View source for Hydroxylation

{{Short description|Chemical reaction which adds an –OH group to an organic compound}}
{{Hatnote|Hydroxylation and hydroxylases are not to be confused with [[hydrolysis]] and [[hydrolase]]s.}}

In [[chemistry]], '''hydroxylation''' refers to the installation of a [[hydroxyl group]] ({{chem2|\sOH}}) into an [[organic compound]].  Hydroxylations generate [[Alcohol (chemistry)|alcohol]]s and phenols, which are very common [[functional group]]s.  Hydroxylation confers some degree of water-solubility.  Hydroxylation of a hydrocarbon is an [[oxidation]], thus a step in degradation.
==Biological hydroxylation==
In [[biochemistry]], hydroxylation reactions are often facilitated by [[enzyme]]s called '''hydroxylases'''. These enzymes insert an O atom into a {{chem2|C\sH}} bond. Typical stoichiometries for the hydroxylation of a generic hydrocarbon are these:
:{{chem2|2R3C\sH + O2 -> 2 R3C\sOH}}
:{{chem2|R3C\sH + O2 + 2e- + 2H+ -> R3C\sOH + H2O}}
Since {{chem2|O2}} itself is a slow and unselective hydroxylating agent, catalysts are required to accelerate the pace of the process and to introduce selectivity.<ref name=JTG/>

Hydroxylation is often the first step in the degradation of organic compounds in air.  Hydroxylation is important in [[detoxification]] since it converts [[lipophilicity|lipophilic]] compounds into water-soluble ([[hydrophile|hydrophilic]]) products that are more readily removed by the [[ultrafiltration (renal)|kidneys]] or [[liver#Breakdown|liver]] and [[excretion|excreted]].  Some [[pharmaceutical drug|drugs]] (for example, [[steroid]]s) are activated or deactivated by hydroxylation.<ref>{{cite journal |doi=10.1007/BF00129093|title=Biodegradation of polycyclic aromatic hydrocarbons|year=1992|last1=Cerniglia|first1=Carl E.|journal=Biodegradation|volume=3|issue=2–3|pages=351–368|s2cid=25516145}}</ref>

The principal hydroxylation catalyst in nature is [[cytochrome P-450]], hundreds of variations of which are known.<ref>{{cite journal|doi= 10.1021/cr9002193|title= Hydrocarbon Hydroxylation by Cytochrome P450 Enzymes|date= 2010|last1= Ortiz De Montellano|first1= Paul R.|journal= Chemical Reviews|volume= 110|issue= 2|pages= 932–948|pmid= 19769330|pmc= 2820140}}</ref> Other hydroxylating agents include flavins, [[alpha-ketoglutarate-dependent hydroxylases]] (2-oxoglutarate-dependent dioxygenases), and some diiron hydroxylases.<ref>Nelson, D. L.; Cox, M. M. "Lehninger, Principles of Biochemistry" 3rd Ed. Worth Publishing: New York, 2000. {{ISBN|1-57259-153-6}}.{{page needed|date=March 2017}}</ref>
[[File:ORebound.png|thumb|center|422px|Steps in an [[oxygen rebound mechanism]] that explains many iron-catalyzed hydroxylations: H-atom abstraction, oxygen rebound, alcohol decomplexation.<ref name=JTG>{{cite journal |author=Huang, X. |author2=Groves, J. T. |author-link2=John T. Groves |title=Beyond ferryl-mediated hydroxylation: 40 years of the rebound mechanism and C–H activation |journal=Journal of Biological Inorganic Chemistry |year=2017 |volume=22 |issue=2–3 |pages=185–207 |doi=10.1007/s00775-016-1414-3 |pmc=5350257 |pmid=27909920}}</ref>]]

=== Of proteins ===
The hydroxylation of proteins occurs as a [[post-translational modification]] and is catalyzed by 2-oxoglutarate-dependent dioxygenases.<ref>{{Cite journal|last1=Zurlo|first1=Giada|last2=Guo|first2=Jianping|last3=Takada|first3=Mamoru|last4=Wei|first4=Wenyi|last5=Zhang|first5=Qing|date=December 2016|title=New Insights into Protein Hydroxylation and Its Important Role in Human Diseases|journal=Biochimica et Biophysica Acta (BBA) - Reviews on Cancer|volume=1866|issue=2|pages=208–220|doi=10.1016/j.bbcan.2016.09.004|issn=0006-3002|pmc=5138100|pmid=27663420}}</ref> Hydroxylation improves water‐solubility, as well as affecting their structure and function. 

The most frequently hydroxylated amino acid residue in human [[protein]]s is [[proline]]. This is because [[collagen]] makes up about 25–35% of the protein in our bodies and contains a [[hydroxyproline]] at almost every 3rd residue in its amino acid sequence. Collagen consists of both 3‐hydroxyproline and 4‐hydroxyproline residues.<ref name="Raju_2019">{{Citation |author=T. Shantha Raju |chapter=Hydroxylation of Proteins|date=2019|title=Co- and Post-Translational Modifications of Therapeutic Antibodies and Proteins|pages=119–131|publisher=John Wiley & Sons |language=en|doi=10.1002/9781119053354.ch10|isbn=978-1-119-05335-4|s2cid=243626930}}</ref> Hydroxylation occurs at the γ-C atom, forming [[hydroxyproline]] (Hyp), which stabilizes the secondary structure of collagen due to the strong electronegative effects of oxygen.<ref>{{cite journal |doi=10.1016/S1074-5521(99)80003-9 |pmid=10021421 |title=A hyperstable collagen mimic |journal=Chemistry & Biology |volume=6 |issue=2 |pages=63–70 |year=1999 |last1=Holmgren |first1=Steven K |last2=Bretscher |first2=Lynn E |last3=Taylor |first3=Kimberly M |last4=Raines |first4=Ronald T |doi-access=free }}</ref> Proline hydroxylation is also a vital component of [[Hypoxia (medical)|hypoxia]] response via [[hypoxia inducible factor]]s. In some cases, proline may be hydroxylated instead on its β-C atom. These three reactions are catalyzed by large, multi-subunit enzymes [[prolyl 4-hydroxylase]], [[prolyl 3-hydroxylase]], and [[lysyl 5-hydroxylase]], respectively.  These enzymes require iron (as well as molecular oxygen and [[α-ketoglutarate]]). They consume oxygen (the oxidant) and [[ascorbic acid]] (vitamin C, the reductant).  Deprivation of ascorbate leads to deficiencies in proline hydroxylation, which leads to less stable collagen, which can manifest itself as the disease [[scurvy]]. Since citrus fruits are rich in vitamin C, British [[sailor]]s were given [[Lime (fruit)|limes]] to combat scurvy on long ocean voyages; hence, they were called "[[limey]]s".<ref>{{Cite book|last1=Voet|first1=Donald|title=Principles of Biochemistry|last2=Voet|first2=Judith G.|last3=Pratt|first3=Charlotte W.|publisher=Wiley|year=2016|isbn=978-1-119-45166-2|pages=143}}</ref>

Several other amino acids aside from proline are susceptible to hydroxylation, especially lysine, asparagine, aspartate and histidine.  Lysine may be hydroxylated on its δ-C atom, forming [[hydroxylysine]] (Hyl).<ref name="pmid15121720">{{cite journal |vauthors=Hausinger RP | s2cid = 85784668 | title = Fe(II)/α-ketoglutarate-dependent hydroxylases and related enzymes | journal = Crit. Rev. Biochem. Mol. Biol. | volume = 39 | issue = 1 | pages = 21–68 |date=January–February 2004 | pmid =15121720 | doi = 10.1080/10409230490440541 }}</ref> Several endogenous proteins contain hydroxyphenylalanine and hydroxytyrosine residues. These residues are formed by hydroxylation of phenylalanine and tyrosine, a process in which the hydroxylation converts phenylalanine residues into tyrosine residues.<ref name="Raju_2019" /> Hydroxylation at C-3 of tyrosine gives 3,4- dihydroxyphenylalanine (DOPA), which is a precursor to hormones and can be converted into [[dopamine]].

===Hydroxylation enzymes===
* [[17α-hydroxylase|17α-Hydroxylase]]
* [[Cholesterol 7 alpha-hydroxylase]]
* [[Dopamine β-hydroxylase]]
* [[Phenylalanine hydroxylase]]
* [[Tyrosine hydroxylase]]

==Synthetic hydroxylations==
Hydroxylations are well explored but only rarely practical in organic synthesis.  [[Peroxytrifluoroacetic acid]] converts some arenes to [[phenol]]s.  Salts of peroxydisulfate converts phenols to quinols in the [[Elbs persulfate oxidation]].  Mixtures of ferrous sulfate and hydrogen peroxide, the [[Fenton reagent]], behaves similarly.<ref>{{March6th|page=964}}</ref>

Installing hydroxyl groups into organic compounds can be effected by biomimetic catalysts, i.e. catalysts whose design is inspired by enzymes such as cytochrome P450.<ref>{{cite journal |doi=10.1021/ar000209h|title=Catalytic Functionalization of Arenes and Alkanes via C−H Bond Activation|year=2001|last1=Jia|first1=Chengguo|last2=Kitamura|first2=Tsugio|last3=Fujiwara|first3=Yuzo|journal=Accounts of Chemical Research|volume=34|issue=8|pages=633–639|pmid=11513570}}</ref>

Whereas many hydroxylations insert O atoms into {{chem2|[[Carbon–hydrogen bond|C\sH]]}} bonds, some reactions ''add'' OH groups to unsaturated substrates.  The [[Sharpless dihydroxylation]] is such a reaction: it converts alkenes into [[diol]]s. The hydroxy groups are provided by [[hydrogen peroxide]], which adds across the double bond of [[alkene]]s.<ref>{{cite journal |doi=10.1021/cr00032a009|title=Catalytic Asymmetric Dihydroxylation|year=1994|last1=Kolb|first1=Hartmuth C.|last2=Vannieuwenhze|first2=Michael S.|last3=Sharpless|first3=K. Barry|journal=Chemical Reviews|volume=94|issue=8|pages=2483–2547}}</ref>

==Hydroxylation of methane==
Methane is one of the most studied substrates for hydroxylation because it is abundant in [[natural gas]].  Although methane is welcome as a fuel, it would be more valuable if it could be converted to methanol.  Studies on the hydroxylation of methane spans both synthetic and biological approaches. Nature has evolved enzymes called [[methane monooxygenase]]s, which are efficient but impractical for commercial applications. Instead, synthetic catalysts have received much attention, but they too are not yet of practical value.<ref>{{cite journal |doi=10.1021/acs.chemrev.2c00439 |title=Methane Oxidation to Methanol |date=2023 |last1=Dummer |first1=Nicholas F. |last2=Willock |first2=David J. |last3=He |first3=Qian |last4=Howard |first4=Mark J. |last5=Lewis |first5=Richard J. |last6=Qi |first6=Guodong |last7=Taylor |first7=Stuart H. |last8=Xu |first8=Jun |last9=Bethell |first9=Don |last10=Kiely |first10=Christopher J. |last11=Hutchings |first11=Graham J. |journal=Chemical Reviews |volume=123 |issue=9 |pages=6359–6411 |pmid=36459432 |pmc=10176486 }}</ref>

==Further reading==
*{{cite journal|title=The Effects of Plant Flavonoids on Mammalian Cells: Implications for Inflammation, Heart Disease, and Cancer |author=Middleton, Elliott Jr |author2=Kandaswami, Chithan |author3=Theoharides, Theoharis C. |authorlink3= Theoharis C. Theoharides |journal=Pharmacological Reviews|year=2000|volume=52|issue=4 |pages=673–751|doi=10.1016/S0031-6997(24)01472-8 |pmid=11121513 }}

==References==
<references/>

{{Protein posttranslational modification}}

[[Category:Organic redox reactions]]
[[Category:Post-translational modification]]