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Gene Review

NMT1  -  glycylpeptide N-tetradecanoyltransferase NMT1

Saccharomyces cerevisiae S288c

Synonyms: CDC72, Cell division control protein 72, Glycylpeptide N-tetradecanoyltransferase, L8167.14, Myristoyl-CoA:protein N-myristoyltransferase, ...
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Disease relevance of NMT1


High impact information on NMT1

  • Insertional mutagenesis of the NMT1 locus on yeast chromosome XII caused recessive lethality, indicating that this protein acyltransferase activity is necessary for vegetative cell growth [6].
  • Overexpression of NMT activity was achieved by means of the yeast episomal plasmid YEp24 without obvious effects on growth kinetics, cell morphology, or acylprotein metabolic labeling patterns [6].
  • We show that Gpa1 is myristoylated by Nmt1, and without this normally stable modification, Gpa1 is unable to inhibit pheromone signaling [7].
  • Surprisingly, polymerases were detected 4.3 kb beyond the nmt1 polyadenylation [poly(A)] site and 2.4 kb beyond the nmt2 poly(A) site, which in each case have transcribed through an entire convergent downstream transcription unit [8].
  • Introduction of a peroxisomal assembly mutation, pas1 delta, into isogenic NMT1 and nmt1-181 strains with wild type FAA alleles revealed that when Fas is inhibited, peroxisomes contribute to myristoylCoA pools used by Nmt1p [9].

Chemical compound and disease context of NMT1


Biological context of NMT1

  • Isogenic, haploid strains containing NMT1, nmt1-72, and nmt1-181 do not manifest any obvious differences in steady state levels of the acyltransferases during growth at permissive temperatures or in the biosynthesis of long chain saturated acyl-CoAs [11].
  • When compared with wild type Nmt1p, Cys217 --> Arg produces 3- and 6-fold increases in Ki for SC-58272 at 24 and 37 degrees C but no change in Ki for S-(2-oxo)pentadecyl-CoA, indicating that the substitution selectively affects Nmt1p's peptide binding site [12].
  • Wild type C. neoformans, C. albicans, and H. sapiens NMTs can fully complement the lethal phenotype of a S. cerevisiae nmt1 null allele at 24 and 37 degrees C when the GAL1-10 promoter controlling their expression is induced by galactose [13].
  • To identify Nmt1p substrates that may affect maintenance of proliferative potential during stationary phase, we searched the yeast genome for known and putative N-myristoylproteins [14].
  • Myristoyl-CoA:protein N-myristoyltransferase (NMT) catalyzes the cotranslational, covalent attachment of a rare fatty acid, myristic acid (C14:0), to the amino-terminal glycine residue of a number of eukaryotic proteins involved in cellular growth and signal transduction as well as several viral proteins necessary for assembly-replication [15].

Anatomical context of NMT1


Associations of NMT1 with chemical compounds

  • Regulation of myristoylCoA pools in Saccharomyces cerevisiae plays an important role in modulating the activity of myristoylCoA:protein N-myristoyltransferase (NMT), an essential enzyme with an ordered Bi Bi reaction that catalyzes the transfer of myristate from myristoylCoA to greater than or equal to 12 cellular proteins [19].
  • Nmt1p has an ordered Bi Bi reaction mechanism with binding of myristoyl-CoA occurring before binding of peptide substrates [12].
  • A NMT1 strain with deletions of all four FAAs is still viable at 30 degrees C on media containing myristate, palmitate, or oleate as the sole carbon source--indicating that S. cerevisiae contains at least one other FAA which directs fatty acids to beta-oxidation pathways [9].
  • When Fas is inactivated by a specific inhibitor (cerulenin), NMT1 cells are not viable unless the media is supplemented with long chain fatty acids [9].
  • Our recent studies of the 455-amino acid Saccharomyces cerevisiae acyltransferase (Nmt1p) suggested that its mechanism of catalysis is ordered Bi Bi with myristoyl-CoA binding occurring prior to binding of peptide and release of CoA occurring prior to release of the myristoyl-peptide [20].

Other interactions of NMT1

  • Analyses of strains containing NMT1 and a faal null mutation indicated that FAA1 is not essential for vegetative growth when an active de novo pathway for fatty acid synthesis is present [19].
  • Although substitution of nmt1-451D for NMT1 results in deficiencies in protein N-myristoylation, these deficiencies are modest and limited by compensatory responses that include augmented expression of nmt1-451D and precocious induction of FAA4 in log phase [14].
  • The ts growth arrest produced by nmt1 alleles correlates with a reduction in myristoyl-Arf1p to </=50% of total cellular Arf1p [12].
  • FAS1 expression is Ino2p-dependent in NMT1 cells at 24-33 degreesC [21].
  • Comparative analysis of the beta transducin family with identification of several new members including PWP1, a nonessential gene of Saccharomyces cerevisiae that is divergently transcribed from NMT1 [22].

Analytical, diagnostic and therapeutic context of NMT1


  1. Protein N-myristoylation in Escherichia coli: reconstitution of a eukaryotic protein modification in bacteria. Duronio, R.J., Jackson-Machelski, E., Heuckeroth, R.O., Olins, P.O., Devine, C.S., Yonemoto, W., Slice, L.W., Taylor, S.S., Gordon, J.I. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  2. 4-oxatetradecanoic acid is fungicidal for Cryptococcus neoformans and inhibits replication of human immunodeficiency virus I. Langner, C.A., Lodge, J.K., Travis, S.J., Caldwell, J.E., Lu, T., Li, Q., Bryant, M.L., Devadas, B., Gokel, G.W., Kobayashi, G.S. J. Biol. Chem. (1992) [Pubmed]
  3. Comparison of the acyl chain specificities of human myristoyl-CoA synthetase and human myristoyl-CoA:protein N-myristoyltransferase. Kishore, N.S., Wood, D.C., Mehta, P.P., Wade, A.C., Lu, T., Gokel, G.W., Gordon, J.I. J. Biol. Chem. (1993) [Pubmed]
  4. The substrate specificity of Saccharomyces cerevisiae myristoyl-CoA: protein N-myristoyltransferase. Polar probes of the enzyme's myristoyl-CoA recognition site. Lu, T., Li, Q., Katoh, A., Hernandez, J., Duffin, K., Jackson-Machelski, E., Knoll, L.J., Gokel, G.W., Gordon, J.I. J. Biol. Chem. (1994) [Pubmed]
  5. Characterization and selective inhibition of myristoyl-CoA:protein N-myristoyltransferase from Trypanosoma brucei and Leishmania major. Panethymitaki, C., Bowyer, P.W., Price, H.P., Leatherbarrow, R.J., Brown, K.A., Smith, D.F. Biochem. J. (2006) [Pubmed]
  6. Disruption of the yeast N-myristoyl transferase gene causes recessive lethality. Duronio, R.J., Towler, D.A., Heuckeroth, R.O., Gordon, J.I. Science (1989) [Pubmed]
  7. N-myristoylation is required for function of the pheromone-responsive G alpha protein of yeast: conditional activation of the pheromone response by a temperature-sensitive N-myristoyl transferase. Stone, D.E., Cole, G.M., de Barros Lopes, M., Goebl, M., Reed, S.I. Genes Dev. (1991) [Pubmed]
  8. Nascent transcription from the nmt1 and nmt2 genes of Schizosaccharomyces pombe overlaps neighbouring genes. Hansen, K., Birse, C.E., Proudfoot, N.J. EMBO J. (1998) [Pubmed]
  9. Saccharomyces cerevisiae contains four fatty acid activation (FAA) genes: an assessment of their role in regulating protein N-myristoylation and cellular lipid metabolism. Johnson, D.R., Knoll, L.J., Levin, D.E., Gordon, J.I. J. Cell Biol. (1994) [Pubmed]
  10. Use of Escherichia coli strains containing fad mutations plus a triple plasmid expression system to study the import of myristate, its activation by Saccharomyces cerevisiae acyl-CoA synthetase, and its utilization by S. cerevisiae myristoyl-CoA:protein N-myristoyltransferase. Knoll, L.J., Gordon, J.I. J. Biol. Chem. (1993) [Pubmed]
  11. Genetic and biochemical studies of a mutant Saccharomyces cerevisiae myristoyl-CoA:protein N-myristoyltransferase, nmt72pLeu99-->Pro, that produces temperature-sensitive myristic acid auxotrophy. Johnson, D.R., Duronio, R.J., Langner, C.A., Rudnick, D.A., Gordon, J.I. J. Biol. Chem. (1993) [Pubmed]
  12. Biochemical studies of Saccharomyces cerevisiae myristoyl-coenzyme A:protein N-myristoyltransferase mutants. Zhang, L., Jackson-Machelski, E., Gordon, J.I. J. Biol. Chem. (1996) [Pubmed]
  13. Comparison of myristoyl-CoA:protein N-myristoyltransferases from three pathogenic fungi: Cryptococcus neoformans, Histoplasma capsulatum, and Candida albicans. Lodge, J.K., Johnson, R.L., Weinberg, R.A., Gordon, J.I. J. Biol. Chem. (1994) [Pubmed]
  14. A role for Saccharomyces cerevisiae fatty acid activation protein 4 in regulating protein N-myristoylation during entry into stationary phase. Ashrafi, K., Farazi, T.A., Gordon, J.I. J. Biol. Chem. (1998) [Pubmed]
  15. Analysis of the compartmentalization of myristoyl-CoA:protein N-myristoyltransferase in Saccharomyces cerevisiae. Knoll, L.J., Levy, M.A., Stahl, P.D., Gordon, J.I. J. Biol. Chem. (1992) [Pubmed]
  16. Purification and characterization of yeast myristoyl CoA:protein N-myristoyltransferase. Towler, D.A., Adams, S.P., Eubanks, S.R., Towery, D.S., Jackson-Machelski, E., Glaser, L., Gordon, J.I. Proc. Natl. Acad. Sci. U.S.A. (1987) [Pubmed]
  17. Crystal structure of the anti-fungal target N-myristoyl transferase. Weston, S.A., Camble, R., Colls, J., Rosenbrock, G., Taylor, I., Egerton, M., Tucker, A.D., Tunnicliffe, A., Mistry, A., Mancia, F., de la Fortelle, E., Irwin, J., Bricogne, G., Pauptit, R.A. Nat. Struct. Biol. (1998) [Pubmed]
  18. Myristoylation. Boutin, J.A. Cell. Signal. (1997) [Pubmed]
  19. Isolation of a Saccharomyces cerevisiae long chain fatty acyl:CoA synthetase gene (FAA1) and assessment of its role in protein N-myristoylation. Duronio, R.J., Knoll, L.J., Gordon, J.I. J. Cell Biol. (1992) [Pubmed]
  20. Use of photoactivatable peptide substrates of Saccharomyces cerevisiae myristoyl-CoA:protein N-myristoyltransferase (Nmt1p) to characterize a myristoyl-CoA-Nmt1p-peptide ternary complex and to provide evidence for an ordered reaction mechanism. Rudnick, D.A., Rocque, W.J., McWherter, C.A., Toth, M.V., Jackson-Machelski, E., Gordon, J.I. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  21. Transcription of INO2 and INO4 is regulated by the state of protein N-myristoylation in Saccharomyces cerevisiae. Cok, S.J., Martin, C.G., Gordon, J.I. Nucleic Acids Res. (1998) [Pubmed]
  22. Comparative analysis of the beta transducin family with identification of several new members including PWP1, a nonessential gene of Saccharomyces cerevisiae that is divergently transcribed from NMT1. Duronio, R.J., Gordon, J.I., Boguski, M.S. Proteins (1992) [Pubmed]
  23. Isothermal titration calorimetric studies of Saccharomyces cerevisiae myristoyl-CoA:protein N-myristoyltransferase. Determinants of binding energy and catalytic discrimination among acyl-CoA and peptide ligands. Bhatnagar, R.S., Jackson-Machelski, E., McWherter, C.A., Gordon, J.I. J. Biol. Chem. (1994) [Pubmed]
  24. Crystallographic phasing of myristoyl-CoA-protein N-myristoyltransferase using an iodinated analog of myristoyl-CoA. Fütterer , K., Murray , C.L., Bhatnagar , R.S., Gokel , G.W., Gordon , J.I., Waksman , G. Acta Crystallogr. D Biol. Crystallogr. (2001) [Pubmed]
  25. Myristoyl-CoA:protein N-myristoyltransferase, an essential enzyme and potential drug target in kinetoplastid parasites. Price, H.P., Menon, M.R., Panethymitaki, C., Goulding, D., McKean, P.G., Smith, D.F. J. Biol. Chem. (2003) [Pubmed]
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