Critical Reviews in Biochemistry and Molecular Biology, 40:1–20, 2005 Copyright  c Taylor & Francis Inc. ISSN: 1040-9238 print / 1549-7798 online DOI: 10.1080/10409230590918577 Relating Structure to Mechanism in Creatine Kinase Michael J. McLeish and George L. Kenyon College of Pharmacy, University of Michigan, Ann Arbor, MI, USA ABSTRACT Found in all vertebrates, creatine kinase catalyzes the reversible reaction of creatine and ATP forming phosphocreatine and ADP. Phosphocre- atine may be viewed as a reservoir of “high-energy phosphate” which is able to supply ATP, the primary energy source in bioenergetics, on demand. Conse- quently, creatine kinase plays a significant role in energy homeostasis of cells with intermittently high energy requirements. The enzyme is of clinical im- portance and its levels are routinely used as an indicator of myocardial and skeletal muscle disorders and for the diagnosis of acute myocardial infarction. First identified in 1928, the enzyme has undergone intensive investigation for over 75 years. There are four major isozymes, two cytosolic and two mitochon- drial, which form dimers and octamers, respectively. Depending on the pH, the enzyme operates by a random or an ordered bimolecular mechanism, with the equilibrium lying towards phosphocreatine production. Evidence suggests that conversion of creatine to phosphocreatine occurs via the in-line transfer of a phosphoryl group from ATP. A recent X-ray structure of creatine kinase bound to a transition state analog complex confirmed many of the predictions based on kinetic, spectroscopic, and mutagenesis studies. This review summarizes and correlates the more significant mechanistic and structural studies on creatine kinase. KEYWORDS energy homeostasis, guanidino kinase, myocardial infarction, phosphagen kinase, phosphoryl group transfer, transition-state analogue complex, X-ray structure INTRODUCTION Creatine kinase (CK; adenosine-5 ′ -triphosphate:creatine phosphotrans- ferase; creatine phosphokinase; phosphocreatine phosphokinase; creatine N -phosphotransferase; EC 2.7.3.2) catalyzes the reversible transfer of a phos- phoryl group from MgATP to creatine (Cr), producing phosphocreatine (PCr) and MgADP (Figure 1). Phosphocreatine was initially identified in muscle tissue (Eggleton & Eggleton, 1928). At that time, it was thought to be the chemical source for the energy required for muscle contraction. However, not long after, the en- zyme now known as creatine kinase was first identified (Lohman, 1934), and it was subsequently shown that ATP was formed by transfer of a phosphoryl Editor: Michael M. Cox Address correspondence to Michael J. McLeish, College of Pharmacy, University of Michigan, 428 Church St., Ann Arbor, MI. E-mail: mcleish@umich.edu 1 Critical Reviews in Biochemistry and Molecular Biology Downloaded from informahealthcare.com by 118.187.37.242 on 05/20/14 For personal use only.