The pathways of mammalian cysteine metabolism are numerous and complex. At least 12 distinct enzymes active toward cysteine have been identified, and the pathways initiated by these enzymes have been shown to lead to a multitude of intermediate products. Many of the pathways eventually intersect to either regenerate cysteine or to form a small number of catabolic products (taurine, sulfate, pyruvate). The multiplicity and complexity of these pathways have impeded attempts to determine the role of individual pathways in the overall metabolism of cysteine. The accurate interpretation of in vivo pulse-labeling studies is seriously hindered, for example, by cysteine recycling and pathway convergence. Further studies would be greatly facilitated by techniques which allow selected pathways to be specifically inhibited in vivo and by the development of cysteine analogs which are metabolized by only a small number of the existing pathways. By reducing the number of metabolic pathways available, these techniques would substantially simplify the interpretation of in vivo experiments. Selective enzyme inhibitors should also be of use in the manipulation of cysteine metabolism for therapeutic purposes; applications are indicated in the chemotherapy of trypanosomiasis, in the sensitization of tumor cells to killing leukocytes, radiation and chemical agents, and in the inhibition of leukotriene C and prostaglandin E2 synthesis. The elucidation of mammalian cysteine metabolism through the design, synthesis and in vivo utilization of modified substrates and enzyme specific inhibitors is the principal objective of the investigations proposed. Although prospective inhibitors and substrate analogs will be tested with isolated enzymes, the investigations will center on studies with intact mice and rats and, to a lesser extent, the perfused rat kidney. The studies will focus initially on three specific areas of cysteine metabolism (i) the pathways of taurine biosynthesis, (ii) the mechanism of extracellular thiol oxidation, and (iii) the control of glutathione turnover. Subsequent studies will define the quantitative importance of taurine biosynthesis relative to the other reactions of cysteine catabolism and will examine factors controlling cysteine homeostasis in the whole animal.
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