glycine hydroxymethyltransferase


Summary: A pyridoxal phosphate enzyme that catalyzes the reaction of glycine and 5,10-methylene-tetrahydrofolate to form serine. It also catalyzes the reaction of glycine with acetaldehyde to form L-threonine. EC

Top Publications

  1. Girgis S, Nasrallah I, Suh J, Oppenheim E, Zanetti K, Mastri M, et al. Molecular cloning, characterization and alternative splicing of the human cytoplasmic serine hydroxymethyltransferase gene. Gene. 1998;210:315-24 pubmed
    ..Multiple tissue Northern blots suggest that the CSHMT message levels and alternative splicing patterns display tissue-specific variations. ..
  2. Geisel J, Hübner U, Bodis M, Schorr H, Knapp J, Obeid R, et al. The role of genetic factors in the development of hyperhomocysteinemia. Clin Chem Lab Med. 2003;41:1427-34 pubmed
    ..Although the TC and COMT mutations influence cellular vitamin B12 metabolism, this effect did not result in overt homocysteine elevation. ..
  3. Wang Y, Guo W, He Y, Chen Z, Wen D, Zhang X, et al. Association of MTHFR C677T and SHMT(1) C1420T with susceptibility to ESCC and GCA in a high incident region of Northern China. Cancer Causes Control. 2007;18:143-52 pubmed
    ..The association between the MTHFR C677T and SHMT ( 1 ) C1420T polymorphisms and the risk of ESCC and GCA was demonstrated. ..
  4. Guerreiro C, Carmona B, Goncalves S, Carolino E, Fidalgo P, Brito M, et al. Risk of colorectal cancer associated with the C677T polymorphism in 5,10-methylenetetrahydrofolate reductase in Portuguese patients depends on the intake of methyl-donor nutrients. Am J Clin Nutr. 2008;88:1413-8 pubmed
    ..0; 95% CI: 1.8, 108.5). No significant associations were seen for MTR or SHMT polymorphisms. These results show an association between the C677T MTHFR variant and different folate intakes on risk of CRC. ..
  5. Steck S, Keku T, Butler L, Galanko J, Massa B, Millikan R, et al. Polymorphisms in methionine synthase, methionine synthase reductase and serine hydroxymethyltransferase, folate and alcohol intake, and colon cancer risk. J Nutrigenet Nutrigenomics. 2008;1:196-204 pubmed publisher
    ..Modest interactions between these SNPs and alcohol or folate intakes were observed. Our results are consistent with other findings and provide needed data on these associations among African-Americans. ..
  6. McNeil J, McIntosh E, Taylor B, Zhang F, Tang S, Bognar A. Cloning and molecular characterization of three genes, including two genes encoding serine hydroxymethyltransferases, whose inactivation is required to render yeast auxotrophic for glycine. J Biol Chem. 1994;269:9155-65 pubmed
    ..Gene disruption studies demonstrated that inactivation of SHM1, SHM2, and GLY1 is required to yield yeast that are completely auxotrophic for glycine. ..
  7. Angelaccio S, Chiaraluce R, Consalvi V, Buchenau B, Giangiacomo L, Bossa F, et al. Catalytic and thermodynamic properties of tetrahydromethanopterin-dependent serine hydroxymethyltransferase from Methanococcus jannaschii. J Biol Chem. 2003;278:41789-97 pubmed publisher
    ..jannaschii, which appear to differ only in its ability to bind and use a modified folate as substrate and increased thermal stability...
  8. Monschau N, Stahmann K, Sahm H, McNeil J, Bognar A. Identification of Saccharomyces cerevisiae GLY1 as a threonine aldolase: a key enzyme in glycine biosynthesis. FEMS Microbiol Lett. 1997;150:55-60 pubmed
    ..On ethanol as carbon source simultaneous disruption of GLY1, SHM1 and SHM2 did not lead to glycine auxotrophy because glycine biosynthesis proceeds via alanine glyoxylate aminotransferase. ..
  9. Woeller C, Anderson D, Szebenyi D, Stover P. Evidence for small ubiquitin-like modifier-dependent nuclear import of the thymidylate biosynthesis pathway. J Biol Chem. 2007;282:17623-31 pubmed

More Information


  1. di Salvo M, Contestabile R, Paiardini A, Maras B. Glycine consumption and mitochondrial serine hydroxymethyltransferase in cancer cells: the heme connection. Med Hypotheses. 2013;80:633-6 pubmed publisher
  2. Ma X, Baraona E, Hernández Muñoz R, Lieber C. High levels of acetaldehyde in nonalcoholic liver injury after threonine or ethanol administration. Hepatology. 1989;10:933-40 pubmed
    ..As a consequence, administration of ethanol (an exogenous source of acetaldehyde) resulted in striking elevations in the levels of acetaldehyde in carbon tetrachloride-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS) ..
  3. Fu T, Scarsdale J, Kazanina G, Schirch V, Wright H. Location of the pteroylpolyglutamate-binding site on rabbit cytosolic serine hydroxymethyltransferase. J Biol Chem. 2003;278:2645-53 pubmed
  4. Garrow T, Brenner A, Whitehead V, Chen X, Duncan R, Korenberg J, et al. Cloning of human cDNAs encoding mitochondrial and cytosolic serine hydroxymethyltransferases and chromosomal localization. J Biol Chem. 1993;268:11910-6 pubmed
    ..The high degree of nucleotide sequence identity between the two isozymes, and the presence of keratin genes in both chromosomal regions, is consistent with these regions of chromosome 12 and 17 arising by a duplication event. ..
  5. Byrne P, Shipley J, Chave K, Sanders P, Snell K. Characterisation of a human serine hydroxymethyltransferase pseudogene and its localisation to 1p32.3-33. Hum Genet. 1996;97:340-4 pubmed
    ..3-33. In addition, an SHMT CDNA clone hybridized to the same region and to 17p11.2-12. The latter is consistent with a previous localisation of the gene for cytosolic SHMT. ..
  6. Bhatt A, Bhakuni V, Kumar A, Khan M, Siddiqi M. Alkaline pH-dependent differential unfolding characteristics of mesophilic and thermophilic homologs of dimeric serine hydroxymethyltransferase. Biochim Biophys Acta. 2010;1804:1294-300 pubmed publisher
    ..Taken together these findings suggest that possibly the presence of these non-identical lysine moieties and a small extension of C-terminal domain may be responsible for low stability of bsSHMT under alkaline pH condition. ..
  7. Sopitthummakhun K, Maenpuen S, Yuthavong Y, Leartsakulpanich U, Chaiyen P. Serine hydroxymethyltransferase from Plasmodium vivax is different in substrate specificity from its homologues. FEBS J. 2009;276:4023-36 pubmed publisher
    ..The substrate specificity difference between PvSHMT and the mammalian enzyme indicates the dissimilarity between their active sites, which could be exploited for the development of specific inhibitors against PvSHMT. ..
  8. Vidal L, Calveras J, Clapés P, Ferrer P, Caminal G. Recombinant production of serine hydroxymethyl transferase from Streptococcus thermophilus and its preliminary evaluation as a biocatalyst. Appl Microbiol Biotechnol. 2005;68:489-97 pubmed
    ..The enzyme showed potential as a biocatalyst for the stereoselective synthesis of beta-hydroxy-alpha-amino acids...
  9. Herbig K, Chiang E, Lee L, Hills J, Shane B, Stover P. Cytoplasmic serine hydroxymethyltransferase mediates competition between folate-dependent deoxyribonucleotide and S-adenosylmethionine biosyntheses. J Biol Chem. 2002;277:38381-9 pubmed
    ..These results indicate that cSHMT is a metabolic switch that, when activated, gives dTMP synthesis higher metabolic priority than SAM synthesis. ..
  10. Nikiforov M, Chandriani S, O Connell B, Petrenko O, Kotenko I, Beavis A, et al. A functional screen for Myc-responsive genes reveals serine hydroxymethyltransferase, a major source of the one-carbon unit for cell metabolism. Mol Cell Biol. 2002;22:5793-800 pubmed
    ..Our data establish a novel functional link between Myc and the regulation of cellular metabolism. ..
  11. Chen J, Kyte C, Valcin M, Chan W, Wetmur J, Selhub J, et al. Polymorphisms in the one-carbon metabolic pathway, plasma folate levels and colorectal cancer in a prospective study. Int J Cancer. 2004;110:617-20 pubmed
    ..Findings from our prospective investigation indicate that these newly identified polymorphisms in one-carbon metabolizing genes have limited functionality in modifying folate status and related CRC risk. ..
  12. Rajaram V, Bhavani B, Kaul P, Prakash V, Appaji Rao N, Savithri H, et al. Structure determination and biochemical studies on Bacillus stearothermophilus E53Q serine hydroxymethyltransferase and its complexes provide insights on function and enzyme memory. FEBS J. 2007;274:4148-60 pubmed
    ..This is the first report to provide direct evidence for enzyme memory based on the crystal structure of enzyme complexes. ..
  13. Scarsdale J, Radaev S, Kazanina G, Schirch V, Wright H. Crystal structure at 2.4 A resolution of E. coli serine hydroxymethyltransferase in complex with glycine substrate and 5-formyl tetrahydrofolate. J Mol Biol. 2000;296:155-68 pubmed
    ..coli enzymes. The structure of the E. coli ternary complex provides the basis for a thorough investigation of its mechanism through characterization and structure determination of site mutants. ..
  14. Stover P, Chen L, Suh J, Stover D, Keyomarsi K, Shane B. Molecular cloning, characterization, and regulation of the human mitochondrial serine hydroxymethyltransferase gene. J Biol Chem. 1997;272:1842-8 pubmed
    ..Mitochondrial SHMT mRNA levels in MCF-7 cells did not vary during the cell cycle and were not affected by the absence of glycine, serine, folate, thymidylate, or purines from the media. ..
  15. Sopitthummakhun K, Thongpanchang C, Vilaivan T, Yuthavong Y, Chaiyen P, Leartsakulpanich U. Plasmodium serine hydroxymethyltransferase as a potential anti-malarial target: inhibition studies using improved methods for enzyme production and assay. Malar J. 2012;11:194 pubmed publisher
    ..In addition to inhibitors of malarial SHMT, the development of species-specific, anti-SHMT inhibitors is plausible due to the presence of differential active sites on the Plasmodium enzymes. ..
  16. Chang W, Tsai J, Chen B, Huang H, Fu T. Serine hydroxymethyltransferase isoforms are differentially inhibited by leucovorin: characterization and comparison of recombinant zebrafish serine hydroxymethyltransferases. Drug Metab Dispos. 2007;35:2127-37 pubmed
    ..Together with the previous report on zebrafish cytosolic SHMT, we suggest that zSHMTs can be used in in vitro assays for folate-related investigation and antifolate drug discovery. ..
  17. Jander G, Norris S, Joshi V, Fraga M, Rugg A, Yu S, et al. Application of a high-throughput HPLC-MS/MS assay to Arabidopsis mutant screening; evidence that threonine aldolase plays a role in seed nutritional quality. Plant J. 2004;39:465-75 pubmed
    ..1.2.5) as the cause of increased seed Thr levels in one mutant. The assay that was developed for this project has broad applicability to Arabidopsis and other plant species. ..
  18. Gutierrez M, Garrabou X, Agosta E, Servi S, Parella T, Joglar J, et al. Serine hydroxymethyl transferase from Streptococcus thermophilus and L-threonine aldolase from Escherichia coli as stereocomplementary biocatalysts for the synthesis of beta-hydroxy-alpha,omega-diamino acid derivatives. Chemistry. 2008;14:4647-56 pubmed publisher
    ..This reaction might be useful for further chemical manipulations of the products...
  19. Read M, M ller I, Mitchell S, Sims P, Hyde J. Dynamic subcellular localization of isoforms of the folate pathway enzyme serine hydroxymethyltransferase (SHMT) through the erythrocytic cycle of Plasmodium falciparum. Malar J. 2010;9:351 pubmed publisher
  20. Angelaccio S, Pascarella S, Fattori E, Bossa F, Strong W, Schirch V. Serine hydroxymethyltransferase: origin of substrate specificity. Biochemistry. 1992;31:155-62 pubmed
    ..This was followed by a very slow first-order formation of a complex absorbing at 425 nm.(ABSTRACT TRUNCATED AT 250 WORDS) ..
  21. Scarsdale J, Kazanina G, Radaev S, Schirch V, Wright H. Crystal structure of rabbit cytosolic serine hydroxymethyltransferase at 2.8 A resolution: mechanistic implications. Biochemistry. 1999;38:8347-58 pubmed
    ..This model explains the properties of several site mutants of SHMT and offers testable hypotheses for a more detailed mechanism of this enzyme. ..
  22. Contestabile R, Angelaccio S, Bossa F, Wright H, Scarsdale N, Kazanina G, et al. Role of tyrosine 65 in the mechanism of serine hydroxymethyltransferase. Biochemistry. 2000;39:7492-500 pubmed
    ..These data are consistent with a role for the Tyr65 hydroxyl group in the conversion of a closed active site to an open structure. ..
  23. Szebenyi D, Liu X, Kriksunov I, Stover P, Thiel D. Structure of a murine cytoplasmic serine hydroxymethyltransferase quinonoid ternary complex: evidence for asymmetric obligate dimers. Biochemistry. 2000;39:13313-23 pubmed
  24. Contestabile R, Paiardini A, Pascarella S, di Salvo M, D Aguanno S, Bossa F. l-Threonine aldolase, serine hydroxymethyltransferase and fungal alanine racemase. A subgroup of strictly related enzymes specialized for different functions. Eur J Biochem. 2001;268:6508-25 pubmed
    ..coli and alanine racemase from Cochliobolus carbonum, and their comparison with the SHMT crystal structure, indicated how the tetrahydrofolate binding site might have evolved and offered a starting point for further investigations. ..
  25. Leartsakulpanich U, Kongkasuriyachai D, Imwong M, Chotivanich K, Yuthavong Y. Cloning and characterization of Plasmodium vivax serine hydroxymethyltransferase. Parasitol Int. 2008;57:223-8 pubmed
    ..Sequencing of 12 P. vivax isolates revealed limited polymorphisms in 3 noncoding regions. Its biological function is also reported. ..
  26. Malerba F, Bellelli A, Giorgi A, Bossa F, Contestabile R. The mechanism of addition of pyridoxal 5'-phosphate to Escherichia coli apo-serine hydroxymethyltransferase. Biochem J. 2007;404:477-85 pubmed
  27. Vatcher G, Thacker C, Kaletta T, Schnabel H, Schnabel R, Baillie D. Serine hydroxymethyltransferase is maternally essential in Caenorhabditis elegans. J Biol Chem. 1998;273:6066-73 pubmed
    ..The C. elegans mel-32 mutation represents the first case where SHMT has been shown to be an essential gene. ..
  28. Florio R, di Salvo M, Vivoli M, Contestabile R. Serine hydroxymethyltransferase: a model enzyme for mechanistic, structural, and evolutionary studies. Biochim Biophys Acta. 2011;1814:1489-96 pubmed publisher
    ..This review will focus on recently highlighted catalytic, structural, and evolutionary aspects of serine hydroxymethyltransferase. This article is part of a Special Issue entitled: Pyridoxal phosphate Enzymology. ..
  29. Skibola C, Smith M, Hubbard A, Shane B, Roberts A, Law G, et al. Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia. Blood. 2002;99:3786-91 pubmed
  30. MacFarlane A, Perry C, McEntee M, Lin D, Stover P. Shmt1 heterozygosity impairs folate-dependent thymidylate synthesis capacity and modifies risk of Apc(min)-mediated intestinal cancer risk. Cancer Res. 2011;71:2098-107 pubmed publisher
  31. van Maris A, Luttik M, Winkler A, van Dijken J, Pronk J. Overproduction of threonine aldolase circumvents the biosynthetic role of pyruvate decarboxylase in glucose-limited chemostat cultures of Saccharomyces cerevisiae. Appl Environ Microbiol. 2003;69:2094-9 pubmed
    ..Like any other Pdc(-) strain, it failed to grow on excess glucose in batch cultures and excreted pyruvate when transferred from glucose limitation to glucose excess. ..
  32. Lee C, Salcedo E, Wang Q, Wang P, Sims P, Hyde J. Characterization of three genes encoding enzymes of the folate biosynthetic pathway in Plasmodium falciparum. Parasitology. 2001;122 Pt 1:1-13 pubmed
  33. Zanetti K, Stover P. Pyridoxal phosphate inhibits dynamic subunit interchange among serine hydroxymethyltransferase tetramers. J Biol Chem. 2003;278:10142-9 pubmed
    ..The results of these studies demonstrate that PLP inhibits dimer exchange among cSHMT tetramers and suggests that cellular PLP concentrations may influence the stability of cSHMT protein in vivo. ..
  34. Salcedo E, Sims P, Hyde J. A glycine-cleavage complex as part of the folate one-carbon metabolism of Plasmodium falciparum. Trends Parasitol. 2005;21:406-11 pubmed
    ..The other isoform probably forms part of the Plasmodium GCV. The GCV is the first enzyme complex involved in folate metabolism in this parasite that can be assumed, with a good degree of certainty, to be located in the mitochondria. ..
  35. Maenpuen S, Sopitthummakhun K, Yuthavong Y, Chaiyen P, Leartsakulpanich U. Characterization of Plasmodium falciparum serine hydroxymethyltransferase-A potential antimalarial target. Mol Biochem Parasitol. 2009;168:63-73 pubmed publisher
    ..Kinetic data in combination with expression result support the proposal of SHMT reaction being a regulatory step for dTMP cycle. This finding suggests that PfSHMT can be a potential target for antimalarial chemotherapy. ..
  36. Tabucchi A, Rainis R, Lorenzi M, Pagani R, Marinello E. Behavior of L-threonine-degrading enzymes during liver regeneration. Biochim Biophys Acta. 1987;926:177-85 pubmed
    ..These findings are useful in the study of the regulation of the enzymes involved in amino acid metabolism during liver regeneration. ..
  37. Kielkopf C, Burley S. X-ray structures of threonine aldolase complexes: structural basis of substrate recognition. Biochemistry. 2002;41:11711-20 pubmed
    ..Variation in the threonine binding pocket may explain preferences for L-allo-threonine versus L-threonine among TA family members...
  38. Byrne P, Sanders P, Snell K. Nucleotide sequence and expression of a cDNA encoding rabbit liver cytosolic serine hydroxymethyltransferase. Biochem J. 1992;286 ( Pt 1):117-23 pubmed
    ..An overall sequence similarity of 34% was noted between all four sequences, whereas the similarity between the rabbit cytosolic and mitochondrial isoforms was 62%. ..
  39. Cai K, Schirch D, Schirch V. The affinity of pyridoxal 5'-phosphate for folding intermediates of Escherichia coli serine hydroxymethyltransferase. J Biol Chem. 1995;270:19294-9 pubmed
    ..These studies support the interpretation that pyridoxal phosphate binds only at the end of the folding pathway to dimeric apoenzyme and plays no significant role in the folding mechanism. ..
  40. Ogawa H, Gomi T, Fujioka M. Serine hydroxymethyltransferase and threonine aldolase: are they identical?. Int J Biochem Cell Biol. 2000;32:289-301 pubmed
    ..Thus, although serine hydroxymethyltransferase from some mammalian livers exhibits a low threonine aldolase activity, the two enzymes are distinct from each other and mammals lack the "genuine" threonine aldolase. ..
  41. Nirmalan N, Flett F, Skinner T, Hyde J, Sims P. Microscale solution isoelectric focusing as an effective strategy enabling containment of hemeoglobin-derived products for high-resolution gel-based analysis of the Plasmodium falciparum proteome. J Proteome Res. 2007;6:3780-7 pubmed
  42. McNeil J, Flynn J, Tsao N, Monschau N, Stahmann K, Haynes R, et al. Glycine metabolism in Candida albicans: characterization of the serine hydroxymethyltransferase (SHM1, SHM2) and threonine aldolase (GLY1) genes. Yeast. 2000;16:167-75 pubmed
    ..cerevisiae. GenBank Accession Nos of the C. albicans SHM1 and SHM2 are AF009965 and AF009966, respectively. Accession No. for C. albicans GLY1 is AF009967. ..
  43. van den Donk M, Visker M, Harryvan J, Kok F, Kampman E. Dietary intake of B-vitamins, polymorphisms in thymidylate synthase and serine hydroxymethyltransferase 1, and colorectal adenoma risk: a Dutch case-control study. Cancer Lett. 2007;250:146-53 pubmed
    ..This study does not provide evidence for a role of SHMT1 genotype in adenoma occurrence. Future research has to indicate whether the TS-B6 interplay is a real effect or a chance finding. ..
  44. Gagnon D, Foucher A, Girard I, Ouellette M. Stage specific gene expression and cellular localization of two isoforms of the serine hydroxymethyltransferase in the protozoan parasite Leishmania. Mol Biochem Parasitol. 2006;150:63-71 pubmed
    ..These findings suggest that folate metabolism is compartmentalised in Leishmania and that SHMT RNA levels are responsive to environmental conditions. ..
  45. Chaves A, Fernandez M, Lerayer A, Mierau I, Kleerebezem M, Hugenholtz J. Metabolic engineering of acetaldehyde production by Streptococcus thermophilus. Appl Environ Microbiol. 2002;68:5656-62 pubmed
    ..These findings can be used to control and improve acetaldehyde production in fermented (dairy) products with S. thermophilus as starter culture. ..
  46. Nirmalan N, Wang P, Sims P, Hyde J. Transcriptional analysis of genes encoding enzymes of the folate pathway in the human malaria parasite Plasmodium falciparum. Mol Microbiol. 2002;46:179-90 pubmed
    ..However, only the latter showed major variation across the cell cycle, with a peak around the time of onset of DNA replication, possibly indicative of a regulatory function. ..
  47. Bhatt A, Prakash K, Subramanya H, Bhakuni V. Different unfolding pathways for mesophilic and thermophilic homologues of serine hydroxymethyltransferase. Biochemistry. 2002;41:12115-23 pubmed
  48. MacFarlane A, Liu X, Perry C, Flodby P, Allen R, Stabler S, et al. Cytoplasmic serine hydroxymethyltransferase regulates the metabolic partitioning of methylenetetrahydrofolate but is not essential in mice. J Biol Chem. 2008;283:25846-53 pubmed publisher
    ..This study suggests that mitochondrial SHMT-derived one-carbon units are essential for folate-mediated one-carbon metabolism in the cytoplasm. ..
  49. Anderson D, Stover P. SHMT1 and SHMT2 are functionally redundant in nuclear de novo thymidylate biosynthesis. PLoS ONE. 2009;4:e5839 pubmed publisher
  50. Renwick S, Snell K, Baumann U. The crystal structure of human cytosolic serine hydroxymethyltransferase: a target for cancer chemotherapy. Structure. 1998;6:1105-16 pubmed
    ..For example, His 151 is not the catalytic base, contrary to the findings of others. A mechanism for the cleavage of serine to glycine and formaldehyde is proposed. ..
  51. Siglioccolo A, Bossa F, Pascarella S. Structural adaptation of serine hydroxymethyltransferase to low temperatures. Int J Biol Macromol. 2010;46:37-46 pubmed publisher
    ..In general, the property variations show a coherent opposite trend in the hyperthermophilic population: in particular, increase of hydrophobicity, packing and decrease of flexibility was observed. ..
  52. Douce R, Bourguignon J, Neuburger M, Rebeille F. The glycine decarboxylase system: a fascinating complex. Trends Plant Sci. 2001;6:167-76 pubmed
    ..Plant mitochondria possess all the necessary enzymatic equipment for de novo synthesis of tetrahydrofolate and lipoic acid, serving as cofactors for glycine decarboxylase and serine hydroxymethyltransferase functioning. ..
  53. Trivedi V, Gupta A, Jala V, Saravanan P, Rao G, Rao N, et al. Crystal structure of binary and ternary complexes of serine hydroxymethyltransferase from Bacillus stearothermophilus: insights into the catalytic mechanism. J Biol Chem. 2002;277:17161-9 pubmed
    ..The four structures presented here correspond to the various reaction intermediates of the catalytic pathway and provide evidence for a direct displacement mechanism for the hydroxymethyl transfer rather than a retroaldol cleavage. ..