Cystine C-S bond cleavage fuels cysteine production under disulfide reductase deficiency.

All organisms have thioredoxin reductase (TR) or glutathione reductase (GR), the only enzymes that use reduced nicotinamide adenine dinucleotide phosphate to reduce cytosolic disulfides into thiols, thereby powering deoxyribonucleotide biosynthesis, elimination of oxidants, oxidative damage repair and reduction of the disulfide nutrient cystine into the thiol amino acid cysteine. Hence, TR/GR-null bacteria or yeast are inviable; yet, remarkably, mice with TR/GR-null livers thrive, in part by synthesizing life-sustaining cysteine through alternative pathways that evolved in metazoans. Although TR/GR-null livers generate some of their cysteine through the serine transsulfuration pathway, we here show that most cysteine in TR/GR-null livers comes from a pathway in which pyridoxal-phosphate-dependent cleavage of a carbon-sulfur bond in cystine generates cysteine persulfide, which decomposes nonenzymatically into cysteine. This potent yet previously unrecognized pathway is regulated by cellular levels of sulfur metabolites and represents a potent cytoprotective response that might be induced in most mammalian cells under conditions that chronically elevate cytosolic cystine levels.