Enzyme sulfhydryl groups

Coumarin, the lactone of o-hydroxycinnamic acid, and some of its derivatives have been isolated from many plant species 31). Thimann and Bonner 141) attributed the growth-inhibiting effects of coumarin to its action on enzyme sulfhydryl groups. Inhibitory effects of coumarin on Avena coleoptiles and pea stem sections could be overcome by 2,3-dimercaptopropanol (BAL). Coumarin has also been reported to disrupt mitosis 29,30). 

In a mechanism involving nucleophilic catalysis, the enzyme would promote nucleophilic attack on the carbonyl carbon to produce a tetrahedral intermediate. In this intermediate, resonance stabilization of the C-N bond has been destroyed and the barrier to rotation about the C-N bond greatly reduced. Collapse of the tetrahedral intermediate with expulsion of nucleophile can produce either the cis or trans Xaa-Pro peptide. In the original work on PPI (Fischer et ai, 1984), results were presented that indicated that an enzyme sulfhydryl group was required for activity. This result was later interpreted to support a mechanism involving nucleophilic catalysis (Fischer et ai, 1989a,b). 

Lewisite-induced vesicant and systemic toxicity are likely due, in part, to interactions with thiol groups (Goldman and Dacre, 1989). The interaction with enzyme sulfhydryl groups may cause inhibition of enzyme by the formation of stable cyclic stmctures with arsenic. These thiol interactions result in energy depletion leading to cell death (Young, 1999). 

Confirmatory evidence for this structure has come from experiments in which citric acid was synthesized from acetyl-CoA and oxaloacetic acid in the presence of the condensing enzyme. Sulfhydryl groups equivalent to the citrate synthesized were released (Stern, 1951). 

When an inhibitor is found to be very much more tightly bound than a substrate, it is important to inquire whether its high affinity is based on a resemblance to activated intermediates in catalysis, or to factors which may be irrelevant to the mechanism (e.g., reaction of enzyme sulfhydryl groups with organic mercurial inhibitors). Among other criteria, the structure of the inhibitor should possess features that would be expected to distinguish activated intermediates from the substrates themselves. 

M. J. Ernest, K. H. Kim, Regulation of rat liver glycogen synthetase D. Rote of glucose 6-phosphate and enzyme sulfhydryl groups in activity and glycogen binding J. Biol. Chem. 249 1974,5011-8. 

All the individual steps are catalyzed by enzymes NAD" (Section 15 11) is required as an oxidizing agent and coenzyme A (Figure 26 16) is the acetyl group acceptor Coen zyme A is a thiol its chain terminates m a sulfhydryl (—SH) group Acetylation of the sulfhydryl group of coenzyme A gives acetyl coenzyme A... 

We can descnbe the major elements of fatty acid biosynthesis by considering the for mation of butanoic acid from two molecules of acetyl coenzyme A The machinery responsible for accomplishing this conversion is a complex of enzymes known as fatty acid synthetase Certain portions of this complex referred to as acyl carrier protein (ACP), bear a side chain that is structurally similar to coenzyme A An important early step m fatty acid biosynthesis is the transfer of the acetyl group from a molecule of acetyl coenzyme A to the sulfhydryl group of acyl carrier protein... 

Mode of Action. The fundamental biochemical lesion produced by arsenicals is the result of reaction between As " and the sulfhydryl groups of key respiratory enzymes such as pymvate and a-ketoglutarate dehydrogenases. 

Disulfides. As shown in Figure 4, the and h-chains of insulin are connected by two disulfide bridges and there is an intrachain cycHc disulfide link on the -chain (see Insulin and other antidiabetic drugs). Vasopressin [9034-50-8] and oxytocin [50-56-6] also contain disulfide links (48). Oxidation of thiols to disulfides and reduction of the latter back to thiols are quite common and important in biological systems, eg, cysteine to cystine or reduced Hpoic acid to oxidized Hpoic acid. Many enzymes depend on free SH groups for activation—deactivation reactions. The oxidation—reduction of glutathione (Glu-Cys-Gly) depends on the sulfhydryl group from cysteine. 

A comparison of the structures of penicillin and Dalanyl-Dalanine (cf. structures 41 and 42) shows that there is a great deal of similarity between the two molecules. Penicillin is essentially an acylated cyclic dipeptide of Dcysteine and Dvaline (84). As such, it contains a peptide bond, that of the /3-lactam ring, that can acylate the enzyme. Labeling studies of the peptidoglycan transpeptidase of Bacillus subtilis indicate that radioactive penicillin reacts with a sulfhydryl group of a cysteine residue of the enzyme (86). 

Indirect evidence for the existence of different conformations of H,K-ATPase has been gained by site-selective reagents. Eor example, Schrijen et al. [67,95] demonstrated that Mg increased exposure of an essential arginine residue near the ATP-binding site and Mg " caused an increase in the number of reactive sulfhydryl groups on the enzyme. 

Heavy metals with no known biological function, such as aluminum, arsenic, lead, and mercury, are nonessential metals.4-5 These metals are toxic because they can irreversibly bind to enzymes that require metal cofactors. Toxic metals readily bind to sulfhydryl groups of proteins.6-7 In fact,... 

Hepatic 0.0015 0.005 (decreased glycogen, RNA, sulfhydryl groups, alterations in activities of oxidizing enzymes) ... 

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