Lactate dehydrogenase inhibitors

Allicin as a lactate dehydrogenase inhibitor is noteworthy. It is an ephemeral compound released when raw garlic is crushed or chewed. The half-life is said to be only 4 hours, so it cannot be routinely obtained in capsule or pill form, although its garlic-derived precursor can be thus obtained, with allicin released during assimilation. 

A primary requirement is that any substance or compoimd used as a lactate dehydrogenase inhibitor should at the same time be nontoxic for other body functions, espedally of the liver and kidneys. It may be noted in this context that most substances or compounds tend to be nonselective, that is, they may inhibit more than one enzyme. This nonselectivity produces the so-called adverse side effects. The encompassing term is cytotoxicity, or cell toxicity, indicating that the... 

Excitotoxic lesions generated in primates using NMDA receptor agonists such as quinolinic acid cause neuronal loss similar to that found in HD, emphasizing, the potential role of excitotoxicity in HD. Intrastriatal injections of the reversible succinate dehydrogenase inhibitor, malonate, into rats caused a decrease in ATP levels and increased lactate and excitotoxic lesions, which could be prevented by NMDA antagonists. 

One of the first measures of how strongly hydrogen bonds can be reflected in isotope effects was the experimental determination of the oxygen isotope effect on binding of an inhibitor, oxamate, to lactate dehydrogenase.7 The inverse isotope effect... 

The aqueous layer is 98% to 99% water combined with electrolytes, glucose, urea, trace elements, and soluble proteins and mucins. It contains immunoglobulins (primarily IgA), lactate dehydrogenase, epidermal growth factor, and inhibitors of proteolytic activity. Protective substances in tears include lactoferrin, lysozyme, nonlysozyme antibacterial fector, complement and anticomplement factor and interferon, and immimoglobulins... 

The activity of the ATP-forming enzyme complex V is usually assessed by determining the reverse reaction ATP — ADP + Pi. The reaction is coupled to reactions catalyzed by pyruvate kinase (ADP + phosphoenolpyruvate —> pyruvate + ATP) and lactate dehydrogenase (pyruvate + NADH — lactate -F NAD+). This final reaction can be followed spectrophotometrically by measuring NADH at 340 nm. The activity of complex V (ATPase) can be derived from the rate of NADH conversion in the presence and absence of the specific complex V inhibitor oligomycin. 

Table 1 Summary of respiratory chain, complex V and PDHc activity assays. All assays are spectrophotometric assays except for the PDHc assay with CO2 detection, which is a radiochemical assay. The specific inhibitor indicated is used for blank measurements. Non-standard abbreviations UQi nbiquinone-Qi DQ decylubiquinone DCIP 2,6-dichlorophenolindophenol, PK pyruvate kinase LDH lactate dehydrogenase AABS / -[p-(aminophenyl)azo]benzene sulfonic acid ArAt arylamine acetyltransferase...

Dando, C., Schroeder, E. R., Hunsaker, L. A., Deck, L. M., Royer, R. E., Zhou, X., Parmley, S. F., and Vander Jagt, D. L. (2001). The kinetic properties and sensitivities to inhibitors of lactate dehydrogenases (LDH1 and LDH2) from Toxoplasma gondii Comparisons with pLDH from Plasmodium falciparum. Mol. Biochem. Parasitol. 118, 23-32. 

It was discovered in 1958 that anaerobically grown yeast contains a form of lactate dehydrogenase which is different from the d- and L-lac-tate cytochrome c reductases of aerobic yeast (306, 319). The enzyme has been partially purified (320, 321), and shown to contain flavin (320-322). Gel filtration studies have suggested a molecular weight of about 100,000 (320, 321). Preparations of the enzyme oxidize several d-2-hydroxyacids to the respective keto acids in a reversible manner (320). For the forward reaction, ferricyanide, 2,6-dichloroindophenol, menadione, and methylene blue have been used as electron acceptors, and for the reverse reaction leucomethyl viologen and FMNHa are effective electron donors (320). A number of L-2-hydroxyacids and 2-keto acids have been shown to be competitive inhibitors. Oxalate, cyanide, o-phenanthro-line, and EDTA are also potent inhibitors (320, 321, 323, 324). The inhibition by metal chelators develops slowly and is reversed by addition of Zn, Co, Mn +, or Fe + (320, 323-326). Substrates prevent the inhibition by chelators at concentrations considerably lower than their respective Km values (327). It has been suggested that EDTA inactivation involves the removal of a metal, most probably Zn +, from the substrate binding site of the enzyme (325, 326, 328, 329). However, others have... 

Mercury is a reactive element and its toxicity is probably due to interaction with proteins. Mercury has a particular affinity for sulphydryl groups in proteins and consequently is an inhibitor of various enzymes such as membrane ATPase, which are sulphydryl dependent. It can also react with amino, phosphoryl and carboxyl groups. Brain pyruvate metabolism is known to be inhibited by mercury, as are lactate dehydrogenase and fatty acid synthetase. The accumulation of mercury in lysosomes increases the activity of lysomal acid phosphatase which may be a cause of toxicity as lysosomal damage releases various hydrolytic enzymes into the cell, which can then cause cellular damage. Mercury accumulates in the kidney and is believed to cause uncoupling of oxidative phsophorylation in the mitochondria of the kidney cells. Thus, a number of mitochondrial enzymes are inhibited by Hg2+. These effects on the mitochondria will lead to a reduction of respiratory control in the renal cells and their functions such as solute reabsorption, will be compromised. 

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