Identification of a Novel One-carbon Metabolism Regulon in Saccharomyces cerevisiae

Abstract

Glycine specifically induces genes encoding subunits of the glycine decarboxylase complex (GCV1, GCV2, and GCV3), and this is mediated by a fall in cytoplasmic levels of 5,10-methylenetetrahydrofolate caused by inhibition of cytoplasmic serine hydroxymethyltransferase. Here it is shown that this control system extends to genes for other enzymes of one-carbon metabolism and de novo purine biosynthesis. Northern analysis of the response to glycine demonstrated that the induction of the GCV genes and the induction of other amino acid metabolism genes are temporally distinct. The genome-wide response to glycine revealed that several other genes are rapidly co-induced with the GCV genes, including SHM2, which encodes cytoplasmic serine hydroxymethyltransferase. These results were refined by examining transcript levels in an shm2Δ strain (in which cytoplasmic 5,10-methylenetetrahydrofolate levels are reduced) and a met13Δ strain, which lacks the main methylenetotrahydrofolate reductase activity of yeast and is effectively blocked at consumption of 5,10-methylene tetrahydrofolate for methionine synthesis. Glycine addition also caused a substantial transient disturbance to metabolism, including a sequence of changes in induction of amino acid biosynthesis and respiratory chain genes. Analysis of the glycine response in the shm2Δ strain demonstrated that apart from the one-carbon regulon, most of these transient responses were not contingent on a disturbance to one-carbon metabolism. The one-carbon response is distinct from the Bas1p purine biosynthesis regulon and thus represents the first example of transcriptional regulation in response to activated one-carbon status.