Discovery of a novel methionine biosynthetic route via O-phospho-L-homoserine

Abstract Methionine (Met), a sulfur-containing amino acid, is essential for the underlying biological processes in living organisms. In addition to its importance as a starting building block for peptide chain elongation in protein biosynthesis, Met is a direct precursor of S-adenosyl-l-methionine, an indispensable methyl donor molecule in primary and secondary metabolism. Streptomycesbacteria are well known to produce diverse secondary metabolites, but many strains lack canonical Met pathway genes for L-homocysteine, a direct precursor of Met in bacteria, plants, and archaea. Here, we report the identification of a novel gene (metM) responsible for the Met biosynthesis in Streptomycesstrains and demonstrate the catalytic function of the gene product, MetM. We further identified the metO gene, a downstream gene of metM, and showed that it encodes a sulfur carrier protein (SCP). In in vitroanalysis, MetO was found to play an important role in a sulfur donor by forming a thiocarboxylated SCP. Together with MetO (thiocarboxylate), MetM directly converted O-phospho-L-homoserine to L-homocysteine. O-phospho-L-homoserine is also known as an intermediate for threonine biosynthesis in bacteria and plants, and MetM shares sequence homology with threonine synthase. Our findings thus revealed that MetM seizes O-phospho-L-homoserine from the threonine biosynthetic pathway and uses it as an intermediate of the Met biosynthesis to generate the sulfur-containing amino acid. Importantly, this MetM/MetO pathway is highly conserved in Streptomyces bacteria and distributed in other bacteria and archaea.