An analysis of the inhibition of pyruvate oxidation by arsenicals in relation to the enzyme theory of vesication

Abstract

I946 cysteine (as ethyl ester); other experiments gave similar results; the inactivation with the-S-S compound and reactivation with-SH was definite. DISCUSSION Systematic investigations upon-SH groups in an enzyme appear to have been first made upon urease by Hellerman, Perkins & Clark (1933) (see Hellerman, 1937). Some facts as to the action of maleate upon brain tissue have already been published by Weil-Malherbe (1938), who quoted earlier literature. He found that 20 mM-maleic acid inhibited the respiration of brain slices in bicarbonate-glucose-Ringer by 10-50 %; the inhibition was comparatively small in presence of pyruvate, and it thus appears that the pyruvate oxidase system is even less sensitive in the slice than in the brei. Our facts are consistent with the idea that an-SH group is essential for the activity of this system, and that this group is so activated as to be specially sensitive to maleate. It is still necessary to qualify this by pointing out that the evidence is indirect, because the enzyme concerned has not yet been obtained in pure form; the evidence has been much strengthened by the dithiol theory of Stocken & Thompson (1940-41) (for a brief account see Peters, Stocken & Thompson, 1945). (Recently, Barron & Singer (1945), see also Waters & Stock (1945), have also concluded that the pyruvate oxidase system is specially sensitive to-SH reagents; independently Bacq (1942) has found the-SH fraction in proteins abolished by some vesicants.) SUMMARY 1. Arising from earlier work on chemical warfare agents, and from a research upon antidotes, the sensitivity of the pyruvate oxidase system from brain to some-SH reagents was investigated. 2. The pyruvate oxidase system and the pyruvate dehydrogenase component were much more sensitive to sodium maleate than succinodehydrogenase. Pyruvate dehydrogenase was inactivated by cystine ester and reactivated by cysteine ester. Both these effects are explained by the presence of an essential-SH group in the enzyme concerned. We are grateful to Dr L. A. Stocken for the preparations of the esters of cystine and cysteine (as hydrochloride).

The action of sulphydryl inhibitors upon isocitric dehydrogenase with especial reference to the behaviour of some trivalent arsenicals

“…This suggests different reactivities of the related -SH groups. It is significant that the -SH group concerned in these i8o-citric dehydrogenase preparations must differ from most of those known at present; considering the order ofsensitivity to -SH reagents, it is different in behaviour from those inhibited by lachrymators (Dixon, 1948;Bacq & Desreux, 1946), from myosin (Bailey & Perry, 1947), from triosephosphate dehydrogenase (Dixon, 1937), fromsuccinodehydrogenase (Hopkins & Morgan, 1938) and from the lewisitesensitive components of the pyruvate oxidase system from brain (Peters et al 1946), which includes the tricarboxylic acid cycle (Peters, 1948), at any rate in part. It is possible that the differences found here between the heart and kidney i8ocitric dehydrogenases might disappear upon further purification.…”

“…It seemed important to examine the effect of arsenical substances on this enzyme in relation to other arsenical studies in this laboratory. (Peters, Sinclair & Thompson, 1946). This paper records some observations.of the effect of several -SH and other inhibitors upon the enzymes prepared from pig heart and from kidney tissue.…”

Observations Upon a Change in an Enzymatic Process in Burns

“…In confirmation, pyruvate was an inhibitor of deamination of DL-alanine by liver slices (Table II). Krebs [1935] also found that the inhibitory effect of pyruvate could be abolished by arsenite; using lewisite 0-6 mM [a more powerful inhibitor; Peters, Sinclair and Thompson, 1946] this has been confirmed for liver slices; it was also To exclude variation in the glycogen content between the burned and the control animals' liver, in some experiments the rats were fasted for 24 hours before analysis. This period of fasting, if anything, tended to increase slightly the deamination in both burned and control livers.…”

Veterans at risk: the health effects of mustard gas and Lewisite

“…It is also believed that the trivalent form of arsenic, which is highly reactive in biological systems, is responsible for the overt toxicity of all arsenicals, including Lewisite, to living systems. Trivalent arsenicals exert their toxic effects through interactions with active tissue sulfhydryl groups (Peters, 1955;Peters et al, 1946;. Trivalent arsenicals interact directly with protein sulfhydryl or thiol (sulfhydryl attached to a carbon) groups.…”