpanzee) – HBA1 gene & protein |website=uniprot.org |url=https://www.uniprot.org/uniprot/P69907 |access-date=2020-03-10 |url-status=live |archive-url=https://web.archive.org/web/20200801122008/https://www.uniprot.org/uniprot/P69907 |archive-date=2020-08-01}}</ref> Human and gorilla hemoglobin differ in one amino acid in both alpha and beta chains, and these differences grow larger between less closely related species.{{citation needed|date=November 2023}}

[[Mutation]]s in the genes for hemoglobin can result in [[hemoglobin variants|variants of hemoglobin]] within a single species, although one sequence is usually "most common" in each species.<ref name="Huisman-1996">{{cite web |title=A Syllabus of Human Hemoglobin Variants |author=Huisman THJ |year=1996 |website=Globin Gene Server |publisher=Pennsylvania State University |url=https://globin.cse.psu.edu/html/huisman/variants/ |access-date=2008-10-12 |url-status=live |archive-url=https://web.archive.org/web/20081211113441/https://globin.cse.psu.edu/html/huisman/variants/ |archive-date=2008-12-11}}</ref><ref>[https://www.labtestsonline.org/understanding/analytes/hemoglobin_var/glance-3.html Hemoglobin Variants] {{Webarchive |url=https://web.archive.org/web/20061105162948/https://www.labtestsonline.org/understanding/analytes/hemoglobin_var/glance-3.html |date=2006-11-05}}. Labtestsonline.org. Retrieved 2013-09-05.</ref> Many of these mutations cause no disease, but some cause a group of [[hereditary disease]]s called ''[[hemoglobinopathy|hemoglobinopathies]]''. The best known hemoglobinopathy is [[sickle-cell disease]], which was the first human disease whose [[mechanism (biology)|mechanism]] was understood at the molecular level. A mostly separate set of diseases called [[thalassemia]]s involves underproduction of normal and sometimes abnormal hemoglobins, through problems and mutations in globin [[gene regulation]]. All these diseases produce [[anemia]].<ref>{{cite web |title=Hemoglobinopathies and Thalassemias |last=Uthman |first=Ed |url=https://web2.airmail.net/uthman/hemoglobinopathy/hemoglobinopathy.html |access-date=2007-12-26 |archive-url=https://web.archive.org/web/20071215043423/https://web2.airmail.net/uthman/hemoglobinopathy/hemoglobinopathy.html |archive-date=2007-12-15}}</ref>

== Evolution ==
[[File:HemoglobinABDAlignment.png|thumb|Protein alignment of human hemoglobin proteins, alpha, beta, and delta subunits respectively. The alignments were created using [[UniProt]]'s alignment tool available online. |right |upright=1.5]]

Globin proteins and thus their genes have an ancient evolutionary origin. Even plants have a form of globin called [[leghemoglobin]] which shares about 15% of its sequence with hemoglobin. While this level of similarity may be caused by chance, the 3-dimensional structure of both proteins is so similar that it is commonly assumed that they have a common origin. This is confirmed by the conservation of [[intron]] positions in both types of genes.<ref>{{Cite journal |last=Loomis |first=William F. |date=January 1990 |title=Similarities in eukaryotic genomes |url=https://linkinghub.elsevier.com/retrieve/pii/030504919090242L |journal=Comparative Biochemistry and Physiology Part B: Comparative Biochemistry |language=en |volume=95 |issue=1 |pages=21–27 |doi=10.1016/0305-0491(90)90242-L|url-access=subscription }}</ref>

Variations in hemoglobin sequences, as with other proteins, may be adaptive. For example, hemoglobin has been found to adapt in different ways to the thin air at high altitudes, where lower partial pressure of oxygen diminishes its binding to hemoglobin compared to the higher pressures at sea level.

Recent studies of deer mice found mutations in four genes that can account for differences between high- and low-elevation populations. It was found that the genes of the two breeds are "virtually identical—except for those that govern the oxygen-carrying capacity of their hemoglobin. . . . The genetic difference enables highland mice to make more efficient use of their oxygen."<ref>Reed, Leslie. "Adaptation found in mouse genes." ''Omaha World-Herald'', 11 Aug. 2009: EBSCO. {{page needed|date=December 2021}}</ref> 

=== Evolution of vertebrate hemoglobin ===
Scientists agree that the event that separated myoglobin from hemoglobin occurred after [[lamprey]]s diverged from [[jawed vertebrate]]s.<ref name="Goodman-1975">{{cite journal |last1=Goodman |first1=Morris |last2=Moore |first2=G. William |last3=Matsuda |first3=Genji |date=1975-02-20 |title=Darwinian evolution in the genealogy of haemoglobin |journal=Nature |volume=253 |issue=5493 |pages=603–08 |bibcode=1975Natur.253..603G |doi=10.1038/253603a0 |pmid=1089897 |s2cid=2979887}}</ref> This separation of myoglobin and hemoglobin allowed for the different functions of the two molecules to arise and develop: myoglobin has more to do with oxygen storage while hemoglobin is tasked with oxygen transport.<ref name="Storz-2013">{{cite journal |last1=Storz |first1=Jay F. |last2=Opazo |first2=Juan C. |last3=Hoffmann |first3=Federico G. |date=2013-02-01 |title=Gene duplication, genome duplication, and the functional diversification of vertebrate globins |journal=Molecular Phylogenetics and Evolution |volume=66 |issue=2 |pages=469–78 |bibcode=2013MolPE..66..469S |doi=10.1016/j.ympev.2012.07.013 |issn=1095-9513 |pmc=4306229 |pmid=22846683}}</ref> The α- and β-like globin genes encode the individual subunits of the protein.<ref name="Hardison-2012" /> The predecessors of these genes arose through another duplication event also after the gnathosome common ancestor derived from jawless fish, approximately 450–500&nbsp;million years ago.<ref name="Goodman-1975" /> Ancestral reconstruction studies suggest that the preduplication ancestor of the α and β genes was a dimer made up of identical globin subunits, which then evolved to assemble into a tetrameric architecture after the duplication.<ref name="Pillai-2020">{{cite journal |last1=Pillai |first1=Arvind S. |last2=Chandler |first2=Shane A. |last3=Liu |first3=Yang |last4=Signore |first4=Anthony V. |last5=Cortez-Romero |first5=Carlos R. |last6=Benesch |first6=Justin L. P. |last7=Laganowsky |first7=Arthur |last8=Storz |first8=Jay F. |last9=Hochberg |first9=Georg K. A. |last10=Thornton |first10=Joseph W. |date=May 2020 |title=Origin of complexity in haemoglobin evolution |journal=Nature |language=en |volume=581 |issue=7809 |pages=480–85 |bibcode=2020Natur.581..480P |doi=10.1038/s41586-020-2292-y |issn=1476-4687 |pmc=8259614 |pmid=32461643 |s2cid=218761566}}</ref> The development of α and β genes created the potential for hemoglobin to be composed of multiple distinct subunits, a physical composition central to hemoglobin's ability to transport oxygen. Having multiple subunits contributes to hemoglobin's ability to bind oxygen cooperatively as well as be regulated allosterically.<ref name="Storz-2013" /><ref name="Pillai-2020" /> Subsequently, the α gene also underwent a duplication event to form the ''HBA1'' and ''HBA2'' genes.<ref name="Zimmer-1980">{{cite journal |vauthors=Zimmer EA, Martin SL, Beverley SM, Kan YW, Wilson AC |date=1980-04-01 |title=Rapid duplication and loss of genes coding for the alpha chains of hemoglobin |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=77 |issue=4 |pages=2158–62 |bibcode=1980PNAS...77.2158Z |doi=10.1073/pnas.77.4.2158 |issn=0027-8424 |pmc=348671 |pmid=6929543 |doi-access=free}}</ref> These further duplications and divergences have created a diverse range of α- and β-like globin genes that are regulated so that certain forms occur at different stages of development.<ref name="Storz-2013" />

=== Fish ===
Most ice fish of the family [[Channichthyidae]] have lost their hemoglobin genes as an adaptation to cold water.<ref name="Sidell-2006" />

=== Birds ===
Birds' unique [[bird anatomy|circulatory lungs]] also promote efficient use of oxygen at low partial pressures of O<sub>2</sub>. These two adaptations reinforce each other and account for birds' remarkable high-altitude performance.<ref>{{Cite journal |last=Scott |first=Graham R. |date=2011-08-01 |title=Elevated performance: the unique physiology of birds that fly at high altitudes |journal=Journal of Experimental Biology |volume=214 |issue=15 |pages=2455–2462 |doi=10.1242/jeb.052548 |issn=0022-0949}}</ref> This was specifically found in hummingbirds that inhabit the Andes. Hummingbirds already expend a lot of energy and thus have high oxygen demands and yet Andean hummingbirds have been found to thrive in high altitudes. Non-synonymous mutations in the hemoglobin gene of multiple species living at high elevations (''Oreotrochilus, A. castelnaudii, C. violifer, P. gigas,'' and ''A. viridicuada'') have caused the protein to have less of an affinity for [[phytic acid|inositol hexaphosphate]] (IHP), a molecule found in birds that has a similar role as 2,3-BPG in humans; this results in the ability to bind oxygen in lower partial pressures.<ref>{{cite journal |title=Repeated elevational transitions in hemoglobin function during the evolution of Andean hummingbirds |journal=Proceedings of the National Academy of Sciences |date=2013-12-17 |issn=0027-8424 |pages=20669–74 |volume=110 |issue=51 |last1=Projecto-Garcia |first1=Joana |last2=Natarajan |first2=Chandrasekhar |last3=Moriyama |first3=Hideaki |last4=Weber |first4=Roy E. |last5=Fago |first5=Angela |last6=Cheviron |first6=Zachary A. |last7=Dudley |first7=Robert |last8=McGuire |first8=Jimmy A. |last9=Witt |first9=Christopher C. |bibcode=2013PNAS..11020669P |pmid=24297909 |doi=10.1073/pnas.1315456110 |doi-access=free |pmc=3870697}}</ref>

=== Mammals ===
[[Mammoth]] hemoglobin featured mutations that allowed for oxygen delivery at lower temperatures, thus enabling mammoths to migrate to higher latitudes during the [[Pleistocene]].<ref>{{cite news |title=Mammoths had 'anti-freeze' blood |publisher=BBC |date=2010-05-02 |url=https://news.bbc.co.uk/2/hi/science/nature/8657464.stm |access-date=2010-05-02 |url-status=live |archive-url=https://web.archive.org/web/20100504162118/https://news.bbc.co.uk/2/hi/science/nature/8657464.stm |archive-date=2010-05-04}}</ref> 

Hemoglobin adaptation extends to '''humans''', as well. There is a higher offspring survival rate among Tibetan women with high oxygen saturation genotypes residing at 4,000 m.<ref>{{cite journal |title=Higher offspring survival among Tibetan women with high oxygen saturation genotypes residing at 4,000 m |journal=Proceedings of the National Academy of Sciences of the United States of America |date=2004-09-28 |issn=0027-8424 |pages=14300–04 |volume=101 |issue=39 |last1=Beall |first1=Cynthia M. |last2=Song |first2=Kijoung |last3=Elston |first3=Robert C. |last4=Goldstein |first4=Melvyn C. |bibcode=2004PNAS..10114300B |pmid=15353580 |doi=10.1073/pnas.0405949101 |doi-access=free |pmc=521103}}</ref> Natural selection seems to be the main force working on this gene because the mortality rate of offspring is significantly lower for women with higher hemoglobin-oxygen affinity when compared to the mortality rate of offspring from women with low hemoglobin-oxygen affinity. While the exact genotype and mechanism by which this occurs is not yet clear, selection is acting on these women's ability to bind oxygen in low partial pressures, which overall allows them to better sustain crucial metabolic processes.{{citation needed|date=November 2023}}

==Synthesis==
Hemoglobin (Hb) is synthesized in a complex series of steps. The heme part is synthesized in a series of steps in the [[mitochondria]] and the [[cytosol]] of immature red blood cells, while the [[globin]] protein parts are synthesized by [[ribosome]]s in the cytosol.<ref>{{cite web |title=Hemoglobin Synthesis |date=April 14, 2002 |url=https://sickle.bwh.harvard.edu/hbsynthesis.html |access-date=2007-12-26 |url-status=live |archive-url=https://web.archive.org/web/20071226195932/https://sickle.bwh.harvard.edu/hbsynthesis.html |archive-date=December 26, 2007}}</ref> Production of Hb continues in the cell throughout its early development from the [[proerythroblast]] to the [[reticulocyte]] in the [[bone marrow]]. At this point, the [[cell nucleus|nucleus]] is lost in mammalian red blood cells, but not in [[bird]]s and many other species. Even after the loss of the nucleus in mammals, residual [[ribosomal RNA]] allows further synthesis of Hb until the reticulocyte loses its RNA soon after entering the [[circulatory system|vasculature]] (this hemoglobin-synthetic RNA in fact gives the reticulocyte its reticulated appearance and name).<ref name="Burka-1969">{{cite journal |last1=Burka |first1=Edward |title=Characteristics of RNA degradation in the erythroid cell |journal=The Journal of Clinical Investigation |year=1969 |volume=48 |issue=7 |pages=1266–72 |pmid=5794250 |doi=10.1172/jci106092 |doi-access=free |pmc=322349}}</ref>

==Structure of heme==
[[File:Heme B.svg|thumb|[[Heme]] b group]]

Hemoglobin has a [[quaternary structure]] characteristic of many multi-subunit globular proteins.<ref name="Van Kessel-2002">{{cite book |last1=Van Kessel |first1=Hans |title=Nelson Chemistry 12 |date=2002 |publisher=Thomson |location=Toronto |isbn=978-0-17-625986-0 |page=122 |chapter=Proteins – Natural Polyamides}}</ref> Most of the amino acids in hemoglobin form [[alpha helix|alpha helices]], and these helices are connected by short non-helical segments. Hydrogen bonds stabilize the helical sections inside this protein, causing attractions within the molecule, which then causes each polypeptide chain to fold into a specific shape.<ref>[https://www.umass.edu/molvis/tutorials/hemoglobin/index.htm "Hemoglobin Tutorial."] {{Webarchive|url=https://web.archive.org/web/20091126133327/https://www.umass.edu/molvis/tutorials/hemoglobin/index.htm |date=2009-11-26}} University of Massachusetts Amherst. Web. 23 Oct. 2009.</ref> Hemoglobin's quaternary structure comes from its four subunits in roughly a tetrahedral arrangement.<ref name="Van Kessel-2002"/>

In most vertebrates, the hemoglobin [[molecule]] is an assembly of four [[globular protein]] subunits. Each subunit is composed of a protein chain tightly associated with a non-protein [[prosthetic group|prosthetic]] [[heme]] group. Each protein chain arranges into a set of [[alpha helix|alpha-helix]] structural segments connected together in a [[globin fold]] arrangement. Such a name is given because this arrangement is the same folding motif used in other heme/globin proteins such as [[myoglobin]].<ref name="Steinberg-2001">{{cite book
|last1=Steinberg |first1=MH
|year=2001
|title=Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management
|publisher=Cambridge University Press
|isbn=978-0-521-63266-9
|page=95
|url=https://books.google.com/books?id=ISBN0521632668
|access-date=2016-02-18
|url-status=live
|archive-url=https://web.archive.org/web/20161117110812/https://books.google.com/books?vid=ISBN0521632668
|archive-date=2016-11-17
}}</ref><ref name="Hardison-1996">{{cite journal
|last1=Hardison |first1=RC
|title=A brief history of hemoglobins: plant, animal, protist, and bacteria
|periodical=Proc Natl Acad Sci USA
|year=1996
|volume=93
|issue=12
|pages=5675–79
|bibcode=1996PNAS...93.5675H
|pmid=8650150
|doi=10.1073/pnas.93.12.5675
|doi-access=free
|pmc=39118
}}</ref> This folding pattern contains a pocket that strongly binds the heme group.{{citation needed|date=November 2023}}

A heme group consists of an iron (Fe) [[ion]] held in a [[heterocyclic compound|heterocyclic]] ring, known as a [[porphyrin]]. This porphyrin ring consists of four [[pyrrole]] molecules cyclically linked together (by [[methine]] bridges) with the iron ion bound in the center.<ref>[https://www.chm.bris.ac.uk/motm/hemoglobin/hemoglobjm.htm "Hemoglobin."] {{Webarchive|url=https://web.archive.org/web/20091113153809/https://www.chm.bris.ac.uk/motm/hemoglobin/hemoglobjm.htm |date=2009-11-13}} School of Chemistry – Bristol University – UK. Web. 12 Oct. 2009.</ref> The iron ion, which is the site of oxygen binding, coordinates with the four [[nitrogen]] atoms in the center of the ring, which all lie in one plane. The heme is bound strongly (covalently) to the globular protein via the N atoms of the [[imidazole]] ring of F8 [[histidine]] residue (also known as the proximal histidine) below the porphyrin ring. A sixth position can reversibly bind oxygen by a [[coordinate covalent bond]],<ref>[https://wikipremed.com/interdisciplinary_course.php?code=0213000100000000 WikiPremed > Coordination Chemistry] {{Webarchive|url=https://web.archive.org/web/20090823044401/https://wikipremed.com/interdisciplinary_course.php?code=0213000100000000 |date=2009-08-23}}. Retrieved July 2, 2009</ref> completing the octahedral group of six ligands. This reversible bonding with oxygen is why hemoglobin is so useful for transporting oxygen around the body.<ref>{{cite web |author=Basic Biology |date=2015 |title=Blood cells |url=https://basicbiology.net/micro/cells/blood |access-date=2020-03-27 |url-status=live |archive-url=https://web.archive.org/web/20210718032539/https://basicbiology.net/micro/cells/blood |archive-date=2021-07-18}}</ref> Oxygen binds in an "end-on bent" geometry where one oxygen atom binds to Fe and the other protrudes at an angle. When oxygen is not bound, a very weakly bonded water molecule fills the site, forming a distorted [[octahedron]].

Even though carbon dioxide is carried by hemoglobin, it does not compete with oxygen for the iron-binding positions but is bound to the amine groups of the protein chains attached to the heme groups.

The iron ion may be either in the [[ferrous|ferrous Fe<sup>2+</sup>]] or in the [[iron(III)|ferric Fe<sup>3+</sup>]] state, but ferrihemoglobin ([[methemoglobin]]) (Fe<sup>3+</sup>) cannot bind oxygen.<ref>{{cite journal |vauthors=Linberg R, Conover CD, Shum KL, Shorr RG |title=Hemoglobin based oxygen carriers: how much methemoglobin is too much? |journal=Artif Cells Blood Substit Immobil Biotechnol |volume=26 |issue=2 |pages=133–48 |year=1998 |pmid=9564432 |doi=10.3109/10731199809119772 |doi-access=free}}</ref> In binding, oxygen temporarily and reversibly oxidizes (Fe<sup>2+</sup>) to (Fe<sup>3+</sup>) while oxygen temporarily turns into the [[superoxide]] ion, thus iron must exist in the +2 oxidation state to bind oxygen. If superoxide ion associated to Fe<sup>3+</sup> is protonated, the hemoglobin iron will remain oxidized and incapable of binding oxygen. In such cases, the enzyme [[cytochrome b5 reductase|methemoglobin reductase]] will be able to eventually reactivate methemoglobin by reducing the iron center.

In adult humans, the most common hemoglobin type is a [[tetrameric protein|tetramer]] (which contains four subunit proteins) called ''hemoglobin A'', consisting of two α and two β subunits non-covalently bound, each made of 141 and 146 amino acid residues, respectively. This is denoted as α<sub>2</sub>β<sub>2</sub>. The subunits are structurally similar and about the same size. Each subunit has a molecular weight of about 16,000&nbsp;[[dalton (unit)|daltons]],<ref>[https://www.worthington-biochem.com/HB/cat.html Hemoglobin] {{Webarchive|url=https://web.archive.org/web/20170315070213/https://www.worthington-biochem.com/HB/cat.html |date=2017-03-15}}. Worthington-biochem.com. Retrieved 2013-09-05.</ref> for a total [[molecular weight]] of the tetramer of about 64,000&nbsp;daltons (64,458 g/mol).<ref name="Van Beekvelt-2001">{{cite journal |vauthors=Van Beekvelt MC, Colier WN, Wevers RA, Van Engelen BG |title=Performance of near-infrared spectroscopy in measuring local O2 consumption and blood flow in skeletal muscle |journal=J Appl Physiol |volume=90 |issue=2 |pages=511–19 |year=2001 |pmid=11160049 |doi=10.1152/jappl.2001.90.2.511 |s2cid=15468862}}</ref> Thus, 1 g/dL=0.1551&nbsp;mmol/L. Hemoglobin A is the most intensively studied of the hemoglobin molecules.{{citation needed|date=November 2023}}

In human infants, the [[fetal hemoglobin]] molecule is made up of 2 α chains and 2 γ chains. The γ chains are gradually replaced by β chains as the infant grows.<ref name="HemoglobinMedicineNet">[https://www.medicinenet.com/hemoglobin/article.htm "Hemoglobin."] {{Webarchive|url=https://web.archive.org/web/20120124064054/https://www.medicinenet.com/hemoglobin/article.htm |date=2012-01-24}} MedicineNet. Web. 12 Oct. 2009.</ref>

The four [[polypeptide chains]] are bound to each other by [[salt bridge (protein)|salt bridges]], [[hydrogen bond]]s, and the [[hydrophobic effect]].

===Oxygen saturation===
In general, hemoglobin can be saturated with oxygen molecules (oxyhemoglobin), or desaturated with oxygen molecules (deoxyhemoglobin).<ref>[https://www.bio.davidson.edu/Courses/Molbio/MolStudents/spring2005/Heiner/hemoglobin.html "Hemoglobin Home."] {{Webarchive|url=https://web.archive.org/web/20091201035525/https://www.bio.davidson.edu/Courses/Molbio/MolStudents/spring2005/Heiner/hemoglobin.html |date=2009-12-01}} Biology @ Davidson. Web. 12 Oct. 2009.</ref>

====Oxyhemoglobin====
''Oxyhemoglobin'' is formed during [[respiration (physiology)|physiological respiration]] when oxygen binds to the heme component of the protein hemoglobin in red blood cells. This process occurs in the [[pulmonary capillaries]] adjacent to the [[pulmonary alveolus|alveoli]] of the lungs. The oxygen then travels through the blood stream to be dropped off at cells where it is utilized as a terminal electron acceptor in the production of [[adenosine triphosphate|ATP]] by the process of [[oxidative phosphorylation]]. It does not, however, help to counteract a decrease in blood pH. [[Ventilation (physiology)|Ventilation]], or breathing, may reverse this condition by removal of [[carbon dioxide]], thus causing a shift up in pH.<ref name="altitude.org">{{cite web |publisher=altitude.org |title=Hemoglobin saturation graph |url=https://www.altitude.org/hemoglobin_saturation.php |access-date=2010-07-06 |archive-url=https://web.archive.org/web/20100831024941/https://www.altitude.org/hemoglobin_saturation.php |archive-date=2010-08-31}}</ref>

Hemoglobin exists in two forms, a ''taut (tense) form'' (T) and a ''relaxed form'' (R). Various factors such as low pH, high CO<sub>2</sub> and high [[2,3 BPG]] at the level of the tissues favor the taut form, which has low oxygen affinity and releases oxygen in the tissues. Conversely, a high pH, low CO<sub>2</sub>, or low 2,3 BPG favors the relaxed form, which can better bind oxygen.<ref name="King-2012">{{cite web |author=King, Michael W |title=The Medical Biochemistry Page – Hemoglobin |url=https://themedicalbiochemistrypage.org/hemoglobin-myoglobin.php#hemoglobin |access-date=2012-03-20 |url-status=live |archive-url=https://web.archive.org/web/20120304095702/https://themedicalbiochemistrypage.org/hemoglobin-myoglobin.php#hemoglobin |archive-date=2012-03-04}}</ref> The partial pressure of the system also affects O<sub>2</sub> affinity where, at high partial pressures of oxygen (such as those present in the alveoli), the relaxed (high affinity, R) state is favoured. Inversely, at low partial pressures (such as those present in respiring tissues), the (low affinity, T) tense state is favoured.<ref>Voet, D. (2008) ''Fundamentals of Biochemistry'', 3rd. ed., Fig. 07_06, John Wiley & Sons. {{ISBN|0470129301}}</ref> Additionally, the binding of oxygen to the iron(II) heme pulls the iron into the plane of the porphyrin ring, causing a slight conformational shift. The shift encourages oxygen to bind to the three remaining heme units within hemoglobin (thus, oxygen binding is cooperative).{{citation needed|date=November 2023}}

Classically, the iron in oxyhemoglobin is seen as existing in the iron(II) oxidation state. However, the complex of oxygen with heme iron is [[diamagnetic]], whereas both oxygen and high-spin iron(II) are [[paramagnetic]]. Experimental evidence strongly suggests heme iron is in the iron(III) oxidation state in oxyhemoglobin, with the oxygen existing as [[superoxide anion]] (O<sub>2</sub><sup>•−</sup>) or in a covalent charge-transfer complex.<ref name="Shikama-2006">{{cite journal |vauthors=Shikama K |title=Nature of the FeO2 bonding in myoglobin and hemoglobin: A new molecular paradigm |journal=Prog Biophys Mol Biol |volume=91 |issue=1–2 |pages=83–162 |year=2006 |pmid=16005052 |doi=10.1016/j.pbiomolbio.2005.04.001 |doi-access=free}}</ref>

====Deoxygenated hemoglobin====
Deoxygenated hemoglobin (deoxyhemoglobin) is the form of hemoglobin without the bound oxygen. The [[absorption spectrum|absorption spectra]] of oxyhemoglobin and deoxyhemoglobin differ. The oxyhemoglobin has significantly lower absorption of the 660&nbsp;nm [[wavelength]] than deoxyhemoglobin, while at 940&nbsp;nm its absorption is slightly higher. This difference is used for the measurement of the amount of oxygen in a patient's blood by an instrument called a [[pulse oximeter]]. This difference also accounts for the presentation of [[cyanosis]], the blue to purplish color that tissues develop during [[hypoxia (medical)|hypoxia]].<ref>{{cite book |last1=Ahrens |last2=Kimberley |first2=Basham |title=Essentials of Oxygenation: Implication for Clinical Practice |year=1993 |publisher=Jones & Bartlett Learning |page=194 |isbn=978-0-86720-332-5}}</ref>

Deoxygenated hemoglobin is [[paramagnetic]]; it is weakly attracted to [[magnetic field]]s.<ref>
{{cite journal
|year=1993
|last1=Ogawa |first1=S
|title=Functional brain mapping by blood oxygenation level-dependent contrast magnetic resonance imaging. A comparison of signal characteristics with a biophysical model
|journal=Biophysical Journal
|volume=64
|issue=3
|pages=803–12
|last2=Menon |first2=R. S.
|last3=Tank |first3=D. W.
|last4=Kim |first4=S. G.
|last5=Merkle |first5=H
|last6=Ellermann |first6=J. M.
|last7=Ugurbil |first7=K
|bibcode=1993BpJ....64..803O
|pmid=8386018
|doi=10.1016/S0006-3495(93)81441-3
|pmc=1262394
}}</ref><ref name="Bren-2015"/> In contrast, oxygenated hemoglobin exhibits [[diamagnetism]], a weak repulsion from a magnetic field.<ref name="Bren-2015">{{cite journal |vauthors=Bren KL, Eisenberg R, Gray HB |title=Discovery of the magnetic behavior of hemoglobin: A beginning of bioinorganic chemistry |journal=Proc Natl Acad Sci U S A |year=2015 |volume=112 |issue=43 |pages=13123–27 |bibcode=2015PNAS..11213123B |pmid=26508205 |doi=10.1073/pnas.1515704112 |doi-access=free |pmc=4629386}}</ref>

==Cooperativity==
[[File:Hemoglobin t-r state ani.gif|frame|A schematic visual model of oxygen-binding process, showing all four [[monomer]]s and [[heme]]s, and [[protein|protein chains]] only as diagrammatic coils, to facilitate visualization into the molecule. [[Oxygen]] is not shown in this model, but, for each of the [[iron]] atoms, it binds to the iron (red sphere) in the flat [[heme]]. For example, in the upper-left of the four hemes shown, oxygen binds at the left of the iron atom shown in the upper-left of diagram. This causes the iron atom to move backward into the heme that holds it (the iron moves upward as it binds oxygen, in this illustration), tugging the [[histidine]] residue (modeled as a red pentagon on the right of the iron) closer, as it does. This, in turn, pulls on the protein chain holding the [[histidine]].]]

When oxygen binds to the iron complex, it causes the iron atom to move back toward the center of the plane of the [[porphyrin]] ring (see moving diagram). At the same time, the [[imidazole]] side-chain of the histidine residue interacting at the other pole of the iron is pulled toward the porphyrin ring. This interaction forces the plane of the ring sideways toward the outside of the tetramer, and also induces a strain in the protein helix containing the histidine as it moves nearer to the iron atom. This strain is transmitted to the remaining three monomers in the tetramer, where it induces a similar conformational change in the other heme sites such that binding of oxygen to these sites becomes easier.

As oxygen binds to one monomer of hemoglobin, the tetramer's conformation shifts from the T (tense) state to the R (relaxed) state. This shift promotes the binding of oxygen to the remaining three monomers' heme groups, thus saturating the hemoglobin molecule with oxygen.<ref>{{cite journal |last1=Mihailescu |first1=Mihaela-Rita |last2=Russu |first2=Irina M. |date=2001-03-27 |title=A signature of the T → R transition in human hemoglobin |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=98 |issue=7 |pages=3773–77 |issn=0027-8424 |bibcode=2001PNAS...98.3773M |pmid=11259676 |doi=10.1073/pnas.071493598 |doi-access=free |pmc=31128}}</ref>

In the tetrameric form of normal adult hemoglobin, the binding of oxygen is, thus, a [[cooperative binding|cooperative process]]. The binding affinity of hemoglobin for oxygen is increased by the oxygen saturation of the molecule, with the first molecules of oxygen bound influencing the shape of the binding sites for the next ones, in a way favorable for binding. This positive cooperative binding is achieved through [[steric effects|steric]] conformational changes of the hemoglobin protein complex as discussed above; i.e., when one subunit protein in hemoglobin becomes oxygenated, a conformational or structural change in the whole complex is initiated, causing the other subunits to gain an increased affinity for oxygen. As a consequence, the oxygen binding curve of hemoglobin is [[sigmoid function|sigmoidal]], or ''S''-shaped, as opposed to the normal [[hyperbolic function|hyperbolic]] curve associated with noncooperative binding.

The dynamic mechanism of the cooperativity in hemoglobin and its relation with low-frequency [[resonance]] has been discussed.<ref name="Chou-1989">{{cite journal |author=Chou KC |title=Low-frequency resonance and cooperativity of hemoglobin |journal=Trends Biochem. Sci. |volume=14 |issue=6 |pages=212–13 |year=1989 |pmid=2763333 |doi=10.1016/0968-0004(89)90026-1}}</ref>

==Binding of ligands other than oxygen==
Besides the oxygen [[ligand (biochemistry)|ligand]], which binds to hemoglobin in a cooperative manner, hemoglobin ligands also include [[competitive inhibition|competitive inhibitors]] such as [[carbon monoxide]] (CO) and [[allosteric regulation|allosteric ligands]] such as carbon dioxide (CO<sub>2</sub>) and [[nitric oxide]] (NO). The carbon dioxide is bound to amino groups of the globin proteins to form [[carbaminohemoglobin]]; this mechanism is thought to account for about 10% of carbon dioxide transport in mammals. [[Nitric oxide]] can also be transported by hemoglobin; it is bound to specific [[thiol]] groups in the globin protein to form an S-nitrosothiol, which dissociates into free nitric oxide and thiol again, as the hemoglobin releases oxygen from its heme site. This nitric oxide transport to peripheral tissues is hypothesized to assist oxygen transport in tissues, by releasing [[vasodilation|vasodilatory]] nitric oxide to tissues in which oxygen levels are low.<ref name="Jensen-2009">{{cite journal
|last=Jensen |first=Frank B
|title=The dual roles of red blood cells in tissue oxygen delivery: oxygen carriers and regulators of local blood flow
|journal=Journal of Experimental Biology
|volume=212 |issue=Pt 21
|pages=3387–93
|year=2009
|pmid=19837879 |doi=10.1242/jeb.023697
|s2cid=906177
}}</ref>

===Competitive===
The binding of oxygen is affected by molecules such as carbon monoxide (for example, from [[tobacco smoking]], [[exhaust gas]], and incomplete combustion in furnaces). CO competes with oxygen at the heme binding site. Hemoglobin's binding affinity for CO is 250 times greater than its affinity for oxygen.<ref>{{cite book |last=Hall |first=John E. |title=Guyton and Hall textbook of medical physiology |year=2010 |publisher=Saunders/Elsevier |location=Philadelphia, Pa. |isbn=978-1-4160-4574-8 |page=502 |edition=12th}}</ref><ref name="Rhodes-2019">{{cite book |last1=Rhodes |first1=Carl E. |last2=Denault |first2=Deanna |last3=Varacallo |first3=Matthew |title=Physiology, Oxygen Transport |date=2019-03-04 |publisher=StatPearls Publishing |place=Treasure Island (FL) |pmid=30855920 |via=NCBI Bookshelf |url=https://www.ncbi.nlm.nih.gov/books/NBK538336/ |access-date=2019-05-04 |url-status=live |archive-url=https://web.archive.org/web/20210827215723/https://www.ncbi.nlm.nih.gov/books/NBK538336/ |archive-date=2021-08-27 |quote=It is important to note that in the setting of carboxyhemoglobinemia, it is not a reduction in oxygen-carrying capacity that causes pathology, but an impaired delivery of bound oxygen to target tissues.}}</ref> Since carbon monoxide is a colorless, odorless, and tasteless gas, and poses a potentially fatal threat, [[carbon monoxide detector]]s have become commercially available to warn of dangerous levels in residences. When hemoglobin combines with CO, it forms a very bright red compound called [[carboxyhemoglobin]], which may cause the skin of [[carbon monoxide poisoning|CO poisoning]] victims to appear pink in death, instead of white or blue. When inspired air contains CO levels as low as 0.02%, [[headache]] and [[nausea]] occur; if the CO concentration is increased to 0.1%, unconsciousness will follow. In heavy smokers, up to 20% of the oxygen-active sites can be blocked by CO.

In similar fashion, hemoglobin also has competitive binding affinity for [[cyanide]] (CN<sup>−</sup>), [[sulfur monoxide]] (SO), and [[sulfide]] (S<sup>2−</sup>), including [[hydrogen sulfide]] (H<sub>2</sub>S). All of these bind to iron in heme without changing its oxidation state, but they nevertheless inhibit oxygen-binding, causing grave toxicity.

The iron atom in the heme group must initially be in the [[ferrous]] (Fe<sup>2+</sup>) oxidation state to support oxygen and other gases' binding and transport (it temporarily switches to ferric during the time oxygen is bound, as explained above). Initial oxidation to the [[ferric]] (Fe<sup>3+</sup>) state without oxygen converts hemoglobin into "hem'''i'''globin" or [[methemoglobin]], which cannot bind oxygen. Hemoglobin in normal red blood cells is protected by a reduction system to keep this from happening. Nitric oxide is capable of converting a small fraction of hemoglobin to methemoglobin in red blood cells. The latter reaction is a remnant activity of the more ancient [[nitric oxide dioxygenase]] function of globins.

===Allosteric===
{{Further|Oxygen-hemoglobin dissociation curve}}
Carbon ''di''oxide occupies a different binding site on the hemoglobin. At tissues, where carbon dioxide concentration is higher, carbon dioxide binds to allosteric site of hemoglobin, facilitating unloading of oxygen from hemoglobin and ultimately its removal from the body after the oxygen has been released to tissues undergoing metabolism. This increased affinity for carbon dioxide by the venous blood is known as the [[Bohr effect]]. Through the enzyme [[carbonic anhydrase]], carbon dioxide reacts with water to give [[carbonic acid]], which decomposes into [[bicarbonate]] and [[proton]]s:

:CO<sub>2</sub> + H<sub>2</sub>O → H<sub>2</sub>CO<sub>3</sub> → HCO<sub>3</sub><sup>−</sup> + H<sup>+</sup>

[[File:Hemoglobin saturation curve.svg|left|thumb|The sigmoidal shape of hemoglobin's oxygen-dissociation curve results from cooperative binding of [[oxygen]] to hemoglobin.]]
Hence, blood with high carbon dioxide levels is also lower in [[pH]] (more [[acid]]ic). Hemoglobin can bind protons and carbon dioxide, which causes a conformational change in the protein and facilitates the release of oxygen. Protons bind at various places on the protein, while carbon dioxide binds at the α-amino group.<ref>Nelson, D. L.; Cox, M. M. (2000). ''Lehninger Principles of Biochemistry'', 3rd ed. New York: Worth Publishers. p. 217, {{ISBN|1572599316}}.</ref> Carbon dioxide binds to hemoglobin and forms [[carbaminohemoglobin]].<ref>{{cite book |edition=11 |publisher=Elsevier Saunders |isbn=978-0-7216-0240-0 |page=511 |last=Guyton |first=Arthur C. |author2=John E. Hall |title=Textbook of Medical Physiology |location=Philadelphia |year=2006}}</ref> This decrease in hemoglobin's affinity for oxygen by the binding of carbon dioxide and acid is known as the [[Bohr effect]]. The Bohr effect favors the T state rather than the R state. (shifts the O<sub>2</sub>-saturation curve to the ''right''). Conversely, when the carbon dioxide levels in the blood decrease (i.e., in the lung capillaries), carbon dioxide and protons are released from hemoglobin, increasing the oxygen affinity of the protein. A reduction in the total binding capacity of hemoglobin to oxygen (i.e. shifting the curve down, not just to the right) due to reduced pH is called the [[root effect]]. This is seen in bony fish.

It is necessary for hemoglobin to release the oxygen that it binds; if not, there is no point in binding it. The sigmoidal curve of hemoglobin makes it efficient in binding (taking up O<sub>2</sub> in lungs), and efficient in unloading (unloading O<sub>2</sub> in tissues).<ref>{{YouTube|6AfRX6oh9-E|Lecture – 12 Myoglobin and Hemoglobin}}</ref>

In people acclimated to high altitudes, the concentration of [[2,3-Bisphosphoglycerate]] (2,3-BPG) in the blood is increased, which allows these individuals to deliver a larger amount of oxygen to tissues under conditions of lower [[oxygen tension]]. This phenomenon, where molecule Y affects the binding of molecule X to a transport molecule Z, is called a ''heterotropic'' allosteric effect. Hemoglobin in organisms at high altitudes has also adapted such that it has less of an affinity for 2,3-BPG and so the protein will be shifted more towards its R state. In its R state, hemoglobin will bind oxygen more readily, thus allowing organisms to perform the necessary metabolic processes when oxygen is present at low partial pressures.<ref>{{cite book |title=Biochemistry |edition=Eighth |publisher=W. H. Freeman |year=2015 |location=New York |isbn=978-1-4641-2610-9}}{{page needed|date=December 2021}}</ref>

Animals other than humans use different molecules to bind to hemoglobin and change its O<sub>2</sub> affinity under unfavorable conditions. Fish use both [[adenosine triphosphate|ATP]] and [[guanosine triphosphate|GTP]]. These bind to a phosphate "pocket" on the fish hemoglobin molecule, which stabilizes the tense state and therefore decreases oxygen affinity.<ref name="Rutjes-2007">{{cite journal |last=Rutjes |first=H. A. |author2=Nieveen, M. C. |author3=Weber, R. E. |author4=Witte, F. |author5=Van den Thillart, G. E. E. J. M. |title=Multiple strategies of Lake Victoria cichlids to cope with lifelong hypoxia include hemoglobin switching |journal=AJP: Regulatory, Integrative and Comparative Physiology |date=20 June 2007 |volume=293 |issue=3 |pages=R1376–83 |pmid=17626121 |doi=10.1152/ajpregu.00536.2006}}</ref> GTP reduces hemoglobin oxygen affinity much more than ATP, which is thought to be due to an extra [[hydrogen bond]] formed that further stabilizes the tense state.<ref name="Gronenborn-1984">{{cite journal |last=Gronenborn |first=Angela M. |author2=Clore, G. Marius |author3=Brunori, Maurizio |author4=Giardina, Bruno |author5=Falcioni, Giancarlo |author6=Perutz, Max F. |title=Stereochemistry of ATP and GTP bound to fish haemoglobins |journal=Journal of Molecular Biology |volume=178 |issue=3 |pages=731–42 |year=1984 |pmid=6492161 |doi=10.1016/0022-2836(84)90249-3}}</ref> Under hypoxic conditions, the concentration of both ATP and GTP is reduced in fish red blood cells to increase oxygen affinity.<ref name="Weber-1988">{{cite journal |last=Weber |first=Roy E. |author2=Frank B. Jensen |title=Functional adaptations in hemoglobins from ectothermic vertebrates |journal=Annual Review of Physiology |year=1988 |volume=50 |pages=161–79 |pmid=3288089 |doi=10.1146/annurev.ph.50.030188.001113}}</ref>

A variant hemoglobin, called [[fetal hemoglobin]] (HbF, α<sub>2</sub>γ<sub>2</sub>), is found in the developing [[fetus]], and binds oxygen with greater affinity than adult hemoglobin. This means that the oxygen binding curve for fetal hemoglobin is left-shifted (i.e., a higher percentage of hemoglobin has oxygen bound to it at lower oxygen tension), in comparison to that of adult hemoglobin. As a result, fetal blood in the [[placenta]] is able to take oxygen from maternal blood.

Hemoglobin also carries [[nitric oxide]] (NO) in the globin part of the molecule. This improves oxygen delivery in the periphery and contributes to the control of respiration. NO binds reversibly to a specific cysteine residue in globin; the binding depends on the state (R or T) of the hemoglobin. The resulting S-nitrosylated hemoglobin influences various NO-related activities such as the control of vascular resistance, blood pressure and respiration. NO is not released in the cytoplasm of red blood cells but transported out of them by an anion exchanger called [[Anion Exchanger 1|AE1]].<ref>{{cite book |last=Rang |first=H.P. |author2=Dale M.M. |author3=Ritter J.M. |author4=Moore P.K. |title=Pharmacology, Fifth Edition |year=2003 |publisher=Elsevier |isbn=978-0-443-07202-4}}{{page needed|date=December 2021}}</ref>

==Types of hemoglobin in humans==
[[Hemoglobin variants]] are a part of the normal [[human embryonic development|embryonic]] and [[human fetal development|fetal]] development. They may also be pathologic mutant forms of hemoglobin in a [[population]], caused by variations in genetics. Some well-known hemoglobin variants, such as [[sickle-cell anemia]], are responsible for diseases and are considered [[hemoglobinopathy|hemoglobinopathies]]. Other variants cause no detectable [[pathology]], and are thus considered non-pathological variants.<ref name="Huisman-1996"/><ref>{{cite web |title=Hemoglobin Variants |date=2007-11-10 |website=Lab Tests Online |publisher=American Association for Clinical Chemistry |url=https://www.labtestsonline.org/understanding/analytes/hemoglobin_var/glance-3.html |access-date=2008-10-12 |url-status=live |archive-url=https://web.archive.org/web/20080920042335/https://www.labtestsonline.org/understanding/analytes/hemoglobin_var/glance-3.html |archive-date=2008-09-20}}</ref>

In [[embryo]]s:
* Gower 1 (ζ<sub>2</sub>ε<sub>2</sub>).
* Gower 2 (α<sub>2</sub>ε<sub>2</sub>) ({{PDB|1A9W}}).
* Hemoglobin Portland I (ζ<sub>2</sub>γ<sub>2</sub>).
* Hemoglobin Portland II (ζ<sub>2</sub>β<sub>2</sub>).

In fetuses:
* [[Hemoglobin F]] (α<sub>2</sub>γ<sub>2</sub>) ({{PDB|1FDH}}).

In [[neonate]]s (newborns inmmediately after birth):
* [[Hemoglobin A]] (adult hemoglobin) (α<sub>2</sub>β<sub>2</sub>) ({{PDB|1BZ0}}) – The most common with a normal amount over 95%
* [[Hemoglobin A2|Hemoglobin A<sub>2</sub>]] (α<sub>2</sub>δ<sub>2</sub>) – δ chain synthesis begins late in the third trimester and, in adults, it has a normal range of 1.5–3.5%
* [[Hemoglobin F]] (fetal hemoglobin) (α<sub>2</sub>γ<sub>2</sub>) – In adults Hemoglobin F is restricted to a limited population of red cells called F-cells. However, the level of Hb F can be elevated in persons with sickle-cell disease and [[beta-thalassemia]].
[[File:Postnatal genetics en.svg|thumb|upright=1.35|Gene expression of hemoglobin before and after birth. Also identifies the types of cells and organs in which the gene expression (data on ''Wood W.G.'', (1976). '''Br. Med. Bull. 32, 282.''')]]

Abnormal forms that occur in diseases:
* [[Hemoglobin D]] – (α<sub>2</sub>β<sup>D</sup><sub>2</sub>) – A variant form of hemoglobin.
* Hemoglobin H (β<sub>4</sub>) – A variant form of hemoglobin, formed by a tetramer of β chains, which may be present in variants of [[alpha-thalassemia|α thalassemia]].
* [[Hemoglobin Barts]] (γ<sub>4</sub>) – A variant form of hemoglobin, formed by a tetramer of γ chains, which may be present in variants of α thalassemia.
* [[Hemoglobin S]] (α<sub>2</sub>β<sup>S</sup><sub>2</sub>) – A variant form of hemoglobin found in people with sickle cell disease. There is a variation in the β-chain gene, causing a change in the properties of hemoglobin, which results in sickling of red blood cells.
* [[Hemoglobin C]] (α<sub>2</sub>β<sup>C</sup><sub>2</sub>) – Another variant due to a variation in the β-chain gene. This variant causes a mild chronic [[hemolytic anemia]].
* [[Hemoglobin E]] (α<sub>2</sub>β<sup>E</sup><sub>2</sub>) – Another variant due to a variation in the β-chain gene. This variant causes a mild chronic hemolytic anemia.
* Hemoglobin AS – A heterozygous form causing [[sickle cell trait]] with one adult gene and one sickle cell disease gene
* Hemoglobin SC disease – A compound heterozygous form with one sickle gene and another encoding [[hemoglobin C]].
* [[Hemoglobin Hopkins-2]] – A variant form of hemoglobin that is sometimes viewed in combination with [[hemoglobin S]] to produce sickle cell disease.

==Degradation in vertebrate animals==
When [[red blood cell]]s reach the end of their life due to aging or defects, they are removed from the circulation by the phagocytic activity of macrophages in the spleen or the liver or hemolyze within the circulation. [[Free hemoglobin]] is then cleared from the circulation via the hemoglobin transporter [[CD163]], which is exclusively expressed on monocytes or macrophages. Within these cells the hemoglobin molecule is broken up, and the iron gets recycled. This process also produces one molecule of carbon monoxide for every molecule of heme degraded.<ref>{{cite journal
|last1=Kikuchi |first1=G.
|last2=Yoshida |first2=T.
|last3=Noguchi |first3=M.
|title=Heme oxygenase and heme degradation
|journal=Biochemical and Biophysical Research Communications
|volume=338
|issue=1
|pages=558–67
|year=2005
|pmid=16115609
|doi=10.1016/j.bbrc.2005.08.020
}}</ref> Heme degradation is the only natural source of carbon monoxide in the human body, and is responsible for the normal blood levels of carbon monoxide in people breathing normal air.<ref>{{cite book |last1=Coomes |first1=Marguerite W. |editor1-last=Devlin |editor1-first=Thomas M. |title=Textbook of Biochemistry: With Clinical Correlations |date=2011 |publisher=John Wiley & Sons |location=Hoboken, NJ |isbn=978-0-470-28173-4 |page=797 |edition=7th |chapter=Amino Acid and Heme Metabolism}}</ref>

The other major final product of heme degradation is [[bilirubin]]. Increased levels of this chemical are detected in the blood if red blood cells are being destroyed more rapidly than usual. Improperly degraded hemoglobin protein or hemoglobin that has been released from the blood cells too rapidly can clog small blood vessels, especially the delicate blood filtering vessels of the [[kidney]]s, causing kidney damage. Iron is removed from heme and salvaged for later use, it is stored as hemosiderin or [[ferritin]] in tissues and transported in plasma by beta globulins as [[transferrin]]s. When the porphyrin ring is broken up, the fragments are normally secreted as a yellow pigment called bilirubin, which is secreted into the intestines as bile. Intestines metabolize bilirubin into urobilinogen. Urobilinogen leaves the body in faeces, in a pigment called stercobilin. Globulin is metabolized into amino acids that are then released into circulation.

==Diseases related to hemoglobin==
<!-- Deleted image removed: [[File:Sickle cell hemoglobin shortened.png|thumb|left|In sickle cell hemoglobin (HbS) glutamic acid in position 6 (in beta chain) is mutated to valine. This change allows the deoxygenated form of the hemoglobin to stick to itself.]] -->
Hemoglobin deficiency can be caused either by a decreased amount of hemoglobin molecules, as in [[anemia]], or by decreased ability of each molecule to bind oxygen at the same partial pressure of oxygen. [[Hemoglobinopathy|Hemoglobinopathies]] (genetic defects resulting in abnormal structure of the hemoglobin molecule)<ref>{{DorlandsDict|four/000048231|hemoglobinopathy}}</ref> may cause both. In any case, hemoglobin deficiency decreases [[blood oxygen-carrying capacity]]. Hemoglobin deficiency is, in general, strictly distinguished from [[hypoxemia]], defined as decreased [[partial pressure]] of oxygen in blood,<ref>[https://www.britannica.com/EBchecked/topic/280141/hypoxemia hypoxemia] {{Webarchive|url=https://web.archive.org/web/20090202104640/https://www.britannica.com/EBchecked/topic/280141/hypoxemia |date=2009-02-02}}. ''Encyclopædia Britannica'', stating ''hypoxemia (reduced oxygen tension in the blood)''.</ref><ref>[https://www.biology-online.org/dictionary/Hypoxemia Biology-Online.org --> Dictionary » H » Hypoxemia] {{Webarchive|url=https://web.archive.org/web/20091121085130/https://www.biology-online.org/dictionary/Hypoxemia |date=2009-11-21}} last modified 29 December 2008</ref><ref name="Wilson-2007">{{cite book |author1=William, C. Wilson |author2=Grande, Christopher M. |author3=Hoyt, David B. |title=Trauma, Volume II: Critical Care |chapter-url=https://books.google.com/books?id=3H3AIEtvc8YC&pg=PA430 |year=2007 |publisher=Taylor & Francis |isbn=978-1-4200-1684-0 |page=430 |chapter=Pathophysiology of acute respiratory failure |access-date=2016-02-18 |url-status=live |archive-url=https://web.archive.org/web/20161117105938/https://books.google.com/books?id=3H3AIEtvc8YC&pg=PA430 |archive-date=2016-11-17}}</ref><ref name="McGaffigan-1996">{{cite journal
|last1=McGaffigan |first1=P. A.
|title=Hazards of hypoxemia: How to protect your patient from low oxygen levels
|journal=Nursing
|volume=26
|issue=5
|pages=41–46; quiz 46
|year=1996
|pmid=8710285
|doi=10.1097/00152193-199626050-00013
|doi-access=free
}}</ref> although both are causes of [[hypoxia (medical)|hypoxia]] (insufficient oxygen supply to tissues).

Other common causes of low hemoglobin include loss of blood, nutritional deficiency, bone marrow problems, chemotherapy, kidney failure, or abnormal hemoglobin (such as that of sickle-cell disease).

The ability of each hemoglobin molecule to carry oxygen is normally modified by altered blood pH or CO<sub>2</sub>, causing an altered [[oxygen–hemoglobin dissociation curve]]. However, it can also be pathologically altered in, e.g., [[carbon monoxide poisoning]].

Decrease of hemoglobin, with or without an absolute decrease of red blood cells, leads to symptoms of anemia. Anemia has many different causes, although [[iron deficiency (medicine)|iron deficiency]] and its resultant [[iron deficiency anemia]] are the most common causes in the Western world. As absence of iron decreases heme synthesis, red blood cells in iron deficiency anemia are ''hypochromic'' (lacking the red hemoglobin pigment) and ''microcytic'' (smaller than normal). Other anemias are rarer. In [[hemolysis]] (accelerated breakdown of red blood cells), associated [[jaundice]] is caused by the hemoglobin metabolite bilirubin, and the circulating hemoglobin can cause [[kidney failure]].

Some mutations in the globin chain are associated with the [[hemoglobinopathy|hemoglobinopathies]], such as sickle-cell disease and [[thalassemia]]. Other mutations, as discussed at the beginning of the article, are benign and are referred to merely as [[hemoglobin variants]].

There is a group of genetic disorders, known as the ''[[porphyria]]s'' that are characterized by errors in metabolic pathways of heme synthesis. King [[George III of the United Kingdom]] was probably the most famous porphyria sufferer.

To a small extent, hemoglobin A slowly combines with [[glucose]] at the terminal valine (an alpha aminoacid) of each β chain. The resulting molecule is often referred to as [[HbA1c|Hb A<sub>1c</sub>]], a [[glycated hemoglobin]]. The binding of glucose to amino acids in the hemoglobin takes place spontaneously (without the help of an enzyme) in many proteins, but whether it serves a useful purpose is unknown. However, as the concentration of glucose in the blood increases, the percentage of Hb A that turns into Hb A<sub>1c</sub> increases. In [[diabetes mellitus|diabetics]] whose glucose usually runs high, the percent Hb A<sub>1c</sub> also runs high. Because of the slow rate of Hb A combination with glucose, the Hb A<sub>1c</sub> percentage reflects a weighted average of blood glucose levels over the lifetime of red cells, which is approximately 120 days.<ref>{{cite web |title=NGSP: HbA1c and eAG |website=ngsp.org |url=https://ngsp.org/A1ceAG.asp |access-date=2015-10-28 |url-status=live |archive-url=https://web.archive.org/web/20151015124504/https://www.ngsp.org/A1ceAG.asp |archive-date=2015-10-15}}</ref> The levels of glycated hemoglobin are therefore measured in order to monitor the long-term control of the chronic disease of type 2 diabetes mellitus (T2DM). Poor control of T2DM results in high levels of glycated hemoglobin in the red blood cells. The normal reference range is approximately 4.0–5.9%. Though difficult to obtain, values less than 7% are recommended for people with T2DM. Levels greater than 9% are associated with poor control of the glycated hemoglobin, and levels greater than 12% are associated with very poor control. Diabetics who keep their glycated hemoglobin levels close to 7% have a much better chance of avoiding the complications that may accompany diabetes (than those whose levels are 8% or higher).<ref>[https://www.medterms.com/script/main/art.asp?articlekey=16295 "Definition of Glycosylated Hemoglobin."] {{Webarchive|url=https://web.archive.org/web/20140123013615/https://www.medterms.com/script/main/art.asp?articlekey=16295 |date=2014-01-23}} Medicine Net. Web. 12 Oct. 2009.</ref> In addition, increased glycated of hemoglobin increases its affinity for oxygen, therefore preventing its release at the tissue and inducing a level of hypoxia in extreme cases.<ref>{{cite journal |last=Madsen |first=H |author2=Ditzel, J |title=Blood-oxygen transport in first trimester of diabetic pregnancy |journal=Acta Obstetricia et Gynecologica Scandinavica |year=1984 |volume=63 |issue=4 |pages=317–20 |pmid=6741458 |doi=10.3109/00016348409155523 |s2cid=12771673}}</ref>

Elevated levels of hemoglobin are associated with increased numbers or sizes of red blood cells, called [[polycythemia]]. This elevation may be caused by [[congenital heart disease]], [[cor pulmonale]], [[pulmonary fibrosis]], too much [[erythropoietin]], or [[polycythemia vera]].<ref>[https://www.medlineplus.gov/ency/article/003645.htm#What%20abnormal%20results%20mean Hemoglobin]  at Medline Plus</ref> High hemoglobin levels may also be caused by exposure to high altitudes, smoking, dehydration (artificially by concentrating Hb), advanced lung disease and certain tumors.<ref name="HemoglobinMedicineNet"/>

==Diagnostic uses==
{{Main|Hemoglobinometer}}
[[File:Hemoglobin Test American Red Cross.jpg|thumb|A hemoglobin concentration measurement being administered before a blood donation at the [[American Red Cross]] Boston Blood Donation Center.]]

Hemoglobin concentration measurement is among the most commonly performed [[blood test]]s, usually as part of a [[complete blood count]]. For example, it is typically tested before or after [[blood donation]]. Results are reported in [[gram|g]]/[[litre|L]], g/[[decilitre|dL]] or [[mole (unit)|mol]]/L. 1 g/dL equals about 0.6206&nbsp;mmol/L, although the latter units are not used as often due to uncertainty regarding the polymeric state of the molecule.<ref>Society for Biomedical Diabetes Research. [https://www.soc-bdr.org/rds/authors/unit_tables_conversions_and_genetic_dictionaries/e5196/index_en.html SI Unit Conversion Calculator] {{Webarchive|url=https://web.archive.org/web/20130309021928/https://www.soc-bdr.org/rds/authors/unit_tables_conversions_and_genetic_dictionaries/e5196/index_en.html |date=2013-03-09}}.</ref> This conversion factor, using the single globin unit molecular weight of 16,000 [[dalton (unit)|Da]], is more common for hemoglobin concentration in blood. For MCHC (mean corpuscular hemoglobin concentration) the conversion factor 0.155, which uses the tetramer weight of 64,500 Da, is more common.<ref>Handin, Robert I.; Lux, Samuel E. and StosselBlood, Thomas P. (2003). ''Blood: Principles & Practice of Hematology''. Lippincott Williams & Wilkins, {{ISBN|0781719933}}</ref> Normal levels are:
* Men: 13.8 to 18.0 g/dL (138 to 180 g/L, or 8.56 to 11.17&nbsp;mmol/L)
* Women: 12.1 to 15.1 g/dL (121 to 151 g/L, or 7.51 to 9.37&nbsp;mmol/L)
* Children: 11 to 16 g/dL (110 to 160 g/L, or 6.83 to 9.93&nbsp;mmol/L)
* Pregnant women: 11 to 14 g/dL (110 to 140 g/L, or 6.83 to 8.69&nbsp;mmol/L) (9.5 to 15 usual value during pregnancy)<ref>{{cite web |title=Hemoglobin Level Test |website=Ibdcrohns.about.com |date=2013-08-16 |url=https://ibdcrohns.about.com/od/diagnostictesting/p/testhemo.htm |access-date=2013-09-05 |archive-url=https://web.archive.org/web/20070129043625/https://ibdcrohns.about.com/od/diagnostictesting/p/testhemo.htm |archive-date=2007-01-29}}</ref>{{efn|Although other sources can have slightly differing values, such as UK's General Practice Notebook.<ref>{{cite web |title=haemoglobin (reference range) |website=General Practice Notebook |url=https://www.gpnotebook.co.uk/simplepage.cfm?ID=1026883654 |archive-url=https://web.archive.org/web/20090925071847/https://www.gpnotebook.co.uk/simplepage.cfm?ID=1026883654 |archive-date=2009-09-25}}</ref>}}

Normal values of hemoglobin in the 1st and 3rd trimesters of pregnant women must be at least 11 g/dL and at least 10.5 g/dL during the 2nd trimester.<ref>Murray S.S. & McKinney E.S. (2006). ''Foundations of Maternal-Newborn Nursing''. 4th ed., p. 919. Philadelphia: Saunders Elsevier. {{ISBN|1416001417}}.</ref>

Dehydration or hyperhydration can greatly influence measured hemoglobin levels. Albumin can indicate hydration status.

If the concentration is below normal, this is called anemia. Anemias are classified by the size of red blood cells, the cells that contain hemoglobin in vertebrates. The anemia is called "microcytic" if red cells are small, "macrocytic" if they are large, and "normocytic" otherwise.

[[Hematocrit]], the proportion of blood volume occupied by red blood cells, is typically about three times the hemoglobin concentration measured in g/dL. For example, if the hemoglobin is measured at 17 g/dL, that compares with a hematocrit of 51%.<ref>{{cite web |title=Hematocrit (HCT) or Packed Cell Volume (PCV) |publisher=DoctorsLounge.com |url=https://www.doctorslounge.com/hematology/labs/hematocrit.htm |access-date=2007-12-26 |url-status=live |archive-url=https://web.archive.org/web/20080102133232/https://www.doctorslounge.com/hematology/labs/hematocrit.htm |archive-date=2008-01-02}}</ref>

Laboratory hemoglobin test methods require a blood sample (arterial, venous, or capillary) and analysis on hematology analyzer and CO-oximeter. Additionally, a new noninvasive hemoglobin (SpHb) test method called Pulse CO-Oximetry is also available with comparable accuracy to invasive methods.<ref>{{cite journal
|last1=Frasca |first1=D.
|last2=Dahyot-Fizelier |first2=C.
|last3=Catherine |first3=K.
|last4=Levrat |first4=Q.
|last5=Debaene |first5=B.
|last6=Mimoz |first6=O.
|title=Accuracy of a continuous noninvasive hemoglobin monitor in intensive care unit patients*
|journal=Critical Care Medicine
|volume=39
|issue=10
|pages=2277–82
|year=2011
|pmid=21666449
|doi=10.1097/CCM.0b013e3182227e2d
|s2cid=205541592
}}</ref>

Concentrations of oxy- and deoxyhemoglobin can be measured continuously, regionally and noninvasively using [[near-infrared spectroscopy|NIRS]].<ref>{{cite journal
|last1=Ferrari |first1=M.
|last2=Binzoni |first2=T.
|last3=Quaresima |first3=V.
|title=Oxidative metabolism in muscle
|journal=Philosophical Transactions of the Royal Society B: Biological Sciences
|volume=352
|issue=1354
|pages=677–83
|year=1997
|bibcode=1997RSPTB.352..677F
|pmid=9232855
|doi=10.1098/rstb.1997.0049
|pmc=1691965
}}</ref><ref>{{cite journal
|last1=Madsen |first1=P. L.
|last2=Secher |first2=N. H.
|title=Near-infrared oximetry of the brain
|journal=Progress in Neurobiology
|volume=58
|issue=6
|pages=541–60
|year=1999
|pmid=10408656
|doi=10.1016/S0301-0082(98)00093-8
|s2cid=1092056}}</ref><ref>{{cite journal
|last1=McCully |first1=K. K.
|last2=Hamaoka |first2=T.
|title=Near-infrared spectroscopy: What can it tell us about oxygen saturation in skeletal muscle?
|journal=Exercise and Sport Sciences Reviews
|volume=28
|issue=3
|pages=123–27
|year=2000
|pmid=10916704
}}</ref><ref>{{cite journal
|last1=Perrey |first1=S. P.
|title=Non-invasive NIR spectroscopy of human brain function during exercise
|journal=Methods
|volume=45
|issue=4
|pages=289–99
|year=2008
|pmid=18539160
|doi=10.1016/j.ymeth.2008.04.005
}}</ref><ref>{{cite journal
|last1=Rolfe |first1=P.
|title=Invivonear-Infraredspectroscopy
|journal=Annual Review of Biomedical Engineering
|volume=2
|pages=715–54
|year=2000
|pmid=11701529
|doi=10.1146/annurev.bioeng.2.1.715
}}</ref> NIRS can be used both on the head and on muscles. This technique is often used for research in e.g. elite sports training, ergonomics, rehabilitation, patient monitoring, neonatal research, functional brain monitoring, [[brain–computer interface]], urology (bladder contraction), neurology (Neurovascular coupling) and more.

Hemoglobin mass can be measured in humans using the non-radioactive, carbon monoxide (CO) rebreathing technique that has been used for more than 100 years. With this technique, a small volume of pure CO gas is inhaled and rebreathed for a few minutes. During rebreathing, CO binds to hemoglobin present in red blood cells. Based on the increase in blood CO after the rebreathing period, the hemoglobin mass can be determined through the dilution principle.<ref>{{cite journal |last1=Siebenmann |first1=Christoph |last2=Keiser |first2=Stefanie |last3=Robach |first3=Paul |last4=Lundby |first4=Carsten |title=CORP: The assessment of total hemoglobin mass by carbon monoxide rebreathing |journal=Journal of Applied Physiology |date=29 June 2017 |volume=123 |issue=3 |pages=645–654 |issn=8750-7587 |pmid=28663373 |doi=10.1152/japplphysiol.00185.2017 |doi-access=free}}</ref>

Long-term control of [[blood sugar]] concentration can be measured by the concentration of Hb A<sub>1c</sub>. Measuring it directly would require many samples because blood sugar levels vary widely through the day. Hb A<sub>1c</sub> is the product of the [[irreversible reaction]] of hemoglobin A with glucose. A higher glucose [[concentration]] results in more Hb A<sub>1c</sub>. Because the reaction is slow, the Hb A<sub>1c</sub> proportion represents glucose level in blood averaged over the half-life of red blood cells, is typically about 120 days. An Hb A<sub>1c</sub> proportion of 6.0% or less show good long-term glucose control, while values above 7.0% are elevated. This test is especially useful for diabetics.{{efn|This Hb A<sub>1c</sub> level is only useful in individuals who have red blood cells (RBCs) with normal survivals (i.e., normal half-life). In individuals with abnormal RBCs, whether due to abnormal hemoglobin molecules (such as Hemoglobin S in Sickle Cell Anemia) or RBC membrane defects – or other problems, the RBC half-life is frequently shortened. In these individuals, an alternative test called "fructosamine level" can be used. It measures the degree of glycation (glucose binding) to albumin, the most common blood protein, and reflects average blood glucose levels over the previous 18–21 days, which is the half-life of albumin molecules in the circulation.}}

The [[functional magnetic resonance imaging]] (fMRI) machine uses the signal from deoxyhemoglobin, which is sensitive to magnetic fields since it is paramagnetic. Combined measurement with [[near-infrared spectroscopy|NIRS]] shows good correlation with both the oxy- and deoxyhemoglobin signal compared to the [[blood-oxygen-level dependent|BOLD signal]].<ref>{{cite journal |year=2002 |vauthors=Mehagnoul-Schipper DJ, van der Kallen BF, Colier WN, van der Sluijs MC, van Erning LJ, Thijssen HO, Oeseburg B, Hoefnagels WH, Jansen RW |title=Simultaneous measurements of cerebral oxygenation changes during brain activation by near-infrared spectroscopy and functional magnetic resonance imaging in healthy young and elderly subjects |volume=16 |issue=1 |pages=14–23 |journal=Hum Brain Mapp |pmid=11870923 |doi=10.1002/hbm.10026 |pmc=6871837}}</ref>

==Athletic tracking and self-tracking uses==
Hemoglobin can be tracked noninvasively, to build an individual data set tracking the hemoconcentration and hemodilution effects of daily activities for better understanding of sports performance and training. Athletes are often concerned about endurance and intensity of exercise. The sensor uses light-emitting diodes that emit red and infrared light through the tissue to a light detector, which then sends a signal to a processor to calculate the absorption of light by the hemoglobin protein.<ref>{{cite web |title=Cercacor – How Ember's non-invasive hemoglobin technology works |website=technology.cercacor.com |url=https://technology.cercacor.com/ |access-date=2016-11-03 |url-status=live |archive-url=https://web.archive.org/web/20161104075209/https://technology.cercacor.com/ |archive-date=2016-11-04}}</ref> This sensor is similar to a [[pulse oximeter]], which consists of a small sensing device that clips to the finger.

==Analogues in non-vertebrate organisms==
A variety of oxygen-transport and -binding proteins exist in organisms throughout the animal and plant kingdoms. Organisms including [[bacteria]], [[protozoa]]ns, and [[fungi]] all have hemoglobin-like proteins whose known and predicted roles include the reversible binding of gaseous [[ligand]]s. Since many of these proteins contain [[globin]]s and the heme [[functional group|moiety]] (iron in a flat porphyrin support), they are often called hemoglobins, even if their overall tertiary structure is very different from that of vertebrate hemoglobin. In particular, the distinction of "myoglobin" and hemoglobin in lower animals is often impossible, because some of these organisms do not contain [[muscle]]s. Or, they may have a recognizable separate [[circulatory system]] but not one that deals with oxygen transport (for example, many [[insect]]s and other [[arthropod]]s). In all these groups, heme/globin-containing molecules (even monomeric globin ones) that deal with gas-binding are referred to as oxyhemoglobins. In addition to dealing with transport and sensing of oxygen, they may also deal with NO, CO<sub>2</sub>, sulfide compounds, and even O<sub>2</sub> scavenging in environments that must be anaerobic.<ref>{{cite journal |author1=L. Int Panis |author2=B. Goddeeris |author3=R Verheyen |title=The hemoglobin concentration of Chironomus cf. Plumosus L. (Diptera: Chironomidae) larvae from two lentic habitats |journal=Netherlands Journal of Aquatic Ecology |volume=29 |issue=1 |pages=1–4 |year=1995 |bibcode=1995NJAqE..29....1P |doi=10.1007/BF02061785 |s2cid=34214741 |url=https://www.researchgate.net/publication/226360004 |access-date=2013-11-10 |url-status=live |archive-url=https://web.archive.org/web/20180905175546/https://www.researchgate.net/publication/226360004 |archive-date=2018-09-05}}</ref> They may even deal with detoxification of chlorinated materials in a way analogous to heme-containing P450 enzymes and peroxidases.

[[File:Riftia tube worms Galapagos 2011.jpg|thumb|right|The giant tube worm ''[[Riftia pachyptila]]'' showing red hemoglobin-containing plumes]]
The structure of hemoglobins varies across species. Hemoglobin occurs in all kingdoms of organisms, but not in all organisms. Primitive species such as bacteria, protozoa, [[algae]], and [[plant]]s often have single-globin hemoglobins. Many [[nematode]] worms, [[Mollusca|molluscs]], and [[crustacean]]s contain very large multisubunit molecules, much larger than those in vertebrates. In particular, chimeric hemoglobins found in [[fungi]] and giant [[annelid]]s may contain both globin and other types of proteins.<ref name="Weber-2001">{{cite journal |vauthors=Weber RE, Vinogradov SN |title=Nonvertebrate hemoglobins: functions and molecular adaptations |journal=Physiol. Rev. |volume=81 |issue=2 |pages=569–628 |year=2001 |pmid=11274340 |doi=10.1152/physrev.2001.81.2.569 |s2cid=10863037}}</ref>

One of the most striking occurrences and uses of hemoglobin in organisms is in the [[giant tube worm]] (''Riftia pachyptila'', also called Vestimentifera), which can reach 2.4 meters length and populates ocean [[volcanic vent]]s. Instead of a [[digestive tract]], these worms contain a population of bacteria constituting half the organism's weight. The bacteria oxidize H<sub>2</sub>S from the vent with O<sub>2</sub> from the water to produce energy to make food from H<sub>2</sub>O and CO<sub>2</sub>. The worms' upper end is a deep-red fan-like structure ("plume"), which extends into the water and absorbs H<sub>2</sub>S and O<sub>2</sub> for the bacteria, and CO<sub>2</sub> for use as synthetic raw material similar to photosynthetic plants. The structures are bright red due to their content of several extraordinarily complex hemoglobins that have up to 144 globin chains, each including associated heme structures. These hemoglobins are remarkable for being able to carry oxygen in the presence of sulfide, and even to carry sulfide, without being completely "poisoned" or inhibited by it as hemoglobins in most other species are.<ref>{{cite journal |vauthors=Zal F, Lallier FH, Green BN, Vinogradov SN, Toulmond A |title=The multi-hemoglobin system of the hydrothermal vent tube worm Riftia pachyptila. II. Complete polypeptide chain composition investigated by maximum entropy analysis of mass spectra |journal=J. Biol. Chem. |volume=271 |issue=15 |pages=8875–81 |year=1996 |pmid=8621529 |doi=10.1074/jbc.271.15.8875 |doi-access=free}}</ref><ref>{{cite journal |vauthors=Minic Z, Hervé G |title=Biochemical and enzymological aspects of the symbiosis between the deep-sea tubeworm Riftia pachyptila and its bacterial endosymbiont |journal=Eur. J. Biochem. |volume=271 |issue=15 |pages=3093–102 |year=2004 |pmid=15265029 |doi=10.1111/j.1432-1033.2004.04248.x |doi-access=free}}</ref>

==Other oxygen-binding proteins==
{{Main|Respiratory pigment}}
;[[Myoglobin]]: Found in the muscle tissue of many vertebrates, including humans, it gives muscle tissue a distinct red or dark gray color. It is very similar to hemoglobin in structure and sequence, but is not a tetramer; instead, it is a monomer that lacks cooperative binding. It is used to store oxygen rather than transport it.

;[[Hemocyanin]]: The second most common oxygen-transporting protein found in nature, it is found in the blood of many arthropods and molluscs. Uses copper prosthetic groups instead of iron heme groups and is blue in color when oxygenated.

;[[Hemerythrin]]: Some marine invertebrates and a few species of annelid use this iron-containing non-heme protein to carry oxygen in their blood. Appears pink/violet when oxygenated, clear when not.

;[[Chlorocruorin]]: Found in many annelids, it is very similar to erythrocruorin, but the heme group is significantly different in structure. Appears green when deoxygenated and red when oxygenated.

;[[Vanabin]]s: Also known as ''[[vanadium]] chromagens'', they are found in the blood of [[sea squirt]]s. They were once hypothesized to use the metal vanadium as an oxygen binding prosthetic group. However, although they do contain vanadium by preference, they apparently bind little oxygen, and thus have some other function, which has not been elucidated (sea squirts also contain some hemoglobin). They may act as toxins.

;[[Erythrocruorin]]: Found in many annelids, including [[earthworm]]s, it is a giant free-floating blood protein containing many dozens—possibly hundreds—of iron- and heme-bearing protein subunits bound together into a single protein complex with a molecular mass greater than 3.5&nbsp;million daltons.

;[[Leghemoglobin]]: In leguminous plants, such as alfalfa or soybeans, the nitrogen fixing bacteria in the roots are protected from oxygen by this iron heme containing oxygen-binding protein. The specific enzyme protected is [[nitrogenase]], which is unable to reduce nitrogen gas in the presence of free oxygen.

;[[Coboglobin]]: A synthetic cobalt-based porphyrin. Coboprotein would appear colorless when oxygenated, but yellow when in veins.

==Presence in nonerythroid cells==
Some nonerythroid cells (i.e., cells other than the red blood cell line) contain hemoglobin. In the brain, these include the A9 [[dopaminergic]] neurons in the [[substantia nigra]], [[astrocyte]]s in the [[cerebral cortex]] and [[hippocampus]], and in all mature [[oligodendrocyte]]s.<ref name="Biagioli-2009"/> It has been suggested that brain hemoglobin in these cells may enable the "storage of oxygen to provide a homeostatic mechanism in anoxic conditions, which is especially important for A9 DA neurons that have an elevated metabolism with a high requirement for energy production".<ref name="Biagioli-2009"/> It has been noted further that "A9 [[dopaminergic]] neurons may be at particular risk of anoxic degeneration since in addition to their high mitochondrial activity they are under intense oxidative stress caused by the production of hydrogen peroxide via autoxidation and/or monoamine oxidase (MAO)-mediated deamination of dopamine and the subsequent reaction of accessible ferrous iron to generate highly toxic hydroxyl radicals".<ref name="Biagioli-2009"/> This may explain the risk of degeneration of these cells in [[Parkinson's disease]].<ref name="Biagioli-2009"/> The hemoglobin-derived iron in these cells is not the cause of the post-mortem darkness of these cells (origin of the Latin name, substantia ''nigra''), but rather is due to [[neuromelanin]].

Outside the brain, hemoglobin has non-oxygen-carrying functions as an [[antioxidant]] and a regulator of [[iron metabolism]] in [[macrophage]]s,<ref>{{cite journal |volume=96 |issue=12 |year=1999 |pages=6643–47 |vauthors=Liu L, Zeng M, Stamler JS |title=Hemoglobin induction in mouse macrophages |journal=Proceedings of the National Academy of Sciences of the United States of America |bibcode=1999PNAS...96.6643L |pmid=10359765 |doi=10.1073/pnas.96.12.6643 |doi-access=free |pmc=21968}}</ref> [[alveolar cell]]s,<ref>{{cite journal |volume=281 |issue=9 |year=2006 |pages=5668–76 |vauthors=Newton DA, Rao KM, Dluhy RA, Baatz JE |title=Hemoglobin Is Expressed by Alveolar Epithelial Cells |journal=Journal of Biological Chemistry |pmid=16407281 |doi=10.1074/jbc.M509314200 |doi-access=free}}</ref> and [[mesangial cell]]s in the kidney.<ref>{{cite journal
|last1=Nishi |first1=H.
|last2=Inagi |first2=R.
|last3=Kato |first3=H.
|last4=Tanemoto |first4=M.
|last5=Kojima |first5=I.
|last6=Son |first6=D.
|last7=Fujita |first7=T.
|last8=Nangaku |first8=M.
|title=Hemoglobin is Expressed by Mesangial Cells and Reduces Oxidant Stress
|journal=Journal of the American Society of Nephrology
|volume=19
|issue=8
|pages=1500–08
|year=2008
|pmid=18448584
|doi=10.1681/ASN.2007101085
|pmc=2488266
}}</ref>

==In history and art==
[[File:Heart of Steel (Hemoglobin).jpg|thumb|right |upright=1.35|''Heart of Steel (Hemoglobin)'' (2005) by [[Julian Voss-Andreae]]. The images show the {{convert|5|ft|m|adj=on}} tall sculpture right after installation, after 10 days, and after several months of exposure to the elements.]]

Historically, an association between the color of blood and rust occurs in the association of the planet [[Mars]], with the Roman god of war, since the planet is an orange-red, which reminded the ancients of blood. Although the color of the planet is due to iron compounds in combination with oxygen in the Martian soil, it is a common misconception that the iron in hemoglobin and its oxides gives blood its red color. The color is actually due to the [[porphyrin]] [[functional group|moiety]] of hemoglobin to which the iron is bound, not the iron itself,<ref>{{cite book |title=Pharmacy Practice Manual: A Guide to the Clinical Experience |last=Boh |first=Larry |year=2001 |publisher=Lippincott Williams & Wilkins |isbn=978-0-7817-2541-5 |url=https://archive.org/details/pharmacypractice00bohl}}</ref> although the ligation and redox state of the iron can influence the pi to pi* or n to pi* electronic transitions of the porphyrin and hence its optical characteristics.

Artist [[Julian Voss-Andreae]] created a [[sculpture]] called ''Heart of Steel (Hemoglobin)'' in 2005, based on the protein's backbone. The sculpture was made from glass and [[weathering steel]]. The intentional rusting of the initially shiny work of art mirrors hemoglobin's fundamental chemical reaction of oxygen binding to iron.<ref>{{cite journal |last=Holden |first=Constance  |year=2005 |title=Blood and Steel |journal=Science |volume=309 |page=2160 |issue=5744 |doi=10.1126/science.309.5744.2160d |s2cid=190178048}}</ref><ref>{{cite book |vauthors=Moran L, Horton RA, Scrimgeour G, Perry M |title=Principles of Biochemistry |publisher=Pearson |location=Boston, MA |year=2011 |page=127 |isbn=978-0-321-70733-8}}</ref>

Montreal artist Nicolas Baier created ''Lustre (Hémoglobine)'', a sculpture in stainless steel that shows the structure of the hemoglobin molecule. It is displayed in the atrium of [[McGill University Health Centre]]'s research centre in Montreal. The sculpture measures about 10 metres × 10 metres × 10 metres.<ref name="Henry-2014">{{cite news |title=Take a sneak peek at the MUHC's art collection |last=Henry |first=Sean |date=August 7, 2014 |publisher=CBC News |url=https://www.cbc.ca/news/canada/montreal/take-a-sneak-peek-at-the-muhc-s-art-collection-1.2730343 |access-date=February 1, 2016 |url-status=live |archive-url=https://web.archive.org/web/20160205200557/https://www.cbc.ca/news/canada/montreal/take-a-sneak-peek-at-the-muhc-s-art-collection-1.2730343 |archive-date=February 5, 2016}}</ref><ref name="Art Public Montréal">{{cite web |title=Lustre (Hémoglobine) 2014 |website=Art Public Montréal |location=Montréal |url=https://artpublicmontreal.ca/oeuvre/lustre-hemoglobine/ |access-date=February 1, 2016 |url-status=live |archive-url=https://web.archive.org/web/20160201224949/https://artpublicmontreal.ca/oeuvre/lustre-hemoglobine/ |archive-date=February 1, 2016}}</ref>

==See also==
{{Portal|Biology|Medicine}}
* [[Carbaminohemoglobin]] (Hb associated with {{CO2}})
* [[Carboxyhemoglobin]] (Hb associated with CO)
* [[Chlorophyll]] (Mg heme)
* [[Complete blood count]]
* [[HBD (gene)|Delta globin]]
* [[Hemoglobinometer]]
* [[Hemoprotein]]
* [[Methemoglobin]] (ferric Hb, or ferrihemoglobin)
* [[Oxyhemoglobin]] (with diatomic [[oxygen]], colored blood-red)
* [[Tegillarca granosa]] - "blood clam"
* [[Vaska's complex]] – iridium organometallic complex notable for its ability to bind to O<sub>2</sub> reversibly

==References==

===Notes===
{{Reflist|group=lower-alpha}}

===Sources===
{{Reflist}}

==Further reading==
{{Library resources box
|lcheading=Hemoglobin}}
* {{cite book
|last1=Campbell |first1=MK
|title=Biochemistry
|year=1999
|edition=third
|publisher=Harcourt
|isbn=978-0-03-024426-1
|url=https://archive.org/details/biochemistry00camp
}}
* {{cite journal
|last1=Eshaghian |first1=S
|last2=Horwich |first2=TB
|last3=Fonarow |first3=GC
|title=An unexpected inverse relationship between HbA1c levels and mortality in patients with diabetes and advanced systolic heart failure
|periodical=Am Heart J
|volume=151
|issue=1
|pages=91.e1–91.e6
|year=2006
|pmid=16368297
|doi=10.1016/j.ahj.2005.10.008}}
* {{cite book
|last1=Ganong |first1=WF
|year=2003
|title=Review of Medical Physiology
|edition=21st
|publisher=Lange
|isbn=978-0-07-140236-1
}}
* {{cite book
|last1=Hager |first1=T
|year=1995
|title=Force of Nature: The Life of Linus Pauling
|publisher=Simon and Schuster
|isbn=978-0-684-80909-0
|url=https://archive.org/details/forceofnaturelif00hage
}}
* Hazelwood, Loren (2001) ''Can't Live Without It: The story of hemoglobin in sickness and in health'', [[Nova Science Publishers]] {{ISBN|1-56072-907-4}}
* {{cite journal
|vauthors=Kneipp J, Balakrishnan G, Chen R, Shen TJ, Sahu SC, Ho NT, Giovannelli JL, Simplaceanu V, Ho C, Spiro T |title=Dynamics of allostery in hemoglobin: roles of the penultimate tyrosine H bonds
|periodical=J Mol Biol
|year=2005
|volume=356
|issue=2
|pages=335–53
|pmid=16368110
|doi=10.1016/j.jmb.2005.11.006
}}
* {{cite journal
|last=Hardison |first=Ross C.
|date=2012
|title=Evolution of Hemoglobin and Its Genes
|journal=Cold Spring Harbor Perspectives in Medicine
|volume=2
|issue=12
|article-number=a011627
|issn=2157-1422
|pmid=23209182
|doi=10.1101/cshperspect.a011627
|pmc=3543078
}}

==External links==
{{Commons category|Hemoglobin}}
* {{Proteopedia|Hemoglobin}}
* [https://web.archive.org/web/20080613202658/https://www.anemia.org/ National Anemia Action Council] at [https://anemia.org anemia.org]
* [https://www.life-of-science.net/medicine/news/new-hemoglobin-type-discovered-causing-mock-diagnosis-of-cardiac-insufficiency.html New hemoglobin type causes mock diagnosis with pulse oxymeters] {{Webarchive|url=https://web.archive.org/web/20160309164714/http://life-of-science.net/medicine/news/new-hemoglobin-type-discovered-causing-mock-diagnosis-of-cardiac-insufficiency.html |date=2016-03-09}} at [https://www.life-of-science.net www.life-of-science.net] {{Webarchive|url=https://web.archive.org/web/20170307055011/http://www.life-of-science.net/ |date=2017-03-07}}
* [https://caloriebite.in/what-is-hemoglobin.html Hemoglobin article]  at [https://caloriebite.in caloriebite.in]

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[[Category:Hemoglobins]]
[[Category:Equilibrium chemistry]]
[[Category:Respiratory physiology]]