SUMMARY PARAGRAPH for MET7
Met7p is a folypolyglutamate synthetase (FPGS) which works in concert with the dihydrofolate synthetase (DHFS) Fol3p to add glutamyl side chains to de novo synthesized folate coenzymes. In organisms that generate folate cofactors de novo (plants, bacteria, and fungi), the binding of glutamate to folate derivatives is achieved by two reactions catalyzed by DHFS and FPGS, respectively. Fol3p catalyzes the binding of the first glutamyl side chain to dihydropteroate to yield dihydrofolate, then Met7p catalyzes the extension of the glutamate chains of folylmonoglutamates in an ATP-dependent reaction (3).
In the cytosol, folate coenzymes are implicated in purine and thymidylate synthesis as well as in the biogenesis of the methyl group of methionine. In mitochondria, 10-formyltetrahydrofolate is necessary for the formylation of the initiator tRNA and thus for mitochondrial protein synthesis. met7 null mutants were originally identified as methionine auxotrophs (1), indicating that Met7p activity is required for methionine biosynthesis. In addition, Met7p is necessary for the maintenance of mitochondrial DNA, as mitochondrial protein synthesis is required for maintenance of an intact mitochondrial genome in S. cerevisiae, and inhibition of mitochondrial protein synthesis by the use of antifolates induces cytoplasmic respiration-deficient strains (3). Studies by Cherest et al. argue for the existence of only a cytosolic form of Met7p, favoring the hypothesis that mitochondrial integrity depends on the presence of a metabolite whose synthesis takes place in the cytosol and is strictly dependent on polyglutamylation of folate coenzymes (3).
In E. coli, which is able to synthesize folates, DHFS and FPGS activities exist in a bifunctional protein encoded by the FolC gene (3). A bifunctional protein also exists in the human malaria parasite Plasmodium falciparum (6). Mammalian cells, which do not synthesize folates de novo, produce only FPGS and thus depend exclusively on the intake of exogenously supplied folic acid (7, 8). Met7p, which shows significant similarities with Fol3p and Rma1p, is more closely related to the human FPGS than to the E. coli FPGS/DHFS enzyme. Fol3p and Rma1p, however, are more similar to the E. coli enzyme (3).
MET7 has also been implicated, by two genome-wide surveys, in the control of telomere length (9, 10).
Last updated: 2006-06-30