Estimation of metabolite pools suggested that these phenotypes could be the result of profound metabolic changes

in the ΔcymR mutant including an increase of the intracellular cysteine pool and hydrogen sulfide formation, as well as a depletion of branched-chain Selleck GPCR Compound Library amino acids. The sulfur-containing amino acid, cysteine, plays a major role in cellular physiology. Cysteine biosynthesis is the primary pathway for incorporating sulfur into cellular components. This amino acid is a precursor of methionine and also thiamine, biotin, lipoic acid, coenzyme A and coenzyme M, and is required for the biogenesis of [Fe–S] clusters. Cysteine residues are found in the catalytic site of several enzymes and aid protein folding and assembly by forming disulfide bonds. Moreover, proteins with active-site cysteines such as thioredoxin or cysteine-containing molecules such as glutathione, mycothiol, coenzyme A and bacillithiol play an important role in protecting cells against oxidative

stress (Masip et al., 2006; Newton et al., 2009). Several studies have shown that cysteine itself plays a role in bacterial sensitivity to oxidative stress (Hung et al., 2003; Park & Imlay, 2003; Hochgrafe et al., 2007). More generally, recent data reported the existence of links between cysteine metabolism and various stress stimuli such as peroxide (H2O2), superoxide, diamide, nitric oxide, thiol-reactive electrophiles and metal ions (Park & Imlay, 2003; Liebeke Tau-protein kinase et al., 2008;

Nguyen et al., 2009; Pother learn more et al., 2009). Two major cysteine biosynthetic pathways are present in Bacillus subtilis: the thiolation pathway, which requires sulfide, and the reverse trans-sulfuration pathway, which converts homocysteine to cysteine via a cystathionine intermediate (Soutourina & Martin-Verstraete, 2007). Homocysteine is synthesized from methionine, while sulfide is yielded mostly from the reduction of sulfate. Finally, thiosulfate or glutathione can also be used as cysteine precursors in this bacterium. Under environmentally oxidizing conditions, cysteine dimerizes to form the disulfide-linked cystine, which is generally the compound transported. Three uptake systems for cystine, two ABC transporters and a symporter, are present in B. subtilis (Burguière et al., 2004). Because of the reactivity of its SH group and its toxicity, the cysteine metabolism is tightly controlled. The CymR repressor has been identified recently as the master regulator of cysteine metabolism in B. subtilis and Staphylococcus aureus (Choi et al., 2006; Even et al., 2006; Soutourina et al., 2009). In B. subtilis, CymR negatively regulates the expression of genes encoding cystine transporters (tcyP and tcyJKLMN) or involved in cysteine synthesis (cysK and mccAB) or sulfonate assimilation (Even et al., 2006).