CK

Creatine kinase (CK, EC 2.7.3.2), also known as creatine phosphokinase, is an enzyme catalyzing the phosphorylation of creatine. CK utilizes adenosine triphosphate (ATP) to reversibly produce phosphocreatine (PCr) and adenosine diphosphate (ADP). Therefore, ATP can be regenerated from PCr and ADP. CK is expressed by various tissues and cell types, mainly found in skeletal muscle, cardiac muscle, and the brain, bladder, stomach, and colon. The ubiquity of CK in many tissues causes a poor specificity. In tissues and cells that consume ATP rapidly, especially skeletal muscle, PCr functions 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. CK is of great importance in skeletal muscle energy metabolism. CK concentration could be elevated by muscle necrosis or disease. Therefore, CK is clinically assayed as a marker of damage of CK-rich tissue and may also be measured to evaluate myopathy.

Figure 1. CK catalyzes the phosphorylation of creatine. (Bais R; et al. 1982)

Types

There are multiple types of CK coded by different genes. CK is a dimer consisting of subunits from either muscle (M) or brain (B). CK mainly exists as three isoenzymes with greatest activity in muscle (CK-MM), heart (CK-MB), and brain (CK-BB). The genes for these subunits are located on different chromosomes: B on 14q32 and M on 19q13. CK isoenzymes have been reported with variable distribution between tissues and species. Skeletal muscle expresses CK-MM (98%) and low levels of CK-MB (1%). In contrast, the myocardium (heart muscle) expresses CK-MM at 70% and CK-MB at 25–30%. CK-BB is predominantly produced in brain and smooth muscle, including vascular and uterine tissue. Normal serum CK is predominantly CK-MM isoenzyme and serum CK concentrations are reflection of muscle mass, which causes males to have higher concentrations than females. CK–MB isoenzyme is found almost in myocardium and the CK–MB level elevation in serum is highly specific and sensitive to myocardial cell wall injury. Additional forms of the CK enzyme are present in mitochondria (mtCK), the ubiquitous and sarcomeric form, which are octamers consisting of four dimers each. These different forms are essential to manage the energy reservoir in many different cell types. Although these forms of CK differ in their amino acid structure, their function remains similar. Slight functional subtleties allow CK to operate in different environments.

Structure

CK is a specific chain of amino acids, whose proper fold takes on a three-dimensional form, enabling CK to interact with certain molecules. The amino acids in CK are specific because, when folded, they increase the interaction ability of CK with both creatine and PCr, thus showing superiority to them over other molecules. Another site on CK is dedicated for interaction with ATP and ADP. Since both molecules could attach to CK, phosphate group from ATP can be added to creatine or phosphate group from PCr can be transferred to ADP, resulting in either the creation or usage of ATP.

A number of genuine CK structures have been identified through high-resolution electron microscopy and protein X-ray crystallography. The first X-ray structure of a CK family member solved was that of sarcomeric muscle-type mitochondrial CK, later followed by the structure of ubiquitous u-mtCK. Both mitochondrial CK isoforms possesses highly symmetrical octameric structures with 4-fold symmetry. Cytosolic CK-BB and muscle-type CK-MM form banana-shaped symmetric dimers with one active site in each subunit.

Functions

The mitochondrial CK exists in the mitochondrial intermembrane space, where it regenerates PCr from ATP generated by mitochondria and creatine imported from cytosol. Mitochondrial CK and cytosolic CK are connected in a so-called PCr/Cr-shuttle or circuit. PCr produced by mtCK in mitochondria is shuttled to cytosolic CK that is coupled to ATP-dependent processes, such as sodium/potassium ATPase related with sodium retention in the kidney as well as acto-myosin ATPase and calcium ATPase involved in muscle contraction. The bound cytosolic CK could accept the PCr shuttled through the cell and employs ADP to regenerate ATP, which can then be used as energy source by ATPases. CK is intimately associated with ATPases to form a functionally coupled microcompartment. PCr acts as not only an energy buffer but also a cellular energy transport form between subcellular sites of ATP production (mitochondria and glycolysis) and ATPases. Thereby, CK enhances the contractility of skeletal, cardiac, and smooth muscle, and is implicated in the generation of blood pressure.

Laboratory Testing

CK is often determined routinely in a medical laboratory. Normal values at rest are usually between 60 and 174 IU/L, where one unit is the amount of enzyme catalyzing1 μmol of substrate per minute under specified conditions. CK levels in the blood may be high in health and disease. Exercise increases the outflow of CK to the blood stream for up to a week, which is the most common cause of high CK in blood. High CK in the blood may also be an indication of damage of CK-rich tissue, such as in myocardial infarction, rhabdomyolysis, myositis and myocarditis. This means blood CK may be elevated in a wide variety of clinical conditions including the use of medication; endocrine disorders, skeletal muscle diseases and neuroleptic malignant syndrome. Furthermore, the isoenzyme determination has been extensively applied as a signal for myocardial damage in heart attacks.

Reference

1. Bais R, Edwards J B. Creatine kinase. Crit Rev Clin Lab Sci, 1982, 16(4):291-335.