Creatine, function

Figure 2.14(A). A summary of the classical role of creatine phosphokinase (CPK) in buffering ATP concentrations during change in tissue energy demand. This view of creatine function assumes that the cytosol is analogous to a simple aqueous solution and it assumes that CPK has access to the complete intracellular pool of phosphocreatine (PCr) and creatine (Cr) at all times.

Creatine functions as a phosphagen in muscle. Neither the small amount of ATP in muscle nor the speed with which metabolic activity can be increased, and hence ADP be rephosphorylated, matches the demand for ATP for rapid or sustained muscle contraction. Muscle contains a relatively large amount... 

Description of Method. Creatine is an organic acid found in muscle tissue that supplies energy for muscle contractions. One of its metabolic products is creatinine, which is excreted in urine. Because the concentration of creatinine in urine and serum is an important indication of renal function, rapid methods for its analysis are clinically important. In this method the rate of reaction between creatinine and picrate in an alkaline medium is used to determine the concentration of creatinine in urine. Under the conditions of the analysis, the reaction is first-order in picrate, creatinine, and hydroxide. 

Mitochondria are surrounded by a simple outer membrane and a more complex inner membrane (Figure 21.1). The space between the inner and outer membranes is referred to as the intermembrane space. Several enzymes that utilize ATP (such as creatine kinase and adenylate kinase) are found in the intermembrane space. The smooth outer membrane is about 30 to 40% lipid and 60 to 70% protein, and has a relatively high concentration of phos-phatidylinositol. The outer membrane contains significant amounts of porin —a transmembrane protein, rich in /3-sheets, that forms large channels across the membrane, permitting free diffusion of molecules with molecular weights of about 10,000 or less. Apparently, the outer membrane functions mainly to... 

Wallimann, T., Wyss. M., Brdicza, D., Nicolay, K.. Eppenberger, H.M. (1992). Intracellular compartmentation. structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands The phosphocreatine circuit for cellular energy homeostasis. Biochem. J. 281,21-40. 

Figure 31-3. Arginine, ornithine, and proline metabolism. Reactions with solid arrows all occur in mammalian tissues. Putrescine and spermine synthesis occurs in both mammals and bacteria. Arginine phosphate of invertebrate muscle functions as a phosphagen analogous to creatine phosphate of mammalian muscle (see Figure 31-6).

Niacin requires baseline tests of liver function (alanine aminotransferase), uric acid, and glucose. Repeat tests are appropriate at doses of 1,000 to 1,500 mg/day. Symptoms of myopathy or diabetes should be investigated and may require creatine kinase or glucose determinations. Patients with diabetes may require more frequent monitoring. 

Miller, J. W Kleven, D. T., Domin, B. A., and Fremau Jr., R. T. (1997) Cloned sodium-land chloride-) dependent high affinity transporters for GABA, glycine, proline, betaine, taurine, and creatine, in Neurotransmitter Transporters Structure, Function, and Regulation (Reith, M. E. A., ed.). Humana Press, Totowa, NJ, pp. 101-150. 

Weidle, U.H., Borgya, A., Mattes, R., Lenz, H., and Buckel, R, Reconstitution of functionally active antibody directed against creatine kinase from separately expressed heavy and light chains in non-lymphoid cells. Gene, 51, 21-29, 1987. 

A number of clinical tests are available to detect kidney damage. The clinician examining a patient or the toxicologist monitoring an animal toxicity stndy collects urine and blood samples. Indications of kidney damage (which, of course, for the human patient could be related to many factors other then chemical toxicity) include urinary excretion of excessive amonnts of proteins and glucose, and excessive levels in the blood of unexcreted waste products such as urea and creatine. A number of additional kidney function tests are available to help pin down the location of kidney dysfunction. 

In the muscle, phosphocreatine and creatine undergo cyclisation to form creatinine (Figure 8.20(b)). Since creatinine cannot be metabohsed, it is released from muscle and is then excreted in the urine. This biochemical process is useful in clinical practice, since creatinine production is spontaneous and is remarkably constant 1.7% of the phosphocreatine and creatine in muscle cyclises each day, so that its concentration in blood provides an indication of the glomerular filtration rate, and hence provides an indication of the function (i.e. the health) of the kidney. 

Undemutrition decreases the levels of ATP and phospho-creatine in muscle which affects function, but they return to normal levels with adequate energy intake (Table 18.3). The store of glutamine in muscle is also decreased. 

Uric acid is the end product of the purine metabolism. When uric acid excretion via the kidneys is disturbed, gout can develop (see p. 190). Creatinine is derived from the muscle metabolism, where it arises spontaneously and irreversibly by cyclization of creatine and creatine phosphate (see p. 336). Since the amount of creatinine an individual excretes per day is constant (it is directly proportional to muscle mass), creatinine as an endogenous substance can be used to measure the glomerular filtration rate. The amount of amino acids excreted in free form is strongly dependent on the diet and on the ef ciency of liver function. Amino acid derivatives are also found in the urine (e.g., hippu-rate, a detoxification product of benzoic acid). 

Skeletal muscle effects The use of fibrates alone, including fenofibrate, may occasionally be associated with myopathy. Treatment with drugs of the fibrate class has been associated on rare occasions with rhabdomyolysis, usually in patients with impaired renal function. Consider myopathy in any patient with diffuse myalgias, muscle tenderness or weakness, or marked elevations of creatine phosphokinase levels. 

Adverse events occurring in at least 3% include abnormal liver function tests, increased ALT and AST, increased creatine phosphokinase, respiratory disorder, abdominal pain, back pain, headache. 

Myopathy and neuropathy Colchicine myoneuropathy appears to be a common cause of weakness in patients on standard therapy who have elevated plasma levels caused by altered renal function. It is often unrecognized and misdiagnosed as polymyositis or uremic neuropathy. Proximal weakness and elevated serum creatine kinase are generally present, and resolve in 3 to 4 weeks following drug withdrawal. Maiabsorption of vitamin B-f2- Colchicine induces reversible malabsorption of vitamin B-12, apparently by altering the function of ileal mucosa. 

Alternatives to FDG for detecting viable myocardium are based on myocardial leak of creatine phos-phokinase, inosine, inorganic phosphate [100-103] due to impaired cell membrane function induced by ischemia and/or necrosis. Therefore, the use of a potassium analogue reflecting myocardial cellular membrane function and the myocardial potassium space represents an alternative for a quantitative assessment of... 

Exploration of Bulk Tolerance. Most affinity labels contain functional groups added to the substrate s basic structure. Discerning just where added bulk can be tolerated by the enzyme is therefore crucial information. In the case of creatine, it has been determined (92,93) that the structures below, for example, are good substitutes for creatine in the creatine-kinase reaction... 

E. Therapeutic response Activase, and other thrombolytic agents, used in a timely manner during an evolving myocardial infarction, decrease mortality and improve left ventricular function. Resolution of chest pain, resolution of baseline EKG changes, reduced total creatine phospho-kinase (CPK) release, and preserved left ventricular function are evidence of cardiac reperfusion. Activase, administered within the first 3 hours of ischemic stroke onset, has been shown to improve recovery. 

A compound that includes a carbonyl group on the imidazoline ring is described as sedative. Treatment of the guanidyl substituted amino acid creatine (87-1) with hydrochloric acid results in cyclization to the iminoimidazolinone creatinine (87-2). Condensation of that intermediate with meta-chlorophenylisocyanate (87-3) leads to the formation of a urea by condensation of the reactive function with the imidazole as its amino tautomer. There is thus obtained fenobam (87-4) [92]. 

ATP -I- creatine = ADP + phosphocreatine (N-ethylglycocyamine can also act as acceptor mitochondrial enzymes, mechanism, overview [1] <5> enzyme is functionally coupled to ouabain-inhibited (Na, K )-ATPase [30] <5> kinetic model of reaction [33] <6> mechanism [55,76])... 

Schlegel, J. Zurbriggen, B. Wegmann, G. Wyss, M. Eppenberger, H.M. Wallimann, T. Native mitochondrial creatine kinase forms octameric structures. I. Isolation of two interconvertible mitochondrial creatine kinase forms, dimeric and octameric mitochondrial creatine kinase characterization, localization, and structure-function relationships. J. Biol. Chem., 263, 16942-16953 (1988)... 

---