Creatine Kinase - Wikipedia

Class of enzymes

Creatine kinase
Crystal structure of human brain-type creatine kinase with ADP and creatine. PDB 3b6r.[1]
Identifiers
EC no.	2.7.3.2
CAS no.	9001-15-4
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / QuickGO
Search PMC articles PubMed articles NCBI proteins

Creatine kinase (CK), also known as creatine phosphokinase (CPK) or phosphocreatine kinase, is an enzyme (EC 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 cells of the retina, hair cells 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.[2] Thus creatine kinase is an important enzyme in such tissues.[3]

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 myositides, and acute kidney injury.[4]

Types

[edit]

In the cells, the cytosolic CK enzymes consist of two subunits, which can be either B (brain type) or M (muscle type). There are, therefore, three different isoenzymes: CK-MM, CK-BB and CK-MB. The genes for these subunits are located on different chromosomes: B on 14q32 and M on 19q13. In addition to those three cytosolic CK isoforms, there are two mitochondrial creatine kinase isoenzymes, the ubiquitous form and the sarcomeric form. The functional entity of the mitochondrial CK isoforms is an octamer consisting of four dimers each.[5]

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.

gene	protein
CKB	creatine kinase, brain, BB-CK
CKBE	creatine kinase, ectopic expression
CKM	creatine kinase, muscle, MM-CK
CKMT1A, CKMT1B	creatine kinase mitochondrial 1; ubiquitous mtCK; or umtCK
CKMT2	creatine kinase mitochondrial 2; sarcomeric mtCK; or smtCK

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

[edit]

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.,[6] followed by the structure of ubiquitous mitochondrial CK (u-mtCK) in 2000.[7][8] The atomic structure of the banana-shaped, dimeric cytosolic brain-type BB-CK was solved in 1999 at a resolution of 1,4 Å.[9] Cytosolic BB-CK, as well as muscle-type MM-CK both form banana-shaped symmetric dimers, with one catalytic active site in each subunit.[10]

Functions

[edit]

Mitochondrial creatine kinase (CKm) is present in the 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).[2]

Thus, CK enhances skeletal, cardiac, and smooth muscle contractility, and is involved in the generation of blood pressure.[11] Further, the ADP-scavenging action of creatine kinase has been implicated in bleeding disorders: persons with highly elevated plasma CK could be prone to major bleeding.[12]

Laboratory testing

[edit] Medical diagnostic method

Serum Creatine kinase
Reference range	60 and 400 IU/L
Purpose	Detection of muscle damage.[13]
Test of	The amount of creatine kinase in the blood.[13]

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/L,[14] 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.[15]) 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.[16] Furthermore, high CK in the blood may be related to high intracellular CK such as in persons of African descent.[17]

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;[18] and skeletal muscle diseases and disorders including malignant hyperthermia,[19] and neuroleptic malignant syndrome.[20]

Furthermore, the 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.

Nomenclature

[edit]

This enzyme is often listed in medical literature under incorrect name "creatinine kinase". Creatinine is not a substrate or a product of the enzyme.[21]

See also

[edit]

• Reference ranges for blood tests
• CPK-MB test

References

[edit]

1. ^ Bong SM, Moon JH, Nam KH, Lee KS, Chi YM, Hwang KY (November 2008). "Structural studies of human brain-type creatine kinase complexed with the ADP-Mg2+-NO3- -creatine transition-state analogue complex". FEBS Letters. 582 (28): 3959–65. Bibcode:2008FEBSL.582.3959B. doi:10.1016/j.febslet.2008.10.039. PMID 18977227. S2CID 21911841.
2. ^ a b Wallimann T, Wyss M, Brdiczka D, Nicolay K, Eppenberger HM (January 1992). "Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the 'phosphocreatine circuit' for cellular energy homeostasis". The Biochemical Journal. 281 ( Pt 1) (1): 21–40. doi:10.1042/bj2810021. PMC 1130636. PMID 1731757.
3. ^ Wallimann T, Hemmer W (1994). "Creatine kinase in non-muscle tissues and cells". Molecular and Cellular Biochemistry. 133–134 (1): 193–220. doi:10.1007/BF01267955. eISSN 1573-4919. PMID 7808454. S2CID 10404672.
4. ^ Moghadam-Kia S, Oddis CV, Aggarwal R (January 2016). "Approach to asymptomatic creatine kinase elevation". Cleveland Clinic Journal of Medicine. 83 (1): 37–42. doi:10.3949/ccjm.83a.14120. PMC 4871266. PMID 26760521.
5. ^ Schlattner U, Tokarska-Schlattner M, Wallimann T (February 2006). "Mitochondrial creatine kinase in human health and disease". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1762 (2): 164–80. doi:10.1016/j.bbadis.2005.09.004. PMID 16236486.
6. ^ Fritz-Wolf K., Schnyder T., Wallimann, T., & W. Kabsch 1996 http://publicationslist.org/data/theo.wallimann/ref-135/Fritz-Wolf-sMtCK%20structure.pdf Archived 2018-07-15 at the Wayback Machine
7. ^ 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 Archived 2018-07-15 at the Wayback Machine. Both mt-CK isoforms form octameric structures (built of 4 banana-like dimers) with a four-fold symmetry and a central channel.
8. ^ 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 Archived 2018-07-15 at the Wayback Machine
9. ^ Eder M, Schlattner U, Wallimann T, Becker A, Kabsch W, Fritz-Wolf K (2008-12-31). "Crystal structure of brain-type creatine kinase at 1.41 Å resolution". Protein Science. 8 (11). Wiley: 2258–2269. doi:10.1110/ps.8.11.2258. ISSN 0961-8368. PMC 2144193. PMID 10595529.
10. ^ Hornemann et al. 2000 http://publicationslist.org/data/theo.wallimann/ref-96/Hornmann-CK-dimer.pdf Archived 2018-07-15 at the Wayback Machine
11. ^ Brewster LM, Mairuhu G, Bindraban NR, Koopmans RP, Clark JF, van Montfrans GA (November 2006). "Creatine kinase activity is associated with blood pressure". Circulation. 114 (19): 2034–9. doi:10.1161/CIRCULATIONAHA.105.584490. PMID 17075013. S2CID 6006006.
12. ^ Brewster LM (June 2020). "Creatine Extracellular creatine kinase may modulate purinergic signalling". Purinergic Signalling. 16 (3): 305–312. doi:10.1007/s11302-020-09707-0. PMC 7524943. PMID 32572751.
13. ^ a b "Creatine Kinase (CK)". labtestsonline.org. Archived from the original on 2020-02-09. Retrieved 2019-12-24.
14. ^ Armstrong AW, Golan DE (2008). "Pharmacology of Hemostasis and Thrombosis". In Golan DE, Tashjian AH, Armstrong EJ, Armstrong AW (eds.). Principles of pharmacology: the pathophysiologic basis of drug therapy. Philadelphia: Lippincott Williams & Wilkins. p. 388. ISBN 978-0-7817-8355-2. OCLC 76262148.
15. ^ Bishop ML, Fody EP, Schoeff LE, eds. (2004). Clinical chemistry: principles, procedures, correlations. Philadelphia: Lippincott Williams & Wilkins. p. 243. ISBN 978-0-7817-4611-3. OCLC 56446391.
16. ^ Johnsen SH, Lilleng H, Wilsgaard T, Bekkelund SI (January 2011). "Creatine kinase activity and blood pressure in a normal population: the Tromsø study". Journal of Hypertension. 29 (1): 36–42. doi:10.1097/HJH.0b013e32834068e0. PMID 21063205. S2CID 7188988.
17. ^ Brewster LM, Coronel CM, Sluiter W, Clark JF, van Montfrans GA (2012-03-16). Saks V (ed.). "Ethnic differences in tissue creatine kinase activity: an observational study". PLOS ONE. 7 (3) e32471. Bibcode:2012PLoSO...732471B. doi:10.1371/journal.pone.0032471. PMC 3306319. PMID 22438879.
18. ^ Hekimsoy Z, Oktem IK (2005). "Serum creatine kinase levels in overt and subclinical hypothyroidism". Endocrine Research. 31 (3): 171–5. doi:10.1080/07435800500371706. PMID 16392619. S2CID 5619524.
19. ^ Johannsen S, Berberich C, Metterlein T, Roth C, Reiners K, Roewer N, Schuster F (May 2013). "Screening test for malignant hyperthermia in patients with persistent hyperCKemia: a pilot study". Muscle & Nerve. 47 (5): 677–81. doi:10.1002/mus.23633. PMID 23400941. S2CID 5126493.
20. ^ O'Dwyer AM, Sheppard NP (May 1993). "The role of creatine kinase in the diagnosis of neuroleptic malignant syndrome". Psychological Medicine. 23 (2): 323–6. doi:10.1017/s0033291700028415. PMID 8101383. S2CID 10818939.
21. ^ Nick Flynn (2021). "CK – What does it stand for?". American Journal of Emergency Medicine. 45: 647. doi:10.1016/j.ajem.2020.11.015. PMC 7656996. PMID 33214021.

External links

[edit]

• Simply stated at mdausa.org
• Creatine+Kinase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• CPK isoenzymes test MedlinePlus Encyclopedia: 003504
• CK at Lab Tests Online

v t e Mitochondrial proteins
Outer membrane	fatty acid degradation Carnitine palmitoyltransferase I Long-chain-fatty-acid—CoA ligase tryptophan metabolism Kynureninase monoamine neurotransmitter metabolism Monoamine oxidase
Intermembrane space	Adenylate kinase Creatine kinase
Inner membrane	oxidative phosphorylation Coenzyme Q – cytochrome c reductase Cytochrome c NADH dehydrogenase Succinate dehydrogenase pyrimidine metabolism Dihydroorotate dehydrogenase mitochondrial shuttle Malate-aspartate shuttle Glycerol phosphate shuttle steroidogenesis Cholesterol side-chain cleavage enzyme Steroid 11-beta-hydroxylase Aldosterone synthase other Glutamate aspartate transporter Glycerol-3-phosphate dehydrogenase ATP synthase Carnitine palmitoyltransferase II Uncoupling protein
Matrix	citric acid cycle Citrate synthase Aconitase Isocitrate dehydrogenase Oxoglutarate dehydrogenase complex Succinyl coenzyme A synthetase Fumarase Malate dehydrogenase anaplerotic reactions Aspartate transaminase Glutamate dehydrogenase Pyruvate dehydrogenase complex urea cycle Carbamoyl phosphate synthetase I Ornithine transcarbamylase N-Acetylglutamate synthase alcohol metabolism ALDH2 PMPCB
Other/to be sorted	Frataxin Mitochondrial membrane transport protein Mitochondrial permeability transition pore Mitochondrial carrier Translocator protein
Mitochondrial DNA	Complex I MT-ND1 MT-ND2 MT-ND3 MT-ND4 MT-ND4L MT-ND5 MT-ND6 Complex III MT-CYB Complex IV MT-CO1 MT-CO2 MT-CO3 ATP synthase MT-ATP6 MT-ATP8 tRNA MT-TA MT-TC MT-TD MT-TE MT-TF MT-TG MT-TH MT-TI MT-TK MT-TL1 MT-TL2 MT-TM MT-TN MT-TP MT-TQ MT-TR MT-TS1 MT-TS2 MT-TT MT-TV MT-TW MT-TY
see also mitochondrial diseases

v t e Metabolism: Protein metabolism, synthesis and catabolism enzymes
Essential amino acids are in Capitals
K→acetyl-CoA	LYSINE→ Saccharopine dehydrogenase Glutaryl-CoA dehydrogenase LEUCINE→ 3-Hydroxybutyryl-CoA dehydrogenase Branched-chain amino acid aminotransferase Branched-chain alpha-keto acid dehydrogenase complex Enoyl-CoA hydratase HMG-CoA lyase HMG-CoA reductase Isovaleryl coenzyme A dehydrogenase α-Ketoisocaproate dioxygenase Leucine 2,3-aminomutase Methylcrotonyl-CoA carboxylase Methylglutaconyl-CoA hydratase (See Template:Leucine metabolism in humans – this diagram does not include the pathway for β-leucine synthesis via leucine 2,3-aminomutase) TRYPTOPHAN→ Indoleamine 2,3-dioxygenase/Tryptophan 2,3-dioxygenase Arylformamidase Kynureninase 3-hydroxyanthranilate oxidase Aminocarboxymuconate-semialdehyde decarboxylase Aminomuconate-semialdehyde dehydrogenase PHENYLALANINE→tyrosine→ (see below)
G	G→pyruvate→citrate glycine→serine→ Serine hydroxymethyltransferase Serine dehydratase glycine→creatine: Guanidinoacetate N-methyltransferase Creatine kinase alanine→ Alanine transaminase cysteine→ D-cysteine desulfhydrase threonine→ L-threonine dehydrogenase G→glutamate→α-ketoglutarate HISTIDINE→ Histidine ammonia-lyase Urocanate hydratase Formiminotransferase cyclodeaminase proline→ Proline oxidase Pyrroline-5-carboxylate reductase 1-Pyrroline-5-carboxylate dehydrogenase/ALDH4A1 PYCR1 arginine→ Ornithine aminotransferase Ornithine decarboxylase Agmatinase →alpha-ketoglutarate→TCA Glutamate dehydrogenase Other cysteine+glutamate→glutathione: Gamma-glutamylcysteine synthetase Glutathione synthetase Gamma-glutamyl transpeptidase glutamate→glutamine: Glutamine synthetase Glutaminase G→propionyl-CoA→succinyl-CoA VALINE→ Branched-chain amino acid aminotransferase Branched-chain alpha-keto acid dehydrogenase complex Enoyl-CoA hydratase 3-hydroxyisobutyryl-CoA hydrolase 3-hydroxyisobutyrate dehydrogenase Methylmalonate semialdehyde dehydrogenase ISOLEUCINE→ Branched-chain amino acid aminotransferase Branched-chain alpha-keto acid dehydrogenase complex 3-hydroxy-2-methylbutyryl-CoA dehydrogenase METHIONINE→ generation of homocysteine: Methionine adenosyltransferase Adenosylhomocysteinase regeneration of methionine: Methionine synthase/Homocysteine methyltransferase Betaine-homocysteine methyltransferase conversion to cysteine: Cystathionine beta synthase Cystathionine gamma-lyase THREONINE→ Threonine aldolase →succinyl-CoA→TCA Propionyl-CoA carboxylase Methylmalonyl CoA epimerase Methylmalonyl-CoA mutase G→fumarate PHENYLALANINE→tyrosine→ Phenylalanine hydroxylase Tyrosine aminotransferase 4-Hydroxyphenylpyruvate dioxygenase Homogentisate 1,2-dioxygenase Fumarylacetoacetate hydrolase tyrosine→melanin: Tyrosinase G→oxaloacetate asparagine→aspartate→ Asparaginase/Asparagine synthetase Aspartate transaminase

v t e Clinical biochemistry blood tests
Electrolytes	Sodium Potassium Chloride Calcium Renal function Creatinine Urea BUN-to-creatinine ratio Plasma osmolality Serum osmolal gap
Acid-base	Anion gap Arterial blood gas Base excess Bicarbonate CO2 content Lactate
Iron tests	Ferritin Serum iron Transferrin saturation Total iron-binding capacity Transferrin Transferrin receptor
Hormones	ACTH stimulation test Thyroid function tests Thyroid-stimulating hormone
Metabolism	Blood glucose Hemoglobin A1c Lipid panel LDL HDL Triglycerides Total cholesterol Basic metabolic panel Comprehensive metabolic panel
Cardiovascular	Cardiac marker Troponin test CPK-MB test Lactate dehydrogenase Myoglobin Glycogen phosphorylase isoenzyme BB
Liver function tests	Proteins Human serum albumin Serum total protein ALP transaminases ALT AST AST/ALT ratio GGT Bilirubin Unconjugated Conjugated
Pancreas	Amylase Lipase Pancreatic lipase
Small molecules	Blood sugar level Hypoglycemia Hyperglycemia Nitrogenous Azotemia Hyperuricemia Hypouricemia
Proteins	LFT Elevated transaminases Elevated ALP Hypoproteinemia Hypoalbuminemia Hyperproteinemia Other Elevated alpha-fetoprotein

v t e Transferases: phosphorus-containing groups (EC 2.7)
2.7.1-2.7.4:phosphotransferase/kinase(PO4)	2.7.1: OH acceptor Hexo- Gluco- Fructo- Hepatic Galacto- Phosphofructo- 1 Liver Muscle Platelet 2 Riboflavin Shikimate Thymidine ADP-thymidine NAD+ Glycerol Pantothenate Mevalonate Pyruvate Deoxycytidine PFP Diacylglycerol Phosphoinositide 3 Class I PI 3 Class II PI 3 Sphingosine Glucose-1,6-bisphosphate synthase 2.7.2: COOH acceptor Phosphoglycerate Aspartate kinase Glutamate 5-kinase 2.7.3: N acceptor Creatine 2.7.4: PO4 acceptor Phosphomevalonate Adenylate Nucleoside-diphosphate Uridylate Guanylate Thiamine-diphosphate
2.7.6: diphosphotransferase(P2O7)	Ribose-phosphate diphosphokinase Thiamine diphosphokinase
2.7.7: nucleotidyltransferase(PO4-nucleoside)	Polymerase DNA polymerase DNA-directed DNA polymerase I/A γ θ ν T7 Taq II/B α δ ε ζ Pfu III/C IV/X β λ μ TDT V/Y η ι κ RNA-directed DNA polymerase Reverse transcriptase Telomerase RNA polymerase Template-directed RNA polymerase I II III IV V ssRNAP POLRMT Primase 1 2 PrimPol RNA-dependent RNA polymerase Polyadenylation PAP PNPase Phosphorolytic3' to 5' exoribonuclease RNase PH PNPase Nucleotidyltransferase UTP—glucose-1-phosphate uridylyltransferase Galactose-1-phosphate uridylyltransferase Guanylyltransferase mRNA capping enzyme Other Recombinase (Integrase) Transposase
2.7.8: miscellaneous	Phosphatidyltransferases CDP-diacylglycerol—glycerol-3-phosphate 3-phosphatidyltransferase CDP-diacylglycerol—serine O-phosphatidyltransferase CDP-diacylglycerol—inositol 3-phosphatidyltransferase CDP-diacylglycerol—choline O-phosphatidyltransferase Glycosyl-1-phosphotransferase N-acetylglucosamine-1-phosphate transferase
2.7.10-2.7.13: protein kinase(PO4; protein acceptor)	2.7.10: protein-tyrosine see tyrosine kinases 2.7.11: protein-serine/threonine see serine/threonine-specific protein kinases 2.7.12: protein-dual-specificity see serine/threonine-specific protein kinases 2.7.13: protein-histidine Protein-histidine pros-kinase Protein-histidine tele-kinase Histidine kinase

v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)

Portal:

• Biology