View source for Creatine kinase

{{Short description|Class of enzymes}}
{{cs1 config|name-list-style=vanc}}
{{infobox enzyme
| Name       = Creatine kinase
| EC_number  = 2.7.3.2
| CAS_number = 9001-15-4
| GO_code    = 0004111
| image      = 3b6r.png
| width      =
| caption    = [[X-ray crystallography|Crystal structure]] of human brain-type creatine kinase with ADP and creatine. PDB {{PDBe|3b6r}}.<ref>{{cite journal | vauthors = Bong SM, Moon JH, Nam KH, Lee KS, Chi YM, Hwang KY | title = Structural studies of human brain-type creatine kinase complexed with the ADP-Mg2+-NO3- -creatine transition-state analogue complex | journal = FEBS Letters | volume = 582 | issue = 28 | pages = 3959–65 | date = November 2008 | pmid = 18977227 | doi = 10.1016/j.febslet.2008.10.039 | bibcode = 2008FEBSL.582.3959B | doi-access =  | s2cid = 21911841 }}</ref> 
}}

'''Creatine kinase''' ('''CK'''), also known as '''creatine phosphokinase''' ('''CPK''') or '''phosphocreatine kinase''', is an [[enzyme]] ({{EC number|2.7.3.2}}) expressed by various tissues and cell types. CK catalyses the conversion of [[creatine]] and uses [[adenosine triphosphate]] (ATP) to create [[phosphocreatine]] (PCr) and [[adenosine diphosphate]] (ADP). This CK enzyme reaction is reversible and thus ATP can be generated from PCr and ADP.

In tissues and cells that consume ATP rapidly, especially [[skeletal muscle]], but also brain, [[photoreceptor cell]]s of the [[retina]], [[hair cell]]s of the [[inner ear]], [[spermatozoa]] and [[smooth muscle]], PCr serves as an energy reservoir for the rapid buffering and regeneration of ATP ''in situ'', as well as for intracellular energy transport by the PCr shuttle or circuit.<ref name=pmid1731757>{{cite journal | vauthors = Wallimann T, Wyss M, Brdiczka D, Nicolay K, Eppenberger HM | title = Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the 'phosphocreatine circuit' for cellular energy homeostasis | journal = The Biochemical Journal | volume = 281 ( Pt 1) | issue = 1 | pages = 21–40 | date = January 1992 | pmid = 1731757 | pmc = 1130636 | doi = 10.1042/bj2810021 }}</ref> Thus creatine [[kinase]] is an important enzyme in such tissues.<ref name=pmid7808454>{{cite journal | vauthors = Wallimann T, Hemmer W | title = Creatine kinase in non-muscle tissues and cells | journal = Molecular and Cellular Biochemistry | volume = 133-134 | issue = 1 | pages = 193–220 | year = 1994 | pmid = 7808454 | doi = 10.1007/BF01267955 | s2cid = 10404672 | eissn = 1573-4919 }}</ref>

Clinically, creatine kinase is assayed in blood tests as a marker of damage of CK-rich tissue such as in [[myocardial infarction]] (heart attack), [[rhabdomyolysis]] (severe muscle breakdown), [[muscular dystrophy]], autoimmune [[Myositis|myositides]], and [[acute kidney injury]].<ref>{{cite journal | vauthors = Moghadam-Kia S, Oddis CV, Aggarwal R | title = Approach to asymptomatic creatine kinase elevation | journal = Cleveland Clinic Journal of Medicine | volume = 83 | issue = 1 | pages = 37–42 | date = January 2016 | pmid = 26760521 | pmc = 4871266 | doi = 10.3949/ccjm.83a.14120 }}</ref>

[[Image:Creatine-Kinase.svg|550px]]

==Types==
In the cells, the [[cytosol]]ic CK enzymes consist of two subunits, which can be either ''B'' (brain type) or ''M'' (muscle type). There are, therefore, three different [[isoenzyme]]s: CK-MM, CK-BB and CK-MB. The genes for these subunits are located on different [[chromosome]]s: ''B'' on 14q32 and ''M'' on 19q13. In addition to those three ''cytosolic'' CK isoforms, there are two [[mitochondrion|mitochondrial]] creatine kinase isoenzymes, the ''ubiquitous'' form and the ''sarcomeric'' form. The functional entity of the mitochondrial CK isoforms is an [[monomer|octamer]] consisting of four [[monomer|dimers]] each.<ref name=pmid16236486>{{cite journal | vauthors = Schlattner U, Tokarska-Schlattner M, Wallimann T | title = Mitochondrial creatine kinase in human health and disease | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1762 | issue = 2 | pages = 164–80 | date = February 2006 | pmid = 16236486 | doi = 10.1016/j.bbadis.2005.09.004 | doi-access =  }}</ref>

While mitochondrial creatine kinase is directly involved in the formation of phosphocreatine from mitochondrial ATP, cytosolic CK regenerates ATP from ADP, using PCr. This happens at intracellular sites where ATP is used in the cell, with CK acting as an ''in situ'' ATP regenerator.
{| class="wikitable"
|-
! gene
! protein
|-
| [[CKB (gene)|CKB]]
| creatine kinase, brain, BB-CK
|-
| [[CKB (gene)#Ectopic expression|CKBE]]
| creatine kinase, ectopic expression
|-
| [[CKM (gene)|CKM]]
| creatine kinase, muscle, MM-CK
|-
| [[CKMT1A]], [[CKMT1B]]
| creatine kinase mitochondrial 1; ubiquitous mtCK; or <sub>u</sub>mtCK
|-
| [[CKMT2]]
| creatine kinase mitochondrial 2; sarcomeric mtCK; or <sub>s</sub>mtCK
|}

Isoenzyme patterns differ in tissues. Skeletal muscle expresses CK-MM (98%) and low levels of CK-MB (1%). The [[myocardium]] (heart muscle), in contrast, expresses CK-MM at 70% and CK-MB at 25–30%. CK-BB is predominantly expressed in brain and smooth muscle, including vascular and uterine tissue.

==Protein structure==

The first structure of a creatine kinase solved by X-ray protein crystallography was that of the octameric, sarcomeric muscle-type mitochondrial CK (s-mtCK) in 1996.,<ref>Fritz-Wolf K., Schnyder T., Wallimann, T., & W. Kabsch 1996 http://publicationslist.org/data/theo.wallimann/ref-135/Fritz-Wolf-sMtCK%20structure.pdf {{Webarchive|url=https://web.archive.org/web/20180715181242/http://publicationslist.org/data/theo.wallimann/ref-135/Fritz-Wolf-sMtCK%20structure.pdf |date=2018-07-15 }}</ref> followed by the structure of ubiquitous mitochondrial CK (u-mtCK) in 2000.<ref name="publicationslist.org">Eder M., Schlattner U., Becker A., Wallimann T., Kabsch W., & K. Frotz-Wolf 2000 http://publicationslist.org/data/theo.wallimann/ref-101/Eder-X-ray.uMtCK.pdf {{Webarchive|url=https://web.archive.org/web/20180715181342/http://publicationslist.org/data/theo.wallimann/ref-101/Eder-X-ray.uMtCK.pdf |date=2018-07-15 }}. Both mt-CK isoforms form octameric structures (built of 4 banana-like dimers) with a four-fold symmetry and a central channel.</ref><ref>Schnyder T., Winkler H., Gross, H. Eppenberger H.M., & T. Wallimann 1991 http://publicationslist.org/data/theo.wallimann/ref-180/SchnyderT_Gross-MtCK-crystal-EMs.pdf {{Webarchive|url=https://web.archive.org/web/20180715151945/http://publicationslist.org/data/theo.wallimann/ref-180/SchnyderT_Gross-MtCK-crystal-EMs.pdf |date=2018-07-15 }}</ref>
The atomic structure of the banana-shaped, dimeric cytosolic brain-type BB-CK was solved in 1999 at a resolution of 1,4&nbsp;[[angstrom (unit)|Å]].<ref name=Eder_1999>{{cite journal | last1=Eder | first1=Michael | last2=Schlattner | first2=Uwe | last3=Wallimann | first3=Theo | last4=Becker | first4=Andreas | last5=Kabsch | first5=Wolfgang | last6=Fritz-Wolf | first6=Karin | title=Crystal structure of brain-type creatine kinase at 1.41 Å resolution | journal=Protein Science | publisher=Wiley | volume=8 | issue=11 | date=2008-12-31 | issn=0961-8368 | doi=10.1110/ps.8.11.2258 | pages=2258–2269|pmid=10595529|pmc=2144193}}</ref> Cytosolic BB-CK, as well as muscle-type MM-CK both form banana-shaped symmetric dimers, with one catalytic [[active site]] in each subunit.<ref>Hornemann et al. 2000 http://publicationslist.org/data/theo.wallimann/ref-96/Hornmann-CK-dimer.pdf {{Webarchive|url=https://web.archive.org/web/20180715181526/http://publicationslist.org/data/theo.wallimann/ref-96/Hornmann-CK-dimer.pdf |date=2018-07-15 }}</ref>

==Functions==
[[Mitochondrial]] creatine kinase (CK<sub>m</sub>) is present in the [[intermembrane space of mitochondria|mitochondrial intermembrane space]], where it regenerates [[phosphocreatine]] (PCr) from mitochondrially generated ATP and [[creatine]] (Cr) imported from the [[cytosol]]. Apart from the two mitochondrial CK isoenzyme forms, that is, ubiquitous mtCK (present in non-muscle tissues) and sarcomeric mtCK (present in sarcomeric muscle), there are three cytosolic CK isoforms present in the cytosol, depending on the tissue. Whereas MM-CK is expressed in sarcomeric muscle, that is, skeletal and cardiac muscle, MB-CK is expressed in cardiac muscle, and BB-CK is expressed in smooth muscle and in most non-muscle tissues.

Mitochondrial mtCK and cytosolic CK are connected in a so-called PCr/Cr-shuttle or circuit. PCr generated by mtCK in mitochondria is shuttled to cytosolic CK that is coupled to ATP-dependent processes, e.g. ATPases, such as acto-myosin ATPase and calcium ATPase involved in muscle contraction, and sodium/potassium ATPase involved in sodium retention in the kidney. The bound cytosolic CK accepts the PCr shuttled through the cell and uses ADP to regenerate ATP, which can then be used as an energy source by the ATPases (CK is associated intimately with the ATPases, forming a functionally coupled [[microcompartment]]). PCr is not only an energy buffer, but also a cellular transport form of energy between subcellular sites of energy (ATP) production (mitochondria and glycolysis) and those of energy utilization (ATPases).<ref name=pmid1731757/>

Thus, CK enhances skeletal, cardiac, and smooth muscle contractility, and is involved in the generation of [[blood pressure]].<ref name="pmid17075013">{{cite journal | vauthors = Brewster LM, Mairuhu G, Bindraban NR, Koopmans RP, Clark JF, van Montfrans GA | title = Creatine kinase activity is associated with blood pressure | journal = Circulation | volume = 114 | issue = 19 | pages = 2034–9 | date = November 2006 | pmid = 17075013 | doi = 10.1161/CIRCULATIONAHA.105.584490 | doi-access =  | s2cid = 6006006 }}</ref> Further, the ADP-scavenging action of creatine kinase has been implicated in [[bleeding disorder]]s: persons with highly elevated plasma CK could be prone to major bleeding.<ref name="pmid32572751">{{cite journal | vauthors = Brewster LM | title = Creatine Extracellular creatine kinase may modulate purinergic signalling | journal = Purinergic Signalling | date = June 2020 | volume = 16 | issue = 3 | pages = 305–312 | pmid = 32572751 | doi = 10.1007/s11302-020-09707-0 | pmc = 7524943 }}</ref>

==Laboratory testing==
{{Infobox diagnostic
| name            = Serum Creatine kinase
| image           = 
| alt             = 
| caption         = 
| pronounce       =  
| purpose         = Detection of [[muscle damage]].<ref name="labtestsonline.org">{{cite web | title=Creatine Kinase (CK) | website=labtestsonline.org | url=https://labtestsonline.org/tests/creatine-kinase-ck | access-date=2019-12-24 | archive-date=2020-02-09 | archive-url=https://web.archive.org/web/20200209112945/https://labtestsonline.org/tests/creatine-kinase-ck | url-status=live }}</ref>
| test of = The amount of creatine kinase in the blood.<ref name="labtestsonline.org"/>
| based on        = 
| synonyms        = 
| reference_range = 60 and 400 IU/L
| calculator      = 
| DiseasesDB      = <!--{{DiseasesDB2|numeric_id}}-->
| ICD10           = <!--{{ICD10|Group|Major|minor|LinkGroup|LinkMajor}} or {{ICD10PCS|code|char1/char2/char3/char4}}-->
| ICD9            = 
| ICDO            =
| MedlinePlus     = <!--article_number-->
| eMedicine       = <!--article_number-->
| MeshID          = 
| OPS301          = <!--{{OPS301|code}}-->
| LOINC           = <!--{{LOINC|code}}-->
}}

CK is often determined routinely in a [[medical laboratory]]. It used to be determined specifically in patients with [[chest pain]] to recognize acute myocardial infarction, but this test has been largely replaced by [[troponin]]. Normal values at rest are usually between 60 and 400 IU/[[litre|L]],<ref name = "Armstrong_2008" /> where one unit is [[enzyme activity]], more specifically the amount of enzyme that will catalyze 1 μmol of substrate per minute under specified conditions (temperature, pH, substrate concentrations and activators.<ref name = "Bishop_2004" />) This test is not specific for the ''type'' of CK that is elevated.

Creatine kinase in the blood may be high in health and disease. Exercise increases the outflow of creatine kinase to the blood stream for up to a week, and this is the most common cause of high CK in blood.<ref name=pmid21063205>{{cite journal | vauthors = Johnsen SH, Lilleng H, Wilsgaard T, Bekkelund SI | title = Creatine kinase activity and blood pressure in a normal population: the Tromsø study | journal = Journal of Hypertension | volume = 29 | issue = 1 | pages = 36–42 | date = January 2011 | pmid = 21063205 | doi = 10.1097/HJH.0b013e32834068e0 | s2cid = 7188988 }}</ref> Furthermore, high CK in the blood may be related to high intracellular CK such as in persons of African descent.<ref name=pmid22438879>{{cite journal | vauthors = Brewster LM, Coronel CM, Sluiter W, Clark JF, van Montfrans GA | title = Ethnic differences in tissue creatine kinase activity: an observational study | journal = PLOS ONE | volume = 7 | issue = 3 | article-number = e32471 | date = 2012-03-16 | pmid = 22438879 | pmc = 3306319 | doi = 10.1371/journal.pone.0032471 | editor-first = Valdur | editor-last = Saks | bibcode = 2012PLoSO...732471B | doi-access = free }}</ref>

Finally, high CK in the blood may be an indication of damage to CK-rich tissue, such as in [[rhabdomyolysis]], [[myocardial infarction]], [[myositis]] and [[myocarditis]]. This means creatine kinase in blood may be elevated in a wide range of clinical conditions including the use of medication such as [[statins]]; endocrine disorders such as [[hypothyroidism]];<ref name="pmid16392619">{{cite journal | vauthors = Hekimsoy Z, Oktem IK | title = Serum creatine kinase levels in overt and subclinical hypothyroidism | journal = Endocrine Research | volume = 31 | issue = 3 | pages = 171–5 | year = 2005 | pmid = 16392619 | doi = 10.1080/07435800500371706 | s2cid = 5619524 }}</ref> and skeletal muscle diseases and disorders including [[malignant hyperthermia]],<ref name="pmid23400941">{{cite journal | vauthors = Johannsen S, Berberich C, Metterlein T, Roth C, Reiners K, Roewer N, Schuster F | title = Screening test for malignant hyperthermia in patients with persistent hyperCKemia: a pilot study | journal = Muscle & Nerve | volume = 47 | issue = 5 | pages = 677–81 | date = May 2013 | pmid = 23400941 | doi = 10.1002/mus.23633 | s2cid = 5126493 }}</ref> and [[neuroleptic malignant syndrome]].<ref name="pmid8101383">{{cite journal | vauthors = O'Dwyer AM, Sheppard NP | title = The role of creatine kinase in the diagnosis of neuroleptic malignant syndrome | journal = Psychological Medicine | volume = 23 | issue = 2 | pages = 323–6 | date = May 1993 | pmid = 8101383 | doi = 10.1017/s0033291700028415 | s2cid = 10818939 }}</ref>

Furthermore, the [[CPK-MB test|isoenzyme determination]] has in the past been used extensively as an indication for myocardial damage in heart attacks. Troponin measurement has largely replaced this in many hospitals, although some centers still rely on CK-MB.

[[File:Blood values sorted by mass and molar concentration.png|thumb|550px|left|[[Reference ranges for blood tests]], comparing blood content of creatine kinase (shown in orange, to left of ammonia [yellow]) with other constituents.]]
{{Clear}}

== Nomenclature ==
This enzyme is often listed in medical literature under incorrect name "creatinine kinase". [[Creatinine]] is not a substrate or a product of the enzyme.<ref>{{cite journal|journal=American Journal of Emergency Medicine|doi=10.1016/j.ajem.2020.11.015|title=CK – What does it stand for?|author=Nick Flynn|date=2021 |volume=45 |page=647 |pmid=33214021 |pmc=7656996}}</ref>

== See also ==
* [[Reference ranges for blood tests]]
* [[CPK-MB test]]

== References ==
{{Reflist|32em|refs =

<ref name = "Armstrong_2008">{{cite book
| first1=April W.
| last1=Armstrong
| first2 = David E. | last2 = Golan
| chapter=Pharmacology of Hemostasis and Thrombosis
| chapter-url=https://books.google.com/books?id=az8uSDkB0mgC&pg=PA387
| editor-first1=David E. | editor-last1 = Golan
| editor-first2=Armen H. | editor-last2 = Tashjian
| editor-first3=Ehrin J. | editor-last3 = Armstrong
| editor-first4=April W. | editor-last4 = Armstrong
| title=Principles of pharmacology: the pathophysiologic basis of drug therapy
| publisher=[[Lippincott Williams & Wilkins]]
| location=[[Philadelphia]]
| year=2008
| page=388
| isbn=978-0-7817-8355-2
| oclc=76262148}}</ref>

<ref name = "Bishop_2004">{{cite book
| editor-first1 = Michael L. | editor-last1 = Bishop
| editor-first2 = Edward P. | editor-last2 = Fody
| editor-first3 = Larry E. | editor-last3 = Schoeff
| title=Clinical chemistry: principles, procedures, correlations
| publisher=[[Lippincott Williams & Wilkins]]
| location=[[Philadelphia]]
| year=2004
| page=243
| isbn=978-0-7817-4611-3
| oclc=56446391}}</ref>

}}

== External links ==
* [https://archive.today/20130113053108/http://static.mda.org/publications/Quest/q71ss-cktest.html Simply stated at mdausa.org]
* {{MeshName|Creatine+Kinase}}
* CPK isoenzymes test {{MedlinePlus|003504}}
* CK at [http://labtestsonline.org/understanding/analytes/ck/tab/test Lab Tests Online]

{{Mitochondrial enzymes}}
{{Amino acid metabolism enzymes}}
{{Blood tests}}
{{Kinases}}
{{Enzymes}}
{{Authority control}}
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[[Category:Chemical pathology]]
[[Category:EC 2.7.3]]