Folate metabolism in Streptococcus faecalis.
Ontology highlight
ABSTRACT:
SUBMITTER: McElwee PG
PROVIDER: S-EPMC1178800 | biostudies-other | 1972 May
REPOSITORIES: biostudies-other
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Project description:Folate metabolism affects ovarian function, implantation, embryogenesis and the entire process of pregnancy. In addition to its well-established effect on the incidence of neural tube defects, associations have been found between reduced folic acid levels and increased homocysteine concentrations on the one hand, and recurrent spontaneous abortions and other complications of pregnancy on the other. In infertility patients undergoing IVF/ICSI treatment, a clear correlation was found between plasma folate concentrations and the incidence of dichorionic twin pregnancies. In patients supplemented with 0.4 mg/d folic acid undergoing ovarian hyperstimulation and oocyte pick-up, carriers of the MTHFR 677T mutation were found to have lower serum estradiol concentrations at ovulation and fewer oocytes could be retrieved from them. It appears that these negative effects can be compensated for in full by increasing the daily dose of folic acid to at least 0.8 mg. In carriers of the MTHFR 677TT genotype who receive appropriate supplementation, AMH concentrations were found to be significantly increased, which could indicate a compensatory mechanism. AMH concentrations in homozygous carriers of the MTHFR 677TT genotype could even be overestimated, as almost 20 % fewer oocytes are retrieved from these patients per AMH unit compared to MTHFR 677CC wild-type individuals.
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Project description:Background & aimsThe inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis, are caused in part by aberrant immune responses to resident intestinal bacteria. Certain dietary components, including carbohydrates, are associated with IBDs and alter intestinal bacterial composition. However, the effects of luminal carbohydrates on the composition and colitogenic potential of intestinal bacteria are incompletely understood. We hypothesize that carbohydrate metabolism by resident proinflammatory intestinal bacteria enhances their growth and worsens intestinal inflammation.MethodsWe colonized germ-free, wild-type, and colitis-susceptible interleukin-10 knockout mice (Il10-/-) with a consortium of resident intestinal bacterial strains and quantified colon inflammation using blinded histologic scoring and spontaneous secretion of IL12/23p40 by colon explants. We measured luminal bacterial composition using real-time 16S polymerase chain reaction, bacterial gene expression using RNA sequencing and real-time polymerase chain reaction, and luminal glucosamine levels using gas chromatography-mass spectrometry.ResultsWe show that a consortium of 8 bacterial strains induces severe colitis in Il10-/- mice and up-regulates genes associated with carbohydrate metabolism during colitis. Specifically, Enterococcus faecalis strain OG1RF is proinflammatory and strongly up-regulates OG1RF_11616-11610, an operon that encodes genes of a previously undescribed phosphotransferase system that we show imports glucosamine. Experimental colitis is associated with increased levels of luminal glucosamine and OG1RF_11616 causes worse colitis, not by increasing E faecalis numbers, but rather by mechanisms that require the presence of complex microbiota.ConclusionsFurther studies of luminal carbohydrate levels and bacterial carbohydrate metabolism during intestinal inflammation will improve our understanding of the pathogenesis of IBDs and may lead to the development of novel therapies for these diseases.
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Project description:The translation process, central to life, is tightly connected to the one-carbon (1-C) metabolism via a plethora of macromolecule modifications and specific effectors. Using manual genome annotations and putting together a variety of experimental studies, we explore here the possible reasons of this critical interaction, likely to have originated during the earliest steps of the birth of the first cells. Methionine, S-adenosylmethionine and tetrahydrofolate dominate this interaction. Yet, 1-C metabolism is unlikely to be a simple frozen accident of primaeval conditions. Reactive 1-C species (ROCS) are buffered by the translation machinery in a way tightly associated with the metabolism of iron-sulfur clusters, zinc and potassium availability, possibly coupling carbon metabolism to nitrogen metabolism. In this process, the highly modified position 34 of tRNA molecules plays a critical role. Overall, this metabolic integration may serve both as a protection against the deleterious formation of excess carbon under various growth transitions or environmental unbalanced conditions and as a regulator of zinc homeostasis, while regulating input of prosthetic groups into nascent proteins. This knowledge should be taken into account in metabolic engineering.
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Project description:OBJECTIVE:The primary aims of this study were to (i) determine whether folate metabolism genetic polymorphisms predict age of onset and occurrence of late life depression; and (ii) determine whether folate metabolism genetic polymorphisms predict response to antidepressant medications in late-life depression. METHODS:This study used the Conte Center for the Neuroscience of Depression and the Neurocognitive Outcomes of Depression in the Elderly Study database, which includes individuals aged ?60. The folate nutrition assessment was determined by the Block Food Frequency Questionnaire. Genotype was evaluated for 15 single nucleotide polymorphisms from 10 folate metabolism genes. Logistic regression models were used to examine genetic polymorphisms and folate estimates with association with depression age of onset and remission status. RESULTS:There were 304 Caucasians in the database, 106 of these were not depressed and 198 had a diagnosis of depression. There were no significant differences between remitters and non-remitters in age, sex or estimated folate intakes. There were no folate estimates or folate metabolism gene single nucleotide polymorphisms that significantly predicted age of onset of depression or occurrence of depression. Methionine synthase reductase (MTRR) A66G (rs1801394) was significantly associated with remission status (p?=?0.0077) such that those with the AA genotype were 3.2 times as likely as those with the GG genotype to be in remission (p?=?0.0020). Methylenetetrahydrofolate reductase A1298C (rs1801131) achieved a borderline significance for association with remission status (p?=?0.0313). CONCLUSION:The major finding from this study is that the MTRR A66G genotype predicts response to selective serotonin reuptake inhibitor antidepressants in late life depression.
| S-EPMC3779127 | biostudies-literature
Project description:Single nucleotide polymorphisms and pre- and peri-conception folic acid (FA) supplementation and dietary data were used to identify one-carbon metabolic factors associated with pregnancy outcomes in 3196 nulliparous women. In 325 participants, we also measured circulating folate, vitamin B12 and homocysteine. Pregnancy outcomes included preeclampsia (PE), gestational hypertension (GHT), small for gestational age (SGA), spontaneous preterm birth (sPTB) and gestational diabetes mellitus (GDM). Study findings show that maternal genotype MTHFR A1298C(CC) was associated with increased risk for PE, whereas TCN2 C766G(GG) had a reduced risk for sPTB. Paternal MTHFR A1298C(CC) and MTHFD1 G1958A(AA) genotypes were associated with reduced risk for sPTB, whereas MTHFR C677T(CT) genotype had an increased risk for GHT. FA supplementation was associated with higher serum folate and vitamin B12 concentrations, reduced uterine artery resistance index and increased birth weight. Women who supplemented with <800 μg daily FA at 15-week gestation had a higher incidence of PE (10.3%) compared with women who did not supplement (6.1%) or who supplemented with ≥800 μg (5.4%) (P < .0001). Higher serum folate levels were found in women who later developed GDM compared with women with uncomplicated pregnancies (Mean ± SD: 37.6 ± 8 nmol L-1 vs. 31.9 ± 11.2, P = .007). Fast food consumption was associated with increased risk for developing GDM, whereas low consumption of green leafy vegetables and fruit were independent risk factors for SGA and GDM and sPTB and SGA, respectively. In conclusion, maternal and paternal genotypes, together with maternal circulating folate and homocysteine concentrations, and pre- and early-pregnancy dietary factors, are independent risk factors for pregnancy complications.
| S-EPMC7729528 | biostudies-literature
Project description:A Streptococcus faecalis genomic bank was obtained by partial digestion with MboI and cloning into the SalI restriction site of pTZ18R. Screening of about 60,000 Escherichia coli transformants for cell wall lysis activity was done by exposing recombinant colonies grown on medium containing lyophilized Micrococcus lysodeikticus cells to chloroform and toluene vapors in order to release proteins. Because this procedure provoked cell death, colonies could not be used directly for transformant recovery; however, recovery was achieved by partial purification of plasmid DNA from active colonies on the agar plate and transformation of E. coli competent cells. About 60 recombinants were found. One of them (pSH6500) codes for a lytic enzyme active against S. faecalis and M. lysodeikticus cell walls. A shorter clone (pSH4000) was obtained by deleting an EcoRI fragment from the 6.5-kb original insert, leaving a 4-kb EcoRI-MboI insert; this subclone expressed the same lytic activity. Sequencing of a portion of pSH4000 revealed a unique open reading frame of 2,013 nucleotides coding for a 641-amino-acid (74-kDa) polypeptide and containing four 204-nucleotide direct repeats.
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Project description:FDH (10-formyltetrahydrofolate dehydrogenase, Aldh1L1, EC 1.5.1.6) converts 10-formyltetrahydrofolate (10-formyl-THF) to tetrahydrofolate and CO(2) in a NADP(+)-dependent reaction. It is a tetramer of four identical 902 amino acid residue subunits. The protein subunit is a product of a natural fusion of three unrelated genes and consists of three distinct domains. The N-terminal domain of FDH (residues 1-310) carries the folate binding site and shares sequence homology and structural topology with other enzymes utilizing 10-formyl-THF as a substrate. In vitro it functions as 10-formyl-THF hydrolase, and evidence indicate that this activity is a part of the overall FDH mechanism. The C-terminal domain of FDH (residues 400-902) originated from an aldehyde dehydrogenase-related gene and is capable of oxidation of short-chain aldehydes to corresponding acids. Similar to classes 1 and 2 aldehyde dehydrogenases, this domain exists as a tetramer and defines the oligomeric structure of the full-length enzyme. The two catalytic domains are connected by an intermediate linker (residues 311-399), which is a structural and functional homolog of carrier proteins possessing a 4'-phosphopantetheine prosthetic group. In the FDH mechanism, the intermediate linker domain transfers a formyl, covalently attached to the sulfhydryl group of the phosphopantetheine arm, from the N-terminal domain to the C-terminal domain. The overall FDH mechanism is a coupling of two sequential reactions, a hydrolase and a formyl dehydrogenase, bridged by a substrate transfer step. In this mechanism, one domain provides the folate binding site and a hydrolase catalytic center to remove the formyl group from the folate substrate, another provides a transfer vehicle between catalytic centers and the third one contributes the dehydrogenase machinery further oxidizing formyl to CO(2).
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Project description:BackgroundPrevious mathematical models for hepatic and tissue one-carbon metabolism have been combined and extended to include a blood plasma compartment. We use this model to study how the concentrations of metabolites that can be measured in the plasma are related to their respective intracellular concentrations.MethodsThe model consists of a set of ordinary differential equations, one for each metabolite in each compartment, and kinetic equations for metabolism and for transport between compartments. The model was validated by comparison to a variety of experimental data such as the methionine load test and variation in folate intake. We further extended this model by introducing random and systematic variation in enzyme activity. OUTCOMES AND CONCLUSIONS: A database of 10,000 virtual individuals was generated, each with a quantitatively different one-carbon metabolism. Our population has distributions of folate and homocysteine in the plasma and tissues that are similar to those found in the NHANES data. The model reproduces many other sets of clinical data. We show that tissue and plasma folate is highly correlated, but liver and plasma folate much less so. Oxidative stress increases the plasma S-adenosylmethionine/S-adenosylhomocysteine (SAM/SAH) ratio. We show that many relationships among variables are nonlinear and in many cases we provide explanations. Sampling of subpopulations produces dramatically different apparent associations among variables. The model can be used to simulate populations with polymorphisms in genes for folate metabolism and variations in dietary input.
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Project description:Enzyme function and evolution are influenced by the larger context of a metabolic pathway. Deleterious mutations or perturbations in one enzyme can often be compensated by mutations to others. We used comparative genomics and experiments to examine evolutionary interactions with the essential metabolic enzyme dihydrofolate reductase (DHFR). Analyses of synteny and co-occurrence across bacterial species indicate that DHFR is coupled to thymidylate synthase (TYMS) but relatively independent from the rest of folate metabolism. Using quantitative growth rate measurements and forward evolution in Escherichia coli, we demonstrate that the two enzymes adapt as a relatively independent unit in response to antibiotic stress. Metabolomic profiling revealed that TYMS activity must not exceed DHFR activity to prevent the depletion of reduced folates and the accumulation of the intermediate dihydrofolate. Comparative genomics analyses identified >200 gene pairs with similar statistical signatures of modular co-evolution, suggesting that cellular pathways may be decomposable into small adaptive units.
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