Biological Thiols and Carbon Disulfide: The Formation and Decay of Trithiocarbonates under Physiologically Relevant Conditions

Abstract

Carbon disulfide is an environmental toxin, but there are suggestions in the literature that it may also have regulatory and/or therapeutic roles in mammalian physiology. Thiols or thiolates would be likely biological targets for an electrophile, such as CS2, and in this context, the present study examines the dynamics of CS2 reactions with various thiols (RSH) in physiologically relevant near-neutral aqueous media to form the respective trithiocarbonate anions (TTC–, also known as “thioxanthate anions”). The rates of TTC– formation are markedly pH-dependent, indicating that the reactive form of RSH is the conjugate base RS–. The rates of the reverse reaction, that is, decay of TTC– anions to release CS2, is pH-independent, with rates roughly antiparallel to the basicities of the RS– conjugate base. These observations indicate that the rate-limiting step of decay is simple CS2 dissociation from RS–, and according to microscopic reversibility, the transition state of TTC– formation would be simple addition of the RS– nucleophile to the CS2 electrophile. At pH 7.4 and 37 °C, cysteine and glutathione react with CS2 at a similar rate but the trithiocarbonate product undergoes a slow cyclization to give 2-thiothiazolidine-4-carboxylic acid. The potential biological relevance of these observations is briefly discussed.