Disease relevance of Dimercaprol butyrate

• [figure: see text] A thioesterase, isolated from a strain of Alcaligenes sp. ISH108, chemoselectively hydrolyzes thiol esters [1].
• 5. It is concluded that the actual substrates of the dehydration are the corresponding thiol esters [2].
• The number of functional thiol esters, however, was reduced in alpha(2)-macroglobulin purified from the multiple sclerosis patients, an observation compatible with the impaired proteinase binding property [3].
• Temperature-dependent biosynthesis of thiol esters in baculovirus recombinant alpha 2M and PZP [4].

High impact information on Dimercaprol butyrate

• Assays of hsUbc6e(S184D) and hsUbc6e(S184E), which mimic the phosphorylated state, suggest that phosphorylation may reduce capacity for forming ubiquitin-enzyme thiol-esters [5].
• Addition of exogenous E1 resulted in an increase in ubiquitin conjugation activity and in the levels of ubiquitin carrier protein (E2)-ubiquitin thiol esters in both the untreated cells and the H2O2-treated cells [6].
• Oxidant-induced decrements in ubiquitin conjugates were associated with 60-80% reductions in E1 and ubiquitin-conjugating enzyme (E2) activities as measured by formation of ubiquitin thiol esters [7].
• The variants' thiol esters reacted with nucleophiles at rates identical to wild-type alpha 2M [8].
• PZP binds proteinases which cause the cleavage of internal thiol esters in the molecule [9].

Biological context of Dimercaprol butyrate

• Pulse-chase kinetics suggested that both ubiquitin thiol esters formed to E2(20kDa) were catalytically competent in H2A ligation [10].
• Covalent binding of insulin, on the contrary, was only observed when it was present during hydrolysis of the internal thiol esters of p-alpha 2M by trypsin treatment, and thus involves the activated Glx residue [11].
• The UV spectra of all of the thiol esters display significant red shifts when the esters are bound to the crotonase active site [12].
• The substrate specificity of 1-O-alkyl-GP acyltransferase was rather broad as regards thiol esters [13].

Associations of Dimercaprol butyrate with other chemical compounds

• This paper examines the environment of the hydrolyzed thiol ester in methylamine-treated human alpha 2M and the separation between the bait region and the thiol ester and between the four thiol esters in the tetramer to try to further our understanding of how bait region proteolysis triggers thiol ester cleavage [14].
• A series of mercaptoacetic acid thiol esters have been identified as metallo-beta-lactamase inhibitors [15].
• The kinetics of the reactions of these thiol esters with N-acetyl-l-cysteine (NAC), N-acetylcysteamine, and N(2)-acetyl-L-lysine (NAL) have been studied, and the thiol addition products have been identified [16].
• Trypsin-induced activation of the thiol esters in alpha 2-macroglobulin generates a short-lived intermediate ('nascent' alpha 2-M) that can react rapidly to incorporate not only methylamine or putrescine but also proteins lacking proteinase activity [17].
• In addition to glutathione (GSH) conjugating activity, glutathione S-transferases (GSTs) catalyze "reverse" reactions, such as the hydrolysis of GSH thiol esters [18].

Gene context of Dimercaprol butyrate

• Trypsin or plasmin treatment of PAPP-A resulted in the generation of a major 85 kDa component and the rapid cleavage of internal thiol esters [19].
• The preparations contain functionally intact beta-cysteinyl-gamma-glutamyl thiol esters, located in the same nonapeptide sequence as found in alpha 2M, and form complexes with a variety of proteinases in which a large fraction of the proteinase is bound covalently [20].
• Thus, the polar environment around substituents on the acyl group is the same for carboxylic acids, thiol esters, and oxygen esters [21].
• Recently it has been shown that nucleophilic cleavage of the four thiol esters in alpha 2M is a reversible process with energy requirements dependent on the nucleophile [Grøn, H., Thøgersen, I. B., Enghild, J. J., and Pizzo, S. V. (1996) Biochem. J. 318, 539-545] [22].
• In both, BAL-tributyrate is used as substrate, in combination with serum esterase inhibitors and a chromogenic reagent for the SH group of the liberated BAL [23].

Analytical, diagnostic and therapeutic context of Dimercaprol butyrate

• When alpha 2-macroglobulin (alpha 2M) from the American horseshoe crab, Limulus polyphemus, reacts with proteinases, its thiol esters, like those of other alpha-macroglobulins, become activated, leading to the formation of covalently crosslinked species that can be detected as high molecular weight bands in reducing SDS-PAGE [24].

References