Creatine kinase

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Creatine kinase
Creatine kinase
Model of the brain-type creatine kinase (CK-BB isozyme) of the domestic chicken ( Gallus gallus domesticus ), from PDB  1qh4 . The X-ray structure of the chicken BB-CK is the molecular structure of a member of the family of so-called phosphagen kinases that has been determined with the highest resolution (1.41  Å ). The dimer is reminiscent of the shape of a banana.

Existing structural data : 1QH4 1CRK 1G0W 1VRP 1U6R 2CRK 2GL6 3B6R 3DRB

Mass / length primary structure 380 amino acids
Secondary to quaternary structure Homodimer, heterodimer
Isoforms BB, MB, MM
Identifier
Gene name (s) CKB , CKM creatine kinase
External IDs
Enzyme classification
EC, category 2.7.3.2 ,  kinase
Response type Phosphorylation
Substrate Creatine
Products Phosphocreatine
Occurrence
Homology family Guanidokinase
Parent taxon Creature

The creatine kinase (also known as CK , CPK , creatine phosphokinase or creatine kinase hereinafter) is an enzyme , the N-phosphoryl group from phosphocreatine to adenosine diphosphate ( ADP transmits) ( phosphorylation is indicative of kinases ). With this enzymatic reaction, adenosine triphosphate ( ATP ), the universal source of energy in all cells, is regenerated. The enzyme is found mainly in all muscle cells and in the brain, but also in the kidneys, testes, sperm and retina, etc. There are four isoenzymes : CK-MM (skeletal muscle type), CK-MB (myocardial type), CK-BB (brain type) and CK-MiMi or mt-CK (mitochondrial type).

The enzyme is often referred to as creatine in kinase . Creatinine , however, is only the breakdown product of creatine contained in urine .

Physiological importance

ATP is particularly important in organisms as a source of energy, but also as a signaling molecule. ATP can be obtained from ADP both by substrate chain phosphorylation and by electron transport phosphorylation (respiratory chain). However, in many tissues with a high energy requirement, for example in skeletal muscles , energy is not exclusively stored in the form of ATP, since the high ATP concentrations required for this would disrupt the ATP-dependent metabolic processes of the cells. Instead, there are high concentrations of the phosphagen, phosphocreatine, whose group transfer potential is so high that it can phosphorylate ADP to ATP. In the case of short-term high energy requirements, ATP can be obtained more quickly through this reaction, which is catalyzed by creatine kinase, than through oxidative phosphorylation. The creatine kinase / phosphocreatine system thus acts as a short-term energy buffer. Furthermore, the phosphorylation of ADP to ATP reduces the intracellular ADP and proton concentration, which counteracts the inactivation of cellular ATPases and acidification of the cytosol when there is a high energy requirement. By localizing creatine kinases in places of high ATPase activity, the local ATP / ADP ratio is also increased in order to increase the thermodynamic efficiency of ATP hydrolysis.

Furthermore, the creatine kinase / phosphocreatine system not only serves as an energy buffer, but also for energy transport. In the mitochondria, a compartment with comparatively high ATP concentrations, creatine is phosphorylated by the mitochondrial isoform of creatine kinase while consuming ATP. The phosphocreatine produced in the process then diffuses to places with a high energy requirement, where it is converted back into creatine by other isoforms of creatine kinase with ATP production.

Atomic structure of the cytosolic and mitochondrial creatine kinase (CK) isoenzymes

The high-resolution structures of various creatine kinase (CK) isoforms could be solved at the atomic level in a cooperation between the two research groups of Theo Wallimann at ETH Zurich and Wolfgang Kabsch at the Max Planck Institute for Medical Research in Heidelberg. The first atomic structure of a creatine kinase that could be solved by X-ray structure analysis of crystallized CK was the sarcomeric (muscle-type) mitochondrial CK (s-mtCK) in 1996, followed by the ubiquitous mitochondrial CK (u-mtCK) 2000 In the crystal, both mitochondrial CK isoforms form octameric structures with 4-fold symmetry. The atomic structure of the banana-shaped, dimeric, cytosolic brain type (brain-type) BB-CK could be solved in 1999 with a resolution of 1.4  Å . Each CK monomer in the dimer contains its own enzymatically active center.

Creatine Kinase in Diagnostics

The total CK is the sum of the four isoenzymes (see above). Because total CK is usually measured in a N- acetylcysteine stabilized manner, the abbreviation CK-NAC is often used to describe total CK activity .

An increase in CK activity in the blood suggests a heart or skeletal muscle disease in which muscle cells have been damaged. The CK is therefore an important enzyme for the diagnosis of those damage to the heart and skeletal muscles that are associated with an increase in CK. The level of a CK increase and the size of the infarct correlate with one another. Since it is difficult to distinguish between cardiac and other muscle damage from the activity of the CK, troponin is used more and more frequently for heart attack diagnosis. If the CK-MB value is greater than 6 percent of the total CK, it is assumed that the myocardium has been damaged. Before it was possible to determine the troponin, a CK-MB increase> 10% together with a characteristic EKG finding or characteristic complaints was considered reliable evidence of an infarction.

The active center of a monomer of a human creatine kinase (brain type). ATP (red), the magnesium ion (green), nitrate (turquoise) and creatine (blue) are shown. This transition state analog is surrounded by a series of amino acids in the active site. These include: valine -92 and 325, glutamic acid -232, arginine -236, 130, 132 and 292, histidine -191, 192 and 66.
Crystals under the microscope. The creatine kinase here comes from rabbits.

Laboratory diagnostics

In laboratory diagnostics, the CK activity is determined from the plasma or serum in the case of suspected cardiac or skeletal muscle diseases. The measurement of CK activity in the context of heart attack diagnosis is no longer necessary today, however, since better tests such as troponin T / I or CK-MB mass (= CK-MB concentration) are available.

Reference range for measurements at 37 ° C according to IFCC (U = enzyme unit , given per liter (l))

  • Women: <145 U / l,
  • Men: <170 U / l.

Children:

  • 0d - 1d: <712 U / l
  • 2d - 5d: <652 U / l
  • 6d - 6m: <295 U / l
  • 7m - 11m: <203 U / l
  • 1a - 3a: <228 U / l
  • 4a - 6a: <149 U / l
  • 7a - 12a:
female: <154 U / l
male: <247 U / l
  • 13a - 17a:
female: <123 U / l
male: <270 U / l

In general muscle diseases, such as progressive muscular dystrophy , post-polio syndrome or myositis , the CK activity is greatly increased to over 25,000 U / l. During a heart attack, the CK activity is usually below 7500 U / l.

In intensive, eccentric (negative, yielding) strength training, EMS training and in top endurance sports, values ​​in the range of 20,000 to 45,000 are often measured, usually two or three days after exercise. An increased value can therefore also be attributed to previous training, whereby a value above 10,000 U / l can lead to kidney failure .

Strength training exercises such as B. deep squats, deadlifts and pull-ups or rowing movements and endurance sports, which put a lot of stress on the large muscles, quickly increase the CK values ​​to values ​​beyond 1000 U / l.

After operations, injections ( intramuscular ) and injuries in which muscle cells are affected, the CK activity also increases. Here the activity depends on the size of the injury.

Drugs such as statins and fibrates can also affect the concentration of CK in the blood.

See also

Individual evidence

  1. ↑ a b M. Eder, U. Schlattner, A. Becker, T. Wallimann, W. Kabsch, K. Fritz-Wolf: Crystal structure of brain-type creatine kinase at 1.41 A resolution. In: Protein science: a publication of the Protein Society. Volume 8, number 11, November 1999, pp. 2258-2269, doi : 10.1110 / ps.8.11.2258 , PMID 10595529 , PMC 2144193 (free full text).
  2. ^ A b U. Schlattner, M. Tokarska-Schlattner, T. Wallimann: Mitochondrial creatine kinase in human health and disease . In: Biochim. Biophys. Acta . 1762, No. 2, February 2006, pp. 164-180. doi : 10.1016 / j.bbadis.2005.09.004 . PMID 16236486 .
  3. ^ T. Wallimann et al.: The Phosphocreatine Circuit: Molecular and Cellular Physiology of Creatine Kinases, Sensitivity to Free Radicals, and Enhancement by Creatine Supplementation. In: Valdur Saks (Ed.): Molecular System Bioenegetics. Wiley 2007, ISBN 978-3-527-31787-5 .
  4. ^ A b T. Wallimann, M. Wyss, D. Brdiczka, K. Nicolay, HM Eppenberger: Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: The 'phosphocreatine circuit' for cellular energy homeostasis . In: The Biochemical Journal . 281 (Pt.1), 1992, pp. 21-40. PMID 1731757 . PMC 1130636 (free full text).
  5. ↑ Fritz-Wolf et al. 1996 http://publicationslist.org/data/theo.wallimann/ref-135/Fritz-Wolf-sMtCK%20structure.pdf
  6. ↑ Eder et al. 2000 http://publicationslist.org/data/theo.wallimann/ref-101/Eder-X-ray.uMtCK.pdf
  7. ↑ 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
  8. ↑ Schnyder et al. 1991 http://publicationslist.org/data/theo.wallimann/ref-180/SchnyderT_Gross-MtCK-crystal-EMs.pdf
  9. ↑ Eder et al. 2000 http://publicationslist.org/data/theo.wallimann/ref-101/Eder-X-ray.uMtCK.pdf
  10. ↑ Hornemann et al. 2000 http://publicationslist.org/data/theo.wallimann/ref-96/Hornmann-CK-dimer.pdf
  11. ↑ CK-MB mass, synonym CK-MB concentration. (No longer available online.) In: Clinical chemistry, preanalytics, examinations (list of services). Ulm University Hospital, September 10, 2013, archived from the original on April 2, 2015 ; Retrieved April 1, 2015 . Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. @1@ 2Template: Webachiv / IABot / www.uniklinik-ulm.de

literature

  • Neumeister, Besenthal, Liebrich: Clinical guidelines for laboratory diagnostics. Urban & Fischer, Munich / Jena, 2003, ISBN 3-437-22231-7 .
  • Lothar Thomas: Laboratory and Diagnosis. TH-Books, Frankfurt am Main 2005, ISBN 3-9805215-5-9 .
  • T. Wallimann, M. Wyss, D. Brdiczka, K. Nicolay, HM Eppenberger: Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the 'phosphocreatine circuit' for cellular energy homeostasis . In: Biochem. J. . 281 (Pt 1), January 1992, pp. 21-40. PMID 1731757 . PMC 1130636 (free full text).
  • G. Schumann, R. Bonora, F. Ceriotti et al: IFCC primary reference procedures for the measurement of catalytic activity concentrations of enzymes at 37 degrees C. Part 2. Reference procedure for the measurement of catalytic concentration of creatine kinase . In: Clin. Chem. Lab. Med. . 40, No. 6, June 2002, pp. 635-642. doi : 10.1515 / CCLM.2002.110 . PMID 12211662 .
  • T. Wallimann, M. Tokarska-Schlattner, U. Schlattner: The creatine kinase system and pleiotropic effects of creatine. In: Amino Acids. 40, No. 5, May 2011, pp. 1271-1296, doi: 10.1007 / s00726-011-0877-3 .
  • FR Clara: Hypothyroidism as the cause of the CPK-MM increase in cardiac patients. In: Switzerland. Med. Wchschr. December 1976.
  • William Graham Wood, Udo Kramer: Re .: Correction to the IFCC primary reference method for the measurement of catalytic activity concentration of enzymes at 37C- part 2: reference procedure for the measurement of creatine kinase . In: Clinical Chemistry and Laboratory Medicine . tape 42 , no. 3 , 2004, p. 635-642 , doi : 10.1515 / CCLM.2004.063 .

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