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Gene Review

MIS1  -  trifunctional formate-tetrahydrofolate...

Saccharomyces cerevisiae S288c

Synonyms: C-1-tetrahydrofolate synthase, mitochondrial, C1-THF synthase, YBR0751, YBR084W
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High impact information on MIS1

  • These results suggest that the catalytic activity of the C1-THF synthase is involved in purine biosynthesis [1].
  • In contrast to their results, our deletion analysis of the ADE3 gene indicates that the presence of either the synthetase or dehydrogenase/cyclohydrolase domains of C1-THF synthase is enough to complement the adenine requirement in ade3 strains [1].
  • In fact, deletion of the MIS1 locus has no detectable effect on cell growth [2].
  • Hybridization analysis shows that the gene (designated MIS1) has a single copy in the yeast genome [2].
  • The sequence of C1-THF synthase does not appear to be homologous to any other sequenced protein, including other proteins that use folate substrates [3].

Biological context of MIS1

  • We have studied yeast mutants carrying chromosomal disruptions of the genes encoding the mitochondrial C(1)-tetrahydrofolate (C(1)-THF) synthase (MIS1), necessary for synthesis of 10-formyl-THF, and the methionyl-tRNA formyltransferase (open reading frame YBL013W; designated FMT1) [4].
  • The human NAD-dependent bifunctional enzyme has a 44% amino acid sequence identity with the dehydrogenase-cyclohydrolase domain of the yeast mitochondrial NADP-dependent trifunctional enzyme encoded by the MIS1 gene, compared to 37% identity with the corresponding domain of the cytosolic trifunctional enzyme [5].
  • The only growth phenotype observed was a longer lag time during growth on nonfermentable carbon sources in minimal media for the mis1 deletion strain but not for the fmt1 deletion strain [4].
  • In vitro studies have considered the kinetics of the C1-THF synthase/SHMT enzyme system in the catalytic conversion of formate to serine [Strong et al. (1987) J. Biol. Chem. 262, 12519-12525] [6].
  • The translated DNA sequence and amino-terminal protein sequences are identical and the amino acid composition predicted from the DNA sequence agrees closely with that determined by hydrolysis of C1-THF synthase protein [3].

Anatomical context of MIS1

  • When yeast are incubated with [13C]formate, 13C NMR spectra establish that production of [3-13C]serine is dependent on C1-THF synthase and occurs primarily in the cytosol [7].

Associations of MIS1 with chemical compounds

  • Recently, 13C NMR has been used to establish that the C1-THF synthase/SHMT enzyme system is the only route from formate to serine in vivo in the yeast Saccharomyces cerevisiae [Pasternack et al. (1992) Biochemistry 31, 8713-8719] [6].
  • In the present work, site-directed mutagenesis of the S. cerevisiae ADE3 gene, which encodes C1-THF synthase, was used to individually change each cysteine contained within the dehydrogenase/cyclohydrolase domain (Cys-11, Cys-144, and Cys-257) to serine [8].
  • Treatment of C1-THF synthase with N-ethylmaleimide (NEM) resulted in significant inactivation of only the dehydrogenase and cyclohydrolase activities, with the cyclohydrolase at least an order of magnitude more sensitive than the dehydrogenase [9].
  • This provides in vivo evidence for the mitochondrial assimilation of formate, activation and conversion to [13C]CH2-THF via mitochondrial C1-THF synthase, and subsequent glycine synthesis via reversal of the glycine cleavage system [7].

Other interactions of MIS1

  • A gene designated RPL19A has been identified in the region downstream from the 3'-end of the Saccharomyces cerevisiae MIS1 gene encoding the mitochondrial C1-tetrahydrofolate synthase [10].

Analytical, diagnostic and therapeutic context of MIS1

  • The availability of yeast strains carrying deletions of cytoplasmic and/or mitochondrial C1-THF synthase allows a dissection of the role each compartment plays in this metabolism [7].


  1. Function of yeast cytoplasmic C1-tetrahydrofolate synthase. Song, J.M., Rabinowitz, J.C. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  2. Isolation and characterization of the Saccharomyces cerevisiae MIS1 gene encoding mitochondrial C1-tetrahydrofolate synthase. Shannon, K.W., Rabinowitz, J.C. J. Biol. Chem. (1988) [Pubmed]
  3. Nucleotide sequence of the Saccharomyces cerevisiae ADE3 gene encoding C1-tetrahydrofolate synthase. Staben, C., Rabinowitz, J.C. J. Biol. Chem. (1986) [Pubmed]
  4. Initiation of protein synthesis in Saccharomyces cerevisiae mitochondria without formylation of the initiator tRNA. Li, Y., Holmes, W.B., Appling, D.R., RajBhandary, U.L. J. Bacteriol. (2000) [Pubmed]
  5. NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase is the mammalian homolog of the mitochondrial enzyme encoded by the yeast MIS1 gene. Yang, X.M., MacKenzie, R.E. Biochemistry (1993) [Pubmed]
  6. Whole-cell detection by 13C NMR of metabolic flux through the C1-tetrahydrofolate synthase/serine hydroxymethyltransferase enzyme system and effect of antifolate exposure in Saccharomyces cerevisiae. Pasternack, L.B., Laude, D.A., Appling, D.R. Biochemistry (1994) [Pubmed]
  7. 13C NMR detection of folate-mediated serine and glycine synthesis in vivo in Saccharomyces cerevisiae. Pasternack, L.B., Laude, D.A., Appling, D.R. Biochemistry (1992) [Pubmed]
  8. Site-directed mutagenesis of yeast C1-tetrahydrofolate synthase: analysis of an overlapping active site in a multifunctional enzyme. Barlowe, C.K., Williams, M.E., Rabinowitz, J.C., Appling, D.R. Biochemistry (1989) [Pubmed]
  9. Evidence for overlapping active sites in a multifunctional enzyme: immunochemical and chemical modification studies on C1-tetrahydrofolate synthase from Saccharomyces cerevisiae. Appling, D.R., Rabinowitz, J.C. Biochemistry (1985) [Pubmed]
  10. Nucleotide sequence and characterization of the Saccharomyces cerevisiae RPL19A gene encoding a homolog of the mammalian ribosomal protein L19. Song, J.M., Cheung, E., Rabinowitz, J.C. Yeast (1995) [Pubmed]
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