Rv3722c governs aspartate-dependent nitrogen metabolism in <i>Mycobacterium tuberculosis</i>

Abstract Organisms are defined by their genomes, yet many distinguishing features of a given organism are encoded by genes that are functionally unannotated. Mycobacterium tuberculosis ( Mtb ), the leading cause of death due to a single microbe, co-evolved with humans as its only known natural reservoir, yet the factors mediating Mtb’s pathogenicity remain incompletely defined. rv3722c is a gene of unknown function predicted to encode a pyridoxal phosphate binding protein and to be essential for in vitro growth of Mtb . Using metabolomic, genetic and structural approaches, we show that Rv3722c is the primary aspartate aminotransferase of Mtb and mediates an essential but underrecognized role in metabolism: nitrogen distribution. Together with the attenuation of Rv3722c-deficient Mtb in macrophages and mice, these results identify aspartate biosynthesis and nitrogen distribution as potential species-selective drug targets in Mtb .