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Genetic variation in folylpolyglutamate synthase and gamma-glutamyl hydrolase and plasma homocysteine levels in the Singapore Chinese Health Study.

ABSTRACT: The enzymes folylpolyglutamate synthase (FPGS) and gamma-glutamyl hydrolase (GGH) are essential for determining intracellular folate availability for one-carbon metabolism (OCM) pathways. FPGS adds glutamyl groups to the folate molecule, thereby converting folate into the preferred substrate for several enzymes in OCM pathways. GGH removes glutamyl groups, allowing folate metabolites to leave the cell. The purpose of this study was to evaluate whether single nucleotide polymorphisms (SNPs) in the FPGS and GGH genes influence measured plasma homocysteine levels. Study participants were a sub-cohort (n=482) from the Singapore Chinese Health Study. SNPs were selected using HapMap tagSNPs and SNPs previously reported in the scientific literature. Multiple linear regression was used to evaluate the association between individual SNPs and plasma homocysteine levels. Two FPGS (rs10106, rs1098774) and 9 GGH (rs719235, rs1031552, rs1800909, rs3758149, rs3780126, rs3824333, rs4617146, rs11545076, rs11545078) SNPs were included in the final analysis. Neither of the FPGS SNPs, but three GGH SNPs were associated with plasma homocysteine levels: rs11545076 (p=0.001), rs1800909 (p=0.02), and rs3758149 (p=0.006). Only one (rs11545076) remained statistically significant after adjusting for multiple comparisons. This study suggests that GGH SNPs, rs11545076, rs1800909, and rs3758149, may have functional relevance and result in alterations in plasma homocysteine levels. Since this is one of the first studies to assess FPGS and GGH genetic variants in relation to plasma homocysteine, further research is needed to confirm these findings and characterize the functional effects of these variants.

SUBMITTER: Oppeneer SJ

PROVIDER: S-EPMC3253895 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Genetic variation in folylpolyglutamate synthase and gamma-glutamyl hydrolase and plasma homocysteine levels in the Singapore Chinese Health Study.

Oppeneer Sarah J SJ Ross Julie A JA Koh Woon-Puay WP Yuan Jian-Min JM Robien Kim K

Molecular genetics and metabolism 20111006 1

The enzymes folylpolyglutamate synthase (FPGS) and gamma-glutamyl hydrolase (GGH) are essential for determining intracellular folate availability for one-carbon metabolism (OCM) pathways. FPGS adds glutamyl groups to the folate molecule, thereby converting folate into the preferred substrate for several enzymes in OCM pathways. GGH removes glutamyl groups, allowing folate metabolites to leave the cell. The purpose of this study was to evaluate whether single nucleotide polymorphisms (SNPs) in th ...[more]

PMID: 22018726

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Project description:Background: Dementia, as a global public health problem, is becoming increasingly serious. As a precursor of dementia, mild cognitive impairment (MCI) plays an important role in the diagnosis and prevention of dementia. Recent studies have found a correlation between gamma-glutamyl transferase (GGT) levels and cognitive function in men. The relationship between GGT levels and cognitive function in women remains unclear because GGT activity and expression differ between the sexes. Method: We recruited a total of 2,943 Chinese women from Jidong and Taian in 2019. We grouped the participants according to GGT levels, diagnosed MCI using the Montreal Cognitive Assessment (MOCA) scale, and modeled the study outcomes using logistic regression to explore the relationship between GGT level and MCI. We also analyzed the interaction of obesity, sleep duration, and hyperuricemia with GGT in the development of MCI. Results: The prevalence of MCI increased with increasing GGT level, from the lowest quartile to the highest quartile of GGT: 8.4% (66/786), 14.2% (119/840), 17.6% (108/613), and 21.4% (151/704), respectively. At the same time, as GGT levels increased, so did the risk of MCI. In the fully adjusted model, compared with those for participants in the lowest GGT quartiles, the odds ratios (ORs), and 95% confidence intervals (CIs) for MCI for participants in the second, third, and fourth GGT quartiles were 1.49 (1.04-2.12), 1.53(1.06-2.21), and 1.88 (1.33-2.65), respectively. The risk of developing MCI was further increased in people with high GGT levels who were obese (OR = 1.96, 95% CI: 1.39-2.76, P < 0.001), slept less (OR = 1.91, 95% CI: 1.35-2.71, P < 0.001), had high levels of uric acid (OR = 1.55, 95% CI: 1.03-2.32, P < 0.001), or after menopause (OR = 2.92, 95% CI: 2.07-4.12, P < 0.001). Conclusion: We found that MCI is more common in women with elevated GGT levels, so GGT could be a potential diagnostic marker for MCI. Meanwhile, our findings indicated that women with high GGT levels had an increased risk of MCI when they were obese, sleep deprived, had high serum uric acid (SUA) levels or underwent menopause.

Project description:The role of glutathione (GSH) in eukaryotic cells is well known. The biosynthesis of this γ-glutamine tripeptide is well studied. However, other γ-glutamyl peptides were found in various sources, and the pathways of their formation were not always clear. The aim of the present study was to determine whether Saccharomyces cerevisiae can produce γ-glutamyl tripeptides other than GSH and to identify the pathways associated with the formation of these peptides. The tripeptide γ-Glu-Val-Gly (γ-EVG) was used as a model. Wild-type yeast cells were shown to produce this peptide during cultivation in minimal synthetic medium. Two different biosynthetic pathways for this peptide were identified. The first pathway consisted of two steps. In the first step, γ-Glu-Val (γ-EV) was produced from glutamate and valine by the glutamate-cysteine ligase (GCL) Gsh1p or by the transfer of the γ-glutamyl group from GSH to valine by the γ-glutamyltransferase (GGT) Ecm38p or by the (Dug2p-Dug3p)2 complex. In the next step, γ-EV was combined with glycine by the glutathione synthetase (GS) Gsh2p. The second pathway consisted of transfer of the γ-glutamyl residue from GSH to the dipeptide Val-Gly (VG). This reaction was carried out mainly by the (Dug2p-Dug3p)2 complex, whereas the GGT Ecm38p did not participate in this reaction. The contribution of each of these two pathways to the intracellular pool of γ-EVG was dependent on cultivation conditions. In this work, we also found that Dug1p, previously identified as a Cys-Gly dipeptidase, played an essential role in the hydrolysis of the dipeptide VG in yeast cells. It was also demonstrated that γ-EV and γ-EVG could be effectively imported from the medium and that γ-EVG was imported by Opt1p, known to be a GSH importer. Our results demonstrated that γ-glutamyl peptides, particularly γ-EVG, are produced in yeast as products of several physiologically important reactions and are therefore natural components of yeast cells.

Project description:BACKGROUND: S-adenosyl-l-homocysteine hydrolase (SAHH) is the only eukaryotic enzyme capable of S-adenosyl-l-homocysteine (SAH) catabolism for the maintenance of cellular transmethylation potential. Recently, biochemical and genetic studies in herbaceous species have obtained important discoveries in the function of SAHH, and an extensive characterization of SAHH family in even one tree species is essential, but currently lacking. RESULTS: Here, we first identified the SAHH family from Populus tomentosa using molecular cloning method. Phylogenetic analyses of 28 SAHH proteins from dicotyledons, monocotyledons, and lower plants revealed that the sequences formed two monophyletic groups: the PtrSAHHA with PtoSAHHA and PtrSAHHB with PtoSAHHB. Examination of tissue-specific expression profiles of the PtoSAHH family revealed similar expression patterns; high levels of expression in xylem were found. Nucleotide diversity and linkage disequilibrium (LD) in the PtoSAHH family, sampled from P. tomentosa natural distribution, revealed that PtoSAHH harbors high single-nucleotide polymorphism (SNP) diversity (? = 0.01059 ± 0.00122 and 0.00930 ± 0.00079,respectively) and low LD (r2 > 0.1, within 800 bp and 2,200 bp, respectively). Using an LD-linkage analysis approach, two noncoding SNPs (PtoSAHHB_1065 and PtoSAHHA_2203) and the corresponding haplotypes were found to significantly associate with ?-cellulose content, and a nonsynonymous SNP (PtoSAHHB_410) within the SAHH signature motifs showed significant association with fiber length, with an average of 3.14% of the phenotypic variance explained. CONCLUSIONS: The present study demonstrates that PtoSAHHs were split off prior to the divergence of interspecies in Populus, and SAHHs may play a key role promoting transmethylation reactions in the secondary cell walls biosynthesis in trees. Hence, our findings provide insights into SAHH function and evolution in woody species and also offer a theoretical basis for marker-aided selection breeding to improve the wood quality of Populus.

Dataset Information

Genetic variation in folylpolyglutamate synthase and gamma-glutamyl hydrolase and plasma homocysteine levels in the Singapore Chinese Health Study.

Publications

Genetic variation in folylpolyglutamate synthase and gamma-glutamyl hydrolase and plasma homocysteine levels in the Singapore Chinese Health Study.

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