Thiols, enzyme inhibition

Garlic s proven mechanisms of action include (a) inhibition of platelet function, (b) increased levels of two antioxidant enzymes, catalase and glutathione peroxidase, and (c) inhibition of thiol enzymes such as coenzyme A and HMG coenzyme A reductase. Garlic s anti-hyperlipidemic effects are believed to be in part due to the HMG coenzyme A reductase inhibition since prescription medications for hyperlipidemia have that mechanism of action (statins). It is unknown whether garlic would have the same drug interactions, side effects, and need for precautions as the statins. 

Analyses of enzyme reaction rates continued to support the formulations of Henri and Michaelis-Menten and the idea of an enzyme-substrate complex, although the kinetics would still be consistent with adsorption catalysis. Direct evidence for the participation of the enzyme in the catalyzed reaction came from a number of approaches. From the 1930s analysis of the mode of inhibition of thiol enzymes—especially glyceraldehyde-phosphate dehydrogenase—by iodoacetate and heavy metals established that cysteinyl groups within the enzyme were essential for its catalytic function. The mechanism by which the SH group participated in the reaction was finally shown when sufficient quantities of purified G-3-PDH became available (Chapter 4). 

This enzyme [EC 3.4.13.3] (also referred to as Xaa-His dipeptidase, X-His dipeptidase, aminoacylhistidine dipeptidase, and homocarnosinase), is a zinc-dependent dipeptidase that catalyzes the hydrolysis of Xaa-His dipeptides. Carnosine, homocarnosine, and anserine are preferred substrates for this mammalian cytosolic enzyme. Other aminoacylhistidine dipeptides are weaker substrates (including homoanserine). The enzyme is activated by thiols and inhibited by metal-chelating agents. O. W. Griffith (1986) Ann. Rev. Biochem. 55, 855. 

Monoamine oxidase (MAO) (E.C. 1.4.3.4) is an enzyme found in all tissues and almost all cells, bound to the outer mitochondrial membrane. Its active site contains flavine adenine dinucleotide (FAD), which is bound to the cysteine of a -Ser-Gly-Gly-Cys-Tyr sequence. Ser and Tyr in this sequence suggest a nucleophilic environment, and histidine is necessary for the activity of the enzyme. Thiol reagents inhibit MAO. There are at least two classes of MAO binding sites, either on the same molecule or on different isozymes. They are designated as MAO-A, which is specific for 5-HT (serotonin) as a substrate, and MAO-B, which prefers phenylethylamine. Similarly, MAO inhibitors show a preference for one or the other active site, as discussed below. 

The cellular injury, which underlies target organ toxicity, may result from various underlying events primary, secondary, and tertiary events. Primary events result from initial damage, for example, lipid peroxidation, enzyme inhibition, covalent binding to crucial macromolecules, ischemia, and changes in thiol status. 

The important primary events that underlie cellular injury are lipid peroxidation, covalent binding, changes in thiol status, enzyme inhibition, and ischemia. 

In a recent study, some authors proposed the employment of thiolated polymers obtained by the immobilization of thiol groups on well-established multifunctional polymers such as poly(acrylates) and chitosans as functional agents having mucoadhesive, penetration enhancement, and enzyme-inhibiting properties [94,95]. 

Chen Q, Ngui JS, Doss GA, et al. Cytochrome P450 3A4-mediated bioactivation of raloxifene irreversible enzyme inhibition and thiol adduct formation. Chem Res Toxicol 2002 15(7) 907-914. 

R3MX are the most poisonous in the R4 MX (M = Sn, Pb) series this is also observed for the isostructural compounds of silicon . The toxic action of compounds of tin and lead is similar. Derivatives of R3MX inhibit oxidative phosphorylation, whereas R2MX2 binds thiol enzymes groups. Fungicidal activity of trialkylstannane R3MX derivatives is maximal when the number of carbon atoms is 9 in all three R substituents. On the whole, the toxicity of organic compounds of tin and lead decreases as the bulk of the substituents about the central metal atom increases. 

Mackworth JR (1948). The inhibition of thiol enzymes by lachrymators. Biochem J, 42, 82-90. 

It is generally accepted that the basis of the biological activity of mercury compounds is their reaction with the thiol groups, but the biological action is rather more complicated. Frank (1955) showed that mercury compounds can influence the effect of enzymes which do not contain thiol groups. Mercury also reacts with the phosphoryl groups of the cell membranes (Bassow et a/., 1961) and with the amino and carboxyl groups of the enzymes (Lipscomb et al., 1968). Webb (1966) lists more than 40 enzymes inhibited by mercury compounds. 

Another possible biochemical mechanism of action for copper complex action is based upon the report that copper decreased the permeability of human synovial lysosomes obtained from arthritic patients by oxidizing membrane thiols to disulphides and, as a result, decreased the release of free lysosomal enzymes [80]. Membrane stabilization as opposed to lysosomal enzyme inhibition is also consistent with the observation that many copper complexes, with the exception of Cu(II)(niflumate)2, failed to inhibit cathepsin-D, a lysosomal proteinase [647]. 

At the molecular level, AS2O3 reacts with thiols to inhibit a variety of enzymes related to the cancer growth. High concentrations act on mitochondria in a thiol-dependent manner to induce cell apoptosis. 

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