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Gene Review

SHMT1  -  serine hydroxymethyltransferase 1 (soluble)

Homo sapiens

Synonyms: CSHMT, Glycine hydroxymethyltransferase, MGC15229, MGC24556, SHMT, ...
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Disease relevance of SHMT1

  • BACKGROUND AND OBJECTIVES: Polymorphisms in thymidylate synthase (TS) 28-bp tandem repeats in the promoter region and in cytosolic serine hydroxymethyltransferase (SHMT1 C1420T) have been reported to modulate the risk of adult acute lymphocytic leukemia (ALL) [1].
  • ATIC 347GG was associated with gastrointestinal side effects (OR 3.0, P < 0.01), while TSER*2/*2 (OR 5.4, P < 0.01) and SHMT1 1420CC (OR 3.2, P < 0.01) were associated with alopecia [2].
  • SHMT is a highly conserved protein with the human isozymes retaining about 43% sequence identity with the E. coli protein [3].
  • The human cytoplasmic serine hydroxymethyltransferase (CSHMT) gene was isolated, sequenced and its expression characterized in human MCF-7 mammary carcinoma and SH_5Y5Y neuroblastoma cells [4].
  • We have isolated phage clones containing human genomic sequences homologous to cytosolic SHMT and have found these to contain a processed pseudogene (SHMT-ps1) with a 90% identity to cloned SHMT cDNAs [5].

High impact information on SHMT1

  • Folate-dependent one-carbon metabolism is critical for the synthesis of numerous cellular constituents required for cell growth, and serine hydroxymethyltransferase (SHMT) is central to this process [6].
  • In conclusion, polymorphisms in the folate-related genes MTHFR, MTRR, and SHMT1 are related to MTX resistance in pediatric patients with ALL [7].
  • SHMT1 1420TT homozygotes only showed decreased MTX sensitivity in the TSI(50, cont) [7].
  • We did not observe any significant differences in genotype frequencies of the SHMT1 and RFC polymorphisms between the cases and controls [8].
  • TS 3R3R individuals who were SHMT1 1420CT/TT had a 13.9-fold decreased ALL risk (OR = 0.072; 95% CI, 0.0067-0.77) [9].

Chemical compound and disease context of SHMT1

  • Expression of malarial SHMT coding sequence (minus the introns) into glyA mutants of Escherichia coli relieved glycine auxotrophy and permitted direct assay of SHMT catalytic activity in bacterial cell lysates [10].
  • SHMT tetramers have surface charge distributions which suggest distinctions in folate binding between eukaryotic and E. coli enzymes [11].
  • The gene (glyA) of Methylobacterium extorquens AM1 encoding serine hydroxymethyltransferase (SHMT), one of the key enzymes of the serine cycle for C1 assimilation, was isolated by using a synthetic oligonucleotide with a sequence based on amino acid sequence conserved in SHMTs from different sources [12].

Biological context of SHMT1

  • A mimosine-responsive transcriptional element was localized within the first 50 base pairs of the human SHMT1 promoter by deletion analyses and gel mobility shift assays [13].
  • In a univariate analysis, SHMT1 1420CT individuals exhibited a 2.1-fold decrease in ALL risk (odds ratio [OR] = 0.48; 95% confidence interval [CI], 0.25-0.91), whereas the 1420TT genotype conferred a 3.3-fold reduction in risk (OR = 0.31; 95% CI, 0.10-0.90) [9].
  • Polyglutamates of HPteGlu and of H4HPteGlu are poor inhibitors of SHMT (IC50, greater than 20 microM) [14].
  • The human cytosolic and mitochondrial SHMT genes were localized to chromosome regions 17p11.2 and 12q13, respectively [3].
  • The open reading frame is interrupted by 10 introns, two of which are positionally conserved within the human mitochondrial SHMT gene [4].

Anatomical context of SHMT1

  • MCF-7 cells cultured in zinc-depleted medium for more than 16 days were viable and lacked cytoplasmic serine hydroxymethyltransferase protein, confirming that mimosine inhibits SHMT1 transcription by chelating zinc [13].
  • Risk genotypes associated with side effects in the central nervous system were MTHFR 677TT (OR 3.3, P < 0.01) and SHMT1 1420CC (OR 2.4, P < 0.05) [2].
  • Serine hydroxymethyltransferase (SHMT) has been purified from the mitochondria of green pea leaves [15].
  • Two different isoforms of SHMT are known, one is present in the cytosol (cSHMT) and the other in the mitochondrion (mSHMT) [16].
  • The Km of SHMT, and the concentration of serine and glycine were all significantly higher in the temporal lobes of brain tissues from schizophrenics than in those from controls [17].

Associations of SHMT1 with chemical compounds

  • Furthermore, this study establishes that SHMT1 is a zinc-inducible gene, which provides the first mechanism for the regulation of folate-mediated one-carbon metabolism by zinc [13].
  • In this study, the mechanism for mimosine-induced inhibition of SHMT1 transcription was elucidated [13].
  • As an enzyme of the thymidylate synthase metabolic cycle, SHMT catalyses the retro-aldol cleavage of serine to glycine, with the resulting hydroxymethyl group being transferred to tetrahydrofolate to form 5, 10-methylene-tetrahydrofolate [18].
  • Plasma homocysteine was not significantly influenced by the SHMT, TS, COMT and TC mutations [19].
  • In the sheep, placental conversion of maternal serine by serine hydroxymethyltransferase (SHMT) provides almost all the glycine transported to the fetus [20].

Other interactions of SHMT1

  • Further, MS 2756AG individuals who were SHMT1 1420CT/TT had a 5.6-fold reduction in ALL risk (OR = 0.18; 95% CI, 0.05-0.63) [9].

Analytical, diagnostic and therapeutic context of SHMT1

  • In a hospital-based, case-control study of 721 non-Hispanic white SCCHN patients and 1,234 control subjects, frequency-matched by age and sex, three known SHMT1 polymorphisms (34761C>T, 34840C>G and 34859C>T) were genotyped [21].
  • Multiple tissue Northern blots suggest that the CSHMT message levels and alternative splicing patterns display tissue-specific variations [4].
  • Elevated activities of SHMT have been correlated with the increased demand for nucleotide biosynthesis in tumors of human and rodent origin, making this enzyme a novel target for cancer chemotherapy [22].
  • Here the purification and crystallization of recombinant human cytosolic SHMT are reported [22].
  • The affinity of phosvitin with serine hydroxymethyl transferase (SHMT), an acidic multi-subunit protein, was evaluated by measurements of enzyme activity, sedimentation velocity, steady-state fluorescence, circular dichroism and kinetic thermal stability [23].


  1. Associations between polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and susceptibility to malignant lymphoma. Hishida, A., Matsuo, K., Hamajima, N., Ito, H., Ogura, M., Kagami, Y., Taji, H., Morishima, Y., Emi, N., Tajima, K. Haematologica (2003) [Pubmed]
  2. Risk genotypes in folate-dependent enzymes and their association with methotrexate-related side effects in rheumatoid arthritis. Weisman, M.H., Furst, D.E., Park, G.S., Kremer, J.M., Smith, K.M., Wallace, D.J., Caldwell, J.R., Dervieux, T. Arthritis Rheum. (2006) [Pubmed]
  3. Cloning of human cDNAs encoding mitochondrial and cytosolic serine hydroxymethyltransferases and chromosomal localization. Garrow, T.A., Brenner, A.A., Whitehead, V.M., Chen, X.N., Duncan, R.G., Korenberg, J.R., Shane, B. J. Biol. Chem. (1993) [Pubmed]
  4. Molecular cloning, characterization and alternative splicing of the human cytoplasmic serine hydroxymethyltransferase gene. Girgis, S., Nasrallah, I.M., Suh, J.R., Oppenheim, E., Zanetti, K.A., Mastri, M.G., Stover, P.J. Gene (1998) [Pubmed]
  5. Characterisation of a human serine hydroxymethyltransferase pseudogene and its localisation to 1p32.3-33. Byrne, P.C., Shipley, J.M., Chave, K.J., Sanders, P.G., Snell, K. Hum. Genet. (1996) [Pubmed]
  6. Haploinsufficiency of cytosolic serine hydroxymethyltransferase in the Smith-Magenis syndrome. Elsea, S.H., Juyal, R.C., Jiralerspong, S., Finucane, B.M., Pandolfo, M., Greenberg, F., Baldini, A., Stover, P., Patel, P.I. Am. J. Hum. Genet. (1995) [Pubmed]
  7. Effect of polymorphisms in folate-related genes on in vitro methotrexate sensitivity in pediatric acute lymphoblastic leukemia. de Jonge, R., Hooijberg, J.H., van Zelst, B.D., Jansen, G., Jansen, G., van Zantwijk, C.H., van Zantwijk, C.H., Kaspers, G.J., Kaspers, G.J., Peters, G.J., Peters, F.G., Ravindranath, Y., Pieters, R., Lindemans, J. Blood (2005) [Pubmed]
  8. Polymorphisms and haplotypes in folate-metabolizing genes and risk of non-Hodgkin lymphoma. Skibola, C.F., Forrest, M.S., Coppedé, F., Agana, L., Hubbard, A., Smith, M.T., Bracci, P.M., Holly, E.A. Blood (2004) [Pubmed]
  9. Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia. Skibola, C.F., Smith, M.T., Hubbard, A., Shane, B., Roberts, A.C., Law, G.R., Rollinson, S., Roman, E., Cartwright, R.A., Morgan, G.J. Blood (2002) [Pubmed]
  10. Gene organization of a Plasmodium falciparum serine hydroxymethyltransferase and its functional expression in Escherichia coli. Alfadhli, S., Rathod, P.K. Mol. Biochem. Parasitol. (2000) [Pubmed]
  11. Crystal structure at 2.4 A resolution of E. coli serine hydroxymethyltransferase in complex with glycine substrate and 5-formyl tetrahydrofolate. Scarsdale, J.N., Radaev, S., Kazanina, G., Schirch, V., Wright, H.T. J. Mol. Biol. (2000) [Pubmed]
  12. Genetics of the serine cycle in Methylobacterium extorquens AM1: cloning, sequence, mutation, and physiological effect of glyA, the gene for serine hydroxymethyltransferase. Chistoserdova, L.V., Lidstrom, M.E. J. Bacteriol. (1994) [Pubmed]
  13. Mimosine attenuates serine hydroxymethyltransferase transcription by chelating zinc. Implications for inhibition of DNA replication. Perry, C., Sastry, R., Nasrallah, I.M., Stover, P.J. J. Biol. Chem. (2005) [Pubmed]
  14. Inhibition of glycinamide ribonucleotide formyltransferase and other folate enzymes by homofolate polyglutamates in human lymphoma and murine leukemia cell extracts. Thorndike, J., Gaumont, Y., Kisliuk, R.L., Sirotnak, F.M., Murthy, B.R., Nair, M.G., Piper, J.R. Cancer Res. (1989) [Pubmed]
  15. Identification and localization of multiple forms of serine hydroxymethyltransferase in pea (Pisum sativum) and characterization of a cDNA encoding a mitochondrial isoform. Turner, S.R., Ireland, R., Morgan, C., Rawsthorne, S. J. Biol. Chem. (1992) [Pubmed]
  16. Is mutated serine hydroxymethyltransferase (SHMT) involved in the etiology of neural tube defects? Heil, S.G., Van der Put, N.M., Waas, E.T., den Heijer, M., Trijbels, F.J., Blom, H.J. Mol. Genet. Metab. (2001) [Pubmed]
  17. Abnormal serine hydroxymethyl transferase activity in the temporal lobes of schizophrenics. Waziri, R., Baruah, S., Hegwood, T.S., Sherman, A.D. Neurosci. Lett. (1990) [Pubmed]
  18. The crystal structure of human cytosolic serine hydroxymethyltransferase: a target for cancer chemotherapy. Renwick, S.B., Snell, K., Baumann, U. Structure (1998) [Pubmed]
  19. The role of genetic factors in the development of hyperhomocysteinemia. Geisel, J., Hübner, U., Bodis, M., Schorr, H., Knapp, J.P., Obeid, R., Herrmann, W. Clin. Chem. Lab. Med. (2003) [Pubmed]
  20. Low serine hydroxymethyltransferase activity in the human placenta has important implications for fetal glycine supply. Lewis, R.M., Godfrey, K.M., Jackson, A.A., Cameron, I.T., Hanson, M.A. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  21. Polymorphisms and haplotypes of serine hydroxymethyltransferase and risk of squamous cell carcinoma of the head and neck: a case-control analysis. Zhang, Z., Shi, Q., Sturgis, E.M., Spitz, M.R., Wei, Q. Pharmacogenet. Genomics (2005) [Pubmed]
  22. Purification, crystallization and preliminary X-ray analysis of human recombinant cytosolic serine hydroxymethyltransferase. Renwick, S.B., Skelly, J.V., Chave, K.J., Sanders, P.G., Snell, K., Baumann, U. Acta Crystallogr. D Biol. Crystallogr. (1998) [Pubmed]
  23. Affinity properties of phosvitin: interaction of phosvitin with serine hydroxymethyl transferase. Lakhey, H.V., Rao, A.G., Prakash, V., Krishnaswamy, P.R., Savithri, H.S., Rao, N.A., Ramadoss, C.S. Indian J. Biochem. Biophys. (1999) [Pubmed]
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