Creatine kinase



Creatine kinase (CK), also known as creatine phosphokinase (CPK) or phospho-creatine kinase (and sometimes incorrectly as creatinine kinase), is an enzyme expressed by various tissues and cell types. CK catalyses the conversion of creatine and consumes adenosine triphosphate (ATP) to create phosphocreatine (PCr) and adenosine diphosphate (ADP). This CK enzyme reaction is reversible, such that also 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. Thus creatine kinase is an important enzyme in such tissues.

Clinically, creatine kinase is assayed in blood tests as a marker of myocardial infarction (heart attack), rhabdomyolysis (severe muscle breakdown), muscular dystrophy, the autoimmune myositides and in acute renal failure.

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 and sarcomeric form. The functional entity of the latter two mitochondrial CK isoforms is an octamer consisting of four dimers each.

While mitochondrial creatine kinase is directly involved in formation of phospho-creatine from mitochondrial ATP, cytosolic CK regenerate 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.

Isoenzyme patterns differ in tissues. CK-BB occurs mainly in tissues, and its levels do rarely have any significance in bloodstream. 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 expressed in all tissues at low levels and has little clinical relevance.

Functions
The mitochondrial creatine kinase (CKm) is present in the mitochondrial intermembrane space, where it produces Phospho-Creatine (PCr) from mitochondrially-generated ATP and imported creatine (Cr) 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, like acto-myosin ATPase for muscle contraction, or ion pumps, like the calcium pump for muscle relaxation. There, the bound cytosolic CK is accepting the PCr shuttled through the cell and converts it to ATP, thus regenerating the ATP used as energy source by the ATPases in vivo, where CK is associated intimately with the ATPases, forming a functionally coupled microcompartment. Thus 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).

Laboratory testing
CK is often determined routinely in emergency patients. In addition, it is determined specifically in patients with chest pain or if acute renal failure is suspected. Normal values are usually between 60 and 400 IU/L, 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. This test is not specific for the type of CK that is elevated.

Elevation of CK is an indication of damage to muscle. It is therefore indicative of injury, rhabdomyolysis, myocardial infarction, myositis and myocarditis. The use of statin medications, which are commonly used to decrease serum cholesterol levels, may be associated with elevation of the CPK level in about 1% of the patients taking these medications, and with actual muscle damage in a much smaller proportion.

Lowered CK can be an indication of alcoholic liver disease and rheumatoid arthritis.

Isoenzyme determination has 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.



Math Model

 * Math Model
 * Detailed Enzyme Kinetics in Terms of Biochemical Species: Study of Citrate Synthase