Regulation of the balance of one-carbon metabolism in Saccharomyces cerevisiae.
One-carbon metabolism in yeast is an essential process that relies on at least one of three one-carbon donor molecules: serine, glycine, or formate. By a combination of genetics and biochemistry we have shown how cells regulate the balance of one-carbon flow between the donors by regulating cytoplasmic serine hydroxymethyltransferase activity in a side reaction occurring in the presence of excess glycine. This control governs the level of 5,10-methylene tetrahydrofolate (5,10-CH(2)-H(4)folate) in the cytoplasm, which has a direct role in signaling transcriptional control of the expression of key genes, particularly those encoding the unique components of the glycine decarboxylase complex (GCV1, GCV2, and GCV3). Based on these and other observations, we propose a model for how cells balance the need to supplement their one-carbon pools when charged folates are limiting or when glycine is in excess. We also propose that under normal conditions, cytoplasmic 5,10-CH(2)-H(4)folate is mainly directed to generating methyl groups via methionine, whereas one-carbon units generated from glycine in mitochondria are more directed to purine biosynthesis. When glycine is in excess, 5, 10-CH(2)-H(4)folate is decreased, and the regulation loop shifts the balance of generation of one-carbon units into the mitochondrion.
Piper
M D
MD
School of Biochemistry and Molecular Genetics and the NMR Facility, The University of New South Wales, Sydney, New South Wales 2052, Australia.
Hong
S P
SP
Ball
G E
GE
Dawes
I W
IW
D000225:Adenine / Q000378:metabolism; D000594:Amino Acid Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000619:Aminohydrolases / Q000378:metabolism; D050960:Aminomethyltransferase; D000818:Animals; D002244:Carbon / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002794:Choline / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005574:Formate-Tetrahydrofolate Ligase / Q000378:metabolism; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D005998:Glycine / Q000378:metabolism; D050959:Glycine Decarboxylase Complex; D050841:Glycine Dehydrogenase (Decarboxylating); D012696:Glycine Hydroxymethyltransferase / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013763:Tetrahydrofolates / Q000138:chemical synthesis / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014166:Transferases; D015854:Up-Regulation; D001616:beta-Galactosidase / Q000378:metabolism
D002352:Carrier Proteins; D005656:Fungal Proteins; D024101:Mitochondrial Proteins; D009097:Multienzyme Complexes; D029701:Saccharomyces cerevisiae Proteins; D013763:Tetrahydrofolates; C013123:5,10-methylenetetrahydrofolic acid; D012694:Serine; C021836:formyl-methenyl-methylenetetrahydrofolate synthetase; D002244:Carbon; D000594:Amino Acid Oxidoreductases; C494237:GCV2 protein, S cerevisiae; D050959:Glycine Decarboxylase Complex; D050841:Glycine Dehydrogenase (Decarboxylating); D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D014166:Transferases; D012696:Glycine Hydroxymethyltransferase; D050960:Aminomethyltransferase; C104785:GCV1 protein, S cerevisiae; D001616:beta-Galactosidase; D000619:Aminohydrolases; D005574:Formate-Tetrahydrofolate Ligase; D000225:Adenine; D002794:Choline; D005998:Glycine