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].

References