Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.3.3.1 (citrate synthase)
 4,488 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fatty acids are the preferred substrate of ischemic, reperfused myocardium and may account for the decreased cardiac efficiency during aerobic recovery. Neonatal cardiac myocytes in culture respond to hypoxia/serum- and glucose-free medium by a slow decline in ATP which reverses upon oxygenation. This model was employed to examine whether carnitine palmitoyltransferase I (CPT-I) modulates high rates of beta-oxidation following oxygen deprivation. After 5 h of hypoxia, ATP levels decline to 30% control values and CPT-I activity is significantly stimulated in hypoxic myocytes with no alteration in cellular carnitine content or in the release of the mitochondrial matrix marker, citrate synthase. This stimulation was attributed to an increase in the affinity of hypoxic CPT-I for carnitine, suggesting that the liver CPT-I isoform is more dominant following hypoxia. However, there was no alteration in hypoxic CPT-I inhibition by malonyl-CoA. DNP-etomoxiryl-CoA, a specific inhibitor of the liver CPT-I isoform, uncovered identical Michaelis kinetics of the muscle isoform in control and hypoxic myocytes with activation of the liver isoform. Northern blotting did not reveal any change in the relative abundance of mRNA for the liver vs. the muscle CPT-I isoforms. The tyrosine phosphatase inhibitor, pervanadate, reversed the hypoxia-induced activation of CPT-I and returned the affinity of cardiac CPT-I for carnitine to control. Reoxygenation was also associated with a return of CPT-I activity to control levels. The data demonstrate that CPT-I is activated upon ATP depletion. Lower enzyme activities are present in control and reoxygenated cells where ATP is abundant or when phosphatases are inhibited. This is the first suggestion that phosphorylation may modulate the activity of the liver CPT-I isoform in heart.
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PMID:The liver isoform of carnitine palmitoyltransferase I is activated in neonatal rat cardiac myocytes by hypoxia. 954 43

Matrix metalloproteinases (MMPs) have recently become interesting as potential anticancer drugs. RO-28-2653 is a promising compound because of its antimetastatic and antiangiogenic activities. Due to the structural similarity of RO-28-2653 to mitochondriotoxic agents, speculation has arisen that this substance might impair mitochondrial function. We, therefore, investigated the effects of RO-28-2653 on mitochondrial enzymes and on the functional properties of isolated mitochondria and skinned muscle fibers from rat hearts. Results were compared to the action of amytal and 2,4-dinitrophenol (2,4-DNP), both of which are well documented mitochondriotoxic compounds. In contrast to 2,4-DNP, RO-28-2653 did not uncouple oxidative phosphorylation, although higher concentrations of the compound did impair mitochondrial function. Using malate/pyruvate as substrate, 50 microM of RO-28-2653 inhibited mitochondrial respiration in isolated mitochondria and skinned fibers by 23 and 11%, respectively while 2mM of amytal elicited almost complete inhibition of the mitochondrial respiration. RO-28-2653 (50 micro) inhibited succinate-dependent respiration in both systems by 43 and 24%, respectively while 2mM of amytal caused 41 and 23% inhibition, respectively. There was no change in the ADP/O ratios. RO-28-2653 (50 microM) did not significantly alter the activity of the respiratory chain complexes or succinate dehydrogenase, although citrate synthase (CS) was inhibited by upto 71%. This inhibition was non-competitive at a K(i) of 25+/-5 microM. Inhibitory effects in the presence of hydrophobic substances, such as BSA and Triton X-100, were significantly lower in both test systems. In conclusion, high concentrations of RO-28-2653 impair mitochondrial function, although compared to amytal and 2,4-DNP, this is rather low. The resultant impairment is less pronounced in the more complex skinned muscle fiber system, and is dependent on hydrophobic interactions.
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PMID:Effect of the new matrix metalloproteinase inhibitor RO-28-2653 on mitochondrial function. 1199 41