Creatine (methyl guanidine-acetic acid) – which is the Greek word for meat, was first identified in 1832 as a component of skeletal muscle by the French scientist, Michel Eugène Chevreul. Phosphocreatine was discovered about a hundred years later (1927) with the observation that its levels changed between resting and contracting muscle [1,2]. Phosphorylation of creatine (Cr) to phosphocreatine (PCr) and back catalyzed by the creatine kinase enzymes (CK, EC 18.104.22.168) is crucial for the supply of high energy phosphates (Fig. 1) in tissues and cells with high and fluctuating energy demands like skeletal and cardiac muscle, brain, spermatozoa and photoreceptor cells . The ATP/ADP ratio, local concentrations of ATP, ADP and AMP are amongst key regulators influencing numerous metabolic processes, reviewed in , as such it doesn’t suffice to merely increase the levels of ATP in these tissues. An example of this can be found in neurons, where the rate of ATP hydrolysis can be increased by several orders of magnitude within seconds for their energy needs, however their intracellular ATP levels remain surprisingly constant. This led to the concept of the stability paradox  which purports that there are … “immediately available, fast and efficiently working energy supporting and back-up systems that connect sites of energy consumption to those of energy production via phosphoryl transfer networks” (reviewed in ). In this regard, it is believed that the Cr/PCr/CK system has evolved to play a major role in the regulation of intracellular energy metabolism. CK is the only existing phosphagen kinase in vertebrates, with at least five subunit isoforms that are expressed in a tissueand cell- specific manner with defined subcellular locations; a brain type (CK-B), a muscle type (CK-M), a hetero-dimeric heart type (MB-CK) and two mitochondrial creatine kinases (mt-CK) that exist as homo-octamers (a sarcomeric mt-CK and a ubiquitously expressed mt-CK) [4,7]. It has long been recognized that efficient energy metabolism requires the close spatial organization of the enzymes generating ATP, co-localization of sites of ATP synthesis with sites of ATP consumption, and the sustained delivery of high energy phosphates to ATPases in cases where ATP generation is separated from consumption . The primary mode of regulation of the CK isoenzymes is by subcellular compartmentation (enabling the functional coupling of the CK reaction to various cellular ATPases) and Cr/PCr due to their relatively smaller size when compared to ATP/ADP as well as their superior concentrations in cytosol (ATP, 3-5mM; ADP, 20-40µM; Cr, 5-10mM; PCr, 20-35mM)  by definition (Fick’s law) have a higher diffusion coefficient. Taken together, this renders the Cr/PCr/CK system very effective in providing sudden and sufficiently high concentrations of high energy phosphates during conditions of rapid ATP hydrolysis. In summary; Cr/PCr are most suited to act as shuttle molecules between sites of ATP hydrolysis (ATPases) and sites of ATP production (glycolysis and mitochondrial oxidative phosphorylation) or the CK/PCr system can be directly coupled to ATPases to regenerate ATP from ADP (Fig. 1).
Updated on June 25, 2020