S ‐Succinylcysteine Breakdown – How Bacillus subtilis Utilizes an Inevitable Product of Metabolite Damage

Cellular thiols such as cysteine and glutathione spontaneously and readily react with the respiratory intermediate fumarate to form stable S ‐succinyl adducts. Succination of thiols by fumarate increases in certain tumors and in response to glucotoxicity associated with diabetes, thus S ‐succinyl adducts such as S ‐succinylcysteine (SSC) are considered to be on cometabolites and biomarkers for human disease. No plausible disposal routes for S ‐succinyl compounds have been demonstrated. Here, we show that Bacillus subtilis has a pathway to metabolize SSC to cysteine and that this pathway is encoded by the yxe operon. The first pathway step is N‐ acetylation mediated by the yxeL gene product, most probably follow‐ed by oxygenation and elimination of oxaloacetate to yield N ‐acetylcysteine, which is then deacetyl‐at‐ed. In support of this breakdown pathway, knockouts of the predicted B. subtilis genes involved in each catabolic step of SSC breakdown lose the ability to grow on SSC as a sulfur source and accumulate the predicted upstream metabolite(s). We further show that N ‐acetylation reduces SSC toxicity. SSC disposal substantiates the emerging concept that cells often handle toxic metabolites by pathways that begin with acetylation and end with deacetylation, in direct analogy to the blocking‐deblocking strategies used in organic chemistry. Support or Funding Information This work was supported by U.S. National Science Foundation grant MCB‐1153413 and by an endowment from the C.V. Griffin Sr Foundation. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .