Creatine kinase, inhibition

Reddy, S.R.R. Watts, D.C. Inhibition of creatine kinase by iodoalkanes. Further appraisal of the essential nature of the reactive thiol group. Bio-chim. Biophys. Acta, 569, 109-113 (1979)... 

Cercken, C. During, V. Inhibition of creatine kinase by creatinine phosphate. FEBS Lett., 46, 87-91 (1974)... 

Didanosine is a synthetic purine nucleoside analog that inhibits the activity of reverse transcriptase in HIV-1, HIV-2, other retroviruses and zidovudine-resistant strains. A nucleobase carrier helps transport it into the cell where it needs to be phosphorylated by 5 -nucleoiidase and inosine 5 -monophosphate phosphotransferase to didanosine S -monophosphate. Adenylosuccinate synthetase and adenylosuccinate lyase then convert didanosine 5 -monophosphate to dideoxyadenosine S -monophosphate, followed by its conversion to diphosphate by adenylate kinase and phosphoribosyl pyrophosphate synthetase, which is then phosphorylated by creatine kinase and phosphoribosyl pyrophosphate synthetase to dideoxyadenosine S -triphosphate, the active reverse transcriptase inhibitor. Dideoxyadenosine triphosphate inhibits the activity of HIV reverse transcriptase by competing with the natural substrate, deoxyadenosine triphosphate, and its incorporation into viral DNA causes termination of viral DNA chain elongation. It is 10-100-fold less potent than zidovudine in its antiviral activity, but is more active than zidovudine in nondividing and quiescent cells. At clinically relevant doses, it is not toxic to hematopoietic precursor cells or lymphocytes, and the resistance to the drug results from site-directed mutagenesis at codons 65 and 74 of viral reverse transcriptase. 

K20. Konorev, E. A., Hogg, N., and Kalyanaraman, B., Rapid and irreversible inhibition of creatine kinase by peroxynitrite. FEBS Lett. 427, 171—174 (1998). 

Further processes involving AMPK include phosphorylation of creatine kinase (GK) (P-CK being less active and thus maximizing ATP levels for immediate use) phosphorylation of hydroxymethylglutarylCoA reductase (ElMGGoAR) (P-ElMGCoAR being inhibited... 

Schimerlik MI, Cleland WW. Inhibition of creatine kinase by chromium nucleotides. J. Biol. Chem. 1973 248 8418-8423. 

EDTA, probably by chelation of metallic cofactors, inhibits alkaline phosphatase, creatine kinase, and leucine aminopeptidase activities. Because it chelates calcium and iron, EDTA is unsuitable for specimens for calcium and iron analyses using photometric or titrimetric techniques. As an... 

Sodium lodoacetate at a concentration of 2 g/L is an effective antiglycolytic agent and a substitute for sodium fluoride. Because it has no effect on urease, it can be used when glucose and urea tests are performed on a single specimen. It inhibits creatine kinase but appears to have no notable effects on other clinical tests. 

Some phenomena of enzyme activation or inhibition are caused by interaction between the modifier and a nonenzy-matic component of the reaction system, such as the substrate (e.g., Mg combining with ATP to form MgATP, the required substrate for the creatine kinase reaction). In most cases, however, the modifier combines with the enzyme itself in a manner analogous to the combination of enzyme and substrate. 

Ezetimibe is used for secondary prevention against established atherosclerotic CVD to achieve an optimal atherogenic cholesterol level in patients with intolerance to high-doses of statins. It can further be used in combination with statins to achieve lower LDL-C levels in very-high-risk patients [59]. Ezetimibe inhibits the Niemann-Pick Cl-Like 1 (NPClLl)-dependent intestinal cholesterol absorption in the apical brush border membrane of jejuna enterocytes [14], and thus it only moderately lowers LDL-C (12-25 %) [60]. Meanwhile, common adverse effects associated with ezetimibe therapy include gastrointestinal disturbances, while infrequent adverse effects such as rash, angioedema, anaphylaxis, hepatitis, cholelithiasis, cholecystitis, thrombocytopenia, raised creatine kinase, myopathy, and rhabdomyolysis may occur [46]. 

Isoquinolinesulfonamides have been selected for broad kinase inhibition by occupying the ATP-binding sites. The probes exhibited indeed specific labeling of several purified kinases including hexokinase and creatine kinase. 

An immunostirrer for the determination of creatine kinase (CK) isoenyzme MB based on alkylamine glass-immobilized anti-IgG antibody has been proposed by Yuan et al. (1981). By binding of creatine kinase to antibody, only the CK-M subunit but not the CK-B subunit is inhibited. The remaining CK-B activity was measured by electrochemical oxidation of ferrocyanide formed in the following coupled reaction ... 

Since metal coordination or immobilization of the transferred phosphoryl group by multiple hydrogen bonds would inhibit the formation of a metaphosphate intermediate in an S l mechanism and would facilitate nucleophilic attack in an Sy2 mechanism, the latter process seems likely for the reactions catalyzed by staphylococcal nuclease, DNA polymerase, pyruvate kinase, fructose diphosphatase, phosphoglucomutase, (Na + K) ATPase and possibly PEP carboxylase. In creatine kinase where an S l mechanism is possible, the enzyme would have to prevent access of nucleophiles other than ADP and creatine to the reactive metaphosphate intermediate. 

The diaphragm is similar to the heart in that it also responds rhythmically to stimulation. After a brief potentiation of muscle twitch, CN (0.1-1 mM) causes a slow progressive depression of contractility of the rat diaphragm. Potentiation is due to an increase in pH from replenishment of ATP by phosphocreatine (creatine kinase mediated transphosphorylation of ADP to ATP). Inhibition of muscle twitch is due to lactate accumulation as well as increased Pj and increased [Mg ] from breakdown of magnesium phosphocreatine. No decreases in ATP or action potential generation were caused by CN treatment in rat diaphragms. Because skeletal muscle,... 

C. A. Broyles, Creatine Kinase Isoenzymes Determination by Selective Inhibition and by Flow Injection Analysis. Diss. Abstr. Int. B, 46 (1985) 1144. 

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