Creatine kinase

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Creatine kinase
3b6r.png
Crystal structure of human brain-type creatine kinase with ADP and creatine. PDB 3b6r . [1]
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EC no. 2.7.3.2
CAS no. 9001-15-4
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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.

Contents

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]

Creatine-Kinase.svg

Types

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.

geneprotein
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

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] Both mt-CK isoforms form octameric structures (built of 4 banana-like dimers) with a four-fold symmetry and a central channel. [8] [9] [7] The atomic structure of the banana-shaped, dimeric cytosolic brain-type BB-CK was solved in 1999 at a resolution of 1,4  Å. [10] Cytosolic BB-CK, as well as muscle-type MM-CK both form banana-shaped symmetric dimers, with one catalytic active site in each subunit. [11]

Functions

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. [12] 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. [13]

Laboratory testing

Serum Creatine kinase
Reference range 60 and 400 IU/L
PurposeDetection of muscle damage. [14]
Test ofThe amount of creatine kinase in the blood. [14]

CK is often determined routinely in a medical laboratory. It used to be determined specifically in patients with chest pain, but this test has been replaced by troponin. Normal values at rest are usually between 60 and 400 IU/L, [15] 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. [16] ) 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. [17] Furthermore, high CK in the blood may be related to high intracellular CK such as in persons of African descent. [18]

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; [19] and skeletal muscle diseases and disorders including malignant hyperthermia, [20] and neuroleptic malignant syndrome. [21]

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.

Reference ranges for blood tests, comparing blood content of creatine kinase (shown in orange, to left of ammonia [yellow]) with other constituents. Blood values sorted by mass and molar concentration.png
Reference ranges for blood tests, comparing blood content of creatine kinase (shown in orange, to left of ammonia [yellow]) with other constituents.

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. [22]

See also

Related Research Articles

<span class="mw-page-title-main">Adenosine triphosphate</span> Energy-carrying molecule in living cells

Adenosine triphosphate (ATP) is a nucleotide that provides energy to drive and support many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms of life, ATP is often referred to as the "molecular unit of currency" of intracellular energy transfer. When consumed in metabolic processes, it converts either to adenosine diphosphate (ADP) or to adenosine monophosphate (AMP). Other processes regenerate ATP. It is also a precursor to DNA and RNA, and is used as a coenzyme. A human adult processes around 50 kg of ATP daily.

<span class="mw-page-title-main">Glycolysis</span> Series of interconnected biochemical reactions

Glycolysis is the metabolic pathway that converts glucose into pyruvate and, in most organisms, occurs in the liquid part of cells. The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH). Glycolysis is a sequence of ten reactions catalyzed by enzymes.

Phosphagens, also known as macroergic compounds, are high energy storage compounds, also known as high-energy phosphate compounds, chiefly found in muscular tissue in animals. They allow a high-energy phosphate pool to be maintained in a concentration range, which, if it all were adenosine triphosphate (ATP), would create problems due to the ATP-consuming reactions in these tissues. As muscle tissues can have sudden demands for much energy, these compounds can maintain a reserve of high-energy phosphates that can be used as needed, to provide the energy that could not be immediately supplied by glycolysis or oxidative phosphorylation. Phosphagens supply immediate but limited energy.

The muscular system is an organ system consisting of skeletal, smooth, and cardiac muscle. It permits movement of the body, maintains posture, and circulates blood throughout the body. The muscular systems in vertebrates are controlled through the nervous system although some muscles can be completely autonomous. Together with the skeletal system in the human, it forms the musculoskeletal system, which is responsible for the movement of the body.

<span class="mw-page-title-main">Creatine</span> Chemical compound

Creatine is an organic compound with the nominal formula (H2N)(HN)CN(CH3)CH2CO2H. It exists in various tautomers in solutions. Creatine is found in vertebrates where it facilitates recycling of adenosine triphosphate (ATP), primarily in muscle and brain tissue. Recycling is achieved by converting adenosine diphosphate (ADP) back to ATP via donation of phosphate groups. Creatine also acts as a buffer.

<span class="mw-page-title-main">Sarcomere</span> Repeating unit of a myofibril in a muscle cell

A sarcomere is the smallest functional unit of striated muscle tissue. It is the repeating unit between two Z-lines. Skeletal muscles are composed of tubular muscle cells which are formed during embryonic myogenesis. Muscle fibers contain numerous tubular myofibrils. Myofibrils are composed of repeating sections of sarcomeres, which appear under the microscope as alternating dark and light bands. Sarcomeres are composed of long, fibrous proteins as filaments that slide past each other when a muscle contracts or relaxes. The costamere is a different component that connects the sarcomere to the sarcolemma.

<span class="mw-page-title-main">Phosphocreatine</span> Chemical compound

Phosphocreatine, also known as creatine phosphate (CP) or PCr (Pcr), is a phosphorylated form of creatine that serves as a rapidly mobilizable reserve of high-energy phosphates in skeletal muscle, myocardium and the brain to recycle adenosine triphosphate, the energy currency of the cell.

<span class="mw-page-title-main">AMP-activated protein kinase</span> Class of enzymes

5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme that plays a role in cellular energy homeostasis, largely to activate glucose and fatty acid uptake and oxidation when cellular energy is low. It belongs to a highly conserved eukaryotic protein family and its orthologues are SNF1 in yeast, and SnRK1 in plants. It consists of three proteins (subunits) that together make a functional enzyme, conserved from yeast to humans. It is expressed in a number of tissues, including the liver, brain, and skeletal muscle. In response to binding AMP and ADP, the net effect of AMPK activation is stimulation of hepatic fatty acid oxidation, ketogenesis, stimulation of skeletal muscle fatty acid oxidation and glucose uptake, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipogenesis, inhibition of adipocyte lipolysis, and modulation of insulin secretion by pancreatic β-cells.

Substrate-level phosphorylation is a metabolism reaction that results in the production of ATP or GTP supported by the energy released from another high-energy bond that leads to phosphorylation of ADP or GDP to ATP or GTP (note that the reaction catalyzed by creatine kinase is not considered as "substrate-level phosphorylation"). This process uses some of the released chemical energy, the Gibbs free energy, to transfer a phosphoryl (PO3) group to ADP or GDP. Occurs in glycolysis and in the citric acid cycle.

<span class="mw-page-title-main">Bioenergetic systems</span> Metabolic processes for energy production

Bioenergetic systems are metabolic processes that relate to the flow of energy in living organisms. Those processes convert energy into adenosine triphosphate (ATP), which is the form suitable for muscular activity. There are two main forms of synthesis of ATP: aerobic, which uses oxygen from the bloodstream, and anaerobic, which does not. Bioenergetics is the field of biology that studies bioenergetic systems.

<span class="mw-page-title-main">CKMT1B</span> Protein and coding gene in humans

Creatine kinase, mitochondrial 1B also known as CKMT1B is one of two genes which encode the ubiquitous mitochondrial creatine kinase.

<span class="mw-page-title-main">CKMT2</span> Protein and coding gene in humans

Creatine kinase S-type, mitochondrial is an enzyme that in humans is encoded by the CKMT2 gene.

<span class="mw-page-title-main">Theo Wallimann</span>

Theo Wallimann is a Swiss biologist who was research group leader and Adjunct-Professor at the Institute of Cell Biology ETH Zurich and later at the Institute of Molecular Health Science at the ETH Zurich at the Biology Department, of the ETH Zurich, Switzerland.

Creatine kinase U-type, mitochondrial, also called ubiquitous mitochondrial creatine kinase (uMtCK), is in humans encoded by CKMT1A gene. CKMT1A catalyzes the reversible transfer of the γ-phosphate group of ATP to the guanidino group of Cr to yield ADP and PCr. The impairment of CKMT1A has been reported in ischaemia, cardiomyopathy, and neurodegenerative disorders. Overexpression of CKMT1A has been reported related with several tumors.

<span class="mw-page-title-main">CKM (gene)</span> Protein and coding gene in humans

Creatine kinase, muscle also known as MCK is a creatine kinase that in humans is encoded by the MCK gene.

<span class="mw-page-title-main">CKB (gene)</span> Protein and coding gene in humans

Brain-type creatine kinase also known as CK-BB is a creatine kinase that in humans is encoded by the CKB gene.

<span class="mw-page-title-main">CPK-MB test</span> Cardiac marker

The CPK-MB test, also known as CK-MB test, is a cardiac marker used to assist diagnoses of an acute myocardial infarction, myocardial ischemia, or myocarditis. It measures the blood level of CK-MB, the bound combination of two variants of the enzyme phosphocreatine kinase.

<span class="mw-page-title-main">Purine nucleotide cycle</span>

The Purine Nucleotide Cycle is a metabolic pathway in protein metabolism requiring the amino acids aspartate and glutamate. The cycle is used to regulate the levels of adenine nucleotides, in which ammonia and fumarate are generated. AMP converts into IMP and the byproduct ammonia. IMP converts to S-AMP (adenylosuccinate), which then converts to AMP and the byproduct fumarate. The fumarate goes on to produce ATP (energy) via oxidative phosphorylation as it enters the Krebs cycle and then the electron transport chain. Lowenstein first described this pathway and outlined its importance in processes including amino acid catabolism and regulation of flux through glycolysis and the Krebs cycle.

<span class="mw-page-title-main">ATP:guanido phosphotransferase family</span>

In molecular biology, the ATP:guanido phosphotransferase family is a family of structurally and functionally related enzymes, that reversibly catalyse the transfer of phosphate between ATP and various phosphagens. The enzymes belonging to this family include:

<span class="mw-page-title-main">Creatine phosphate shuttle</span> Intracellular energy shuttle in muscles

The creatine phosphate shuttle is an intracellular energy shuttle which facilitates transport of high energy phosphate from muscle cell mitochondria to myofibrils. This is part of phosphocreatine metabolism. In mitochondria, Adenosine triphosphate (ATP) levels are very high as a result of glycolysis, TCA cycle, oxidative phosphorylation processes, whereas creatine phosphate levels are low. This makes conversion of creatine to phosphocreatine a highly favored reaction. Phosphocreatine is a very-high-energy compound. It then diffuses from mitochondria to myofibrils.

References

  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. doi:10.1016/j.febslet.2008.10.039. PMID   18977227. S2CID   21911841.
  2. 1 2 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 et al. 1996 http://publicationslist.org/data/theo.wallimann/ref-135/Fritz-Wolf-sMtCK%20structure.pdf
  7. 1 2 Eder et al. 2000 http://publicationslist.org/data/theo.wallimann/ref-101/Eder-X-ray.uMtCK.pdf
  8. ↑ Schnyder et al. 1990 http://publicationslist.org/data/theo.wallimann/ref-184/Schnyder%201990%20Crystallization%20and%20preliminary%20X-ray%20of%20MtCk%20J%20Mol%20Biol.pdf
  9. ↑ Schnyder et al. 1991 http://publicationslist.org/data/theo.wallimann/ref-180/SchnyderT_Gross-MtCK-crystal-EMs.pdf
  10. ↑ 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. Wiley. 8 (11): 2258–2269. doi:10.1110/ps.8.11.2258. ISSN   0961-8368. PMC   2144193 . PMID   10595529.
  11. ↑ Hornemann et al. 2000 http://publicationslist.org/data/theo.wallimann/ref-96/Hornmann-CK-dimer.pdf
  12. ↑ 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.
  13. ↑ 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.
  14. 1 2 "Creatine Kinase (CK)". labtestsonline.org. Retrieved 2019-12-24.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ Nick Flynn. "CK – What does it stand for?". American Journal of Emergency Medicine. doi:10.1016/j.ajem.2020.11.015.
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