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Results for “Glycine Hydroxymethyltransferase”

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At least 19 recordsLinked to original sources
PubMed1978

Interaction of pyridoxal 5-phosphate with apo-serine hydroxymethyltransferase.

The interaction of pyridoxal 5-phosphate with beef liver serine hydroxymethyltransferase (5,10-methylenetetrahydrofolate:glycine hydroxymethyltransferase, EC 2.1.2.1) has been investigated using sedimentation velocity, kinetic and equilibrium techniques. No evidence for an aggregating system could be found in sedimentation velocity experiments in the presence or absence of pyridoxal 5-phosphate. Reassociation of pyridoxal 5-phosphate with apoenzyme and reacquisition of enzymic activity follow identical kinetics. An initial fast step is followed by a second order process with a rate constant of 66 M-1. s-1. A dissociation constant of 27.5 micrometer was obtained from equilibrium studies. No interaction of binding sites was exposed by altering pH or in the presence of glycine or folate. Maxima observed in pH profiles with both binding and reactivation are interpreted as the composite fo two overlapping processes, one of which is ionization of the pyridinium nitrogen of pyridoxal 5-phosphate and the other a functional group on the apoenzyme. Evidence is presented to indicate the necessity for the formation of an enzyme . pyridoxal 5-phosphate Schiff's base complex during catalytic turnover.

Apoenzymes↗
PubMed1978

Serine transhydroxymethylase. Equilibrium binding of folate analogs as active site probes.

Formation of a quinoid-like structure within the glycyl-pyridoxal phosphate moiety of serine transhydroxymethylase (5,10-methylenetetrahydrofolate: glycine hydroxymethyltransferase, EC 2.1.2.1) is dependent upon the dissociation of the 2-S hydrogen of glycine which in turn requires the presence of tetrahydrofolate or analogs thereof. Equilibrium binding studies with the series folate, dihydrofolate, and tetrahydrofolate showed that reduction of the pteridine ring enhances both quinoid formation and binding. A 5,8-deazafolate series showed that modifications in the 4 position, 10 position and the glutamyl position yield interrelated alterations of quinoid formation which could not be correlated with binding.

Binding Sites↗
PubMed1979

Serine hydroxymethylase. Specificity of bond cleaveage to form quinonoid intermediates and rate of holoenzyme formation.

L-Serine transhydroxymethylase (5,10-methylenetetrahydrofolate:glycine hydroxymethyltransferase, EC 2.1.2.1) a pyridoxal phosphate-dependent enzyme, has been obtained as a homogeneous preparation with a specific activity of 6.7 mumol benzaldehyde per minute at 30 degrees C at pH 7.5 in N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (Hepes) buffer, with DL-threo-beta-phenylserine as a substrate. This enzyme has been used to study the specificity of bond cleavage in forming quinonoid intermediates from DL and non-asymmetric amino acids. The ability of the generated quinonoids to react with formaldehyde and acetaldehyde has also been studied and evidence obtained for formation of the corresponding beta-hydroxymethyl and beta-hydroxyethyl amino acid derivaties. Apotranshydroxymethylase has been prepared and the rate of holoenzyme formation was found to be 0.52 min-1 by measuring Schiff base formation at 425 nm and 0.66 min-1 as determined from restoration of enzymic activity. A requirement for the presence of mercaptoethanol for complete reactivation was also established by these studies.

Aldehydes↗
PubMed1979

Production of L-serine by Sarcina albida.

Conditions for the production of microbial L-serine hydroxymethyltransferase and for the conversion of glycine to L-serine were studied. A number of microorganisms were screened for their abilities to form and accululate L-serine from glycine, and Sarcina albida was selected as the best organism. Enzyme activity in this organism as high as 0.12 U/ml could be produced in shaken cultures at 30 degrees C in a medium containing glucose, ammonium sulfate, glycine, yeast extract, and inorganic salts. L-Serine was produced most efficiently by shaking cells at 30 degrees C in a reaction mixture containing 20% glycine, 5 X 10(-3) M formaldehyde, and 3 X 10(-4) M pyridoxal phosphate in yields of 22 mg of broth in 5 days. L-Serine was easily isolated in 84% yields by ion-exchange resin.

Bacteria↗
PubMed1977

Influence of methionine biosynthesis on serine transhydroxymethylase regulation in Salmonella typhimurium LT2.

The enzyme serine transhydroxymethylase (EC 2.1.2.1; L-serine:tetrahydrofolate-5,10-hydroxymethyltransferase) is responsible both for the synthesis of glycine from serine and production of the 5,10-methylenetetrahydrofolate necessary as a methyl donor for methionine synthesis. Two mutants selected for alteration in serine transhydroxymethylase regulation also have phenotypes characteristic of metK (methionine regulatory) mutants, including ethionine, norleucine, and alpha-methylmethionine resistance and reduced levels of S-adenosylmethionine synthetase (EC 2.5.1.6; adenosine 5'-triphosphate:L-methionine S-adenosyltransferase) activity. Because this suggested the existence of a common regulatory component, the regulation of serine transhydroxymethylase was examined in other methionine regulatory mutants (metK and metJ mutants). Normally, serine transhydroxymethylase levels are repressed three- to sixfold in cells grown in the presence of serine, glycine, methionine, adenine, guanine, and thymine. This does not occur in metK and metJ mutants; thus, these mutations do affect the regulation of both serine transhydroxymethylase and the methionine biosynthetic enzymes. Lesions in the metK gene have been reported to reduce S-adenosylmethionine synthetase levels. To determine whether the metK gene actually encodes for S-adenosylmethionine synthetase, a mutant was characterized in which this enzyme has a 26-fold increased apparent Km for methionine. This mutation causes a phenotype associated with metK mutants and is cotransducible with the serA locus at the same frequency as metK lesions. Thus, the affect of metK mutations on the regulation of glycine and methionine synthesis in Salmonella typhimurium appears to be due to either an altered S-adenosylmethionine synthetase or altered S-adenosylmethionine pools.

Enzyme Repression↗
PubMed1978

Selection of Salmonella typhimurium mutants with altered serine transhydroxymethylase regulation.

In Salmonella typhimurium the glyA gene product, serine transhydroxymethylase (E.C. 2.1.2.1.; L-serine:tetrahydrofolate-5,10-hydroxymethyltransferase) is responsible for the interconversion of serine and glycine. This reaction also provides the cell with one-carbon units from the 5,10-methylene-tetrahydrofolate formed during glycine synthesis. Despite the importance of this enzyme, however, no mutants in which its regulation has been specificially altered have been isolated. To isolate such mutants, we have devised a selection procedure using a strain (glyA951) in which the serine transhydroxymethylase activity is reduced. When this enzyme is completely repressed, the mutant requires gylcine for growth. Revertants which retain the glyA951 lesion, but no longer require glycine, have been isolated and the serine transhydroxymethylase regulation examined. One revertant has a 7-fold elevated serine transhydroxymethylase level, which can be repressed the normal amount (about 5-fold) when the cells are grown in supplemented media. Another revertant has only a 2-fold higher serine transhydroxymethylase level; however, the amount of repression is reduced. The new lesions in both mutants cotransduce with the glyA gene and are distinct from other mutations that alter the regulation of both serine transhydroxymethylase and the methionine biosyntheitc enzymes.

Enzyme Repression↗
PubMed1976

One-carbon metabolism in Neurospora crassa wild-type and in mutants partially deficient in serine hydroxymethyltransferase.

1. The concentrations of folate-dependent enzymes in Neurospora crassa Lindegren A wild type (FGSC no. 853), Ser-l mutant, strain H605a (FGSC no. 118), and for mutant, strain C-24 (FGSC no. 9), were compared during exponential growth on defined minimal media. Both mutants were partially lacking in serine hydroxymethyltransferase, but contained higher concentrations of 10-formyltetrahydrofolate synthetase than did the wild type. Mycelia of the mutants contained higher concentrations of these enzymes when growth media were supplemented with 1mM-glycine. In the wild-type, this glycine supplement also increased the specific activities of 5,10-methylenetetrahydrofolate dehydrogenase and 5,10-methylenetetrahydrofolate reductase. 5. During growth, total folate and polyglutamyl folate concentrations were greatest in the wild-type. Methylfolates were not detected in mutant Ser-l, and were only present in the for mutant after growth in glycine-supplemented media. Exogenous glycine increased folate concentration threefold in the wild type, mainly owing to increases in unsubstituted polyglutamyl derivatives. 3. Feeding experiments using 14C-labelled substrates showed that C1 units were generated from formate, glycine and serine in the wild type. Greater incorporation of 14C occurred when mycelia were cultured in glycine-supplemented media. Formate and serine were precursors of C1 units in the mutants, but the ability to cleave glycine was slight or lacking.

Alcohol Oxidoreductases↗
PubMed1979

Serine hydroxymethyltransferase activity and serine incorporation in leukocytes.

Studies of serine hydroxymethyltransferase activity in extracts of leukocytes from normal and leukemic subjects showed that the enzyme is present in lymphocytes and granulocytes but that activity is higher in lymphocytes. It is also higher than normal in lymphocytes from patients with chronic lymphocytic leukemia and to a lesser extent in the leukocytes of patients with acute myelocytic leukemia and acute lymphocytic leukemia. A striking increase in activity occurs in lymphocytes stimulated by phytohemagglutinin to divide in culture. Enzyme activity rises severalfold before cell number increases. Stimulated lymphocytes take up [3-14C]serine from the medium and incorporate its radioactivity into DNA, RNA, and other cell fractions. The rate of incorporation increases sharply before the rise in cell number. Thus, serine hydroxymethyltransferase activity and serine incorporation in vivo show a temporal correlation in stimulated lymphocytes. Inhibitors of DNA synthesis (e.g., fluorodeoxyuridine or high concentrations of adenosine or thymidine) block incorporation of serine radioactivity into DNA and other cell fractions. The results suggest that serine hydroxymethyltransferase activity and cellular uptake of serine have a significant role in proliferating cells.

DNA↗
PubMed1978

Regulation of monkey liver serine hydroxymethyltransferase by nicotinamide nucleotide.

The positive homotropic binding of tetrahydrofolate to monkey liver serine hydroxymethyltransferase was abolished on preincubating the enzyme with NADH and NADPH. NAD+ was a negative heterotropic effector, whereas NADP+ was without effect. The allosteric effects of nicotinamide nucleotides on the serine hydroxymethyltransferase, reported for the first time, lead to a better understanding of the regulation of the metabolic interconversion of folate coenzymes.

Animals↗
PubMed1978

Effect of methionine-loading on methyl group synthesis and activation in rat brain and liver.

Much greater increases in S-adenosylmethionine concentrations are observed in the liver in response to methionine-loading than in the brain due to differences in the methionine adenosyltransferase activities in these tissues. Liver methione adenosyltransferase exhibits a bimodal saturation curve with a nonlinear Line-weaver-Burk plot, indicating that high methionine concentrations are required for saturation. In the brain the methionine adenosyltransferase is saturated in vitro at a methionine concentration less than the normal physiological concentration. The increased S-adenosylmethionine concentrations in the livers of methionine-treated rats also account for the observed inhibition of N5,N10-methylenetetrahydrofolate reductase activity in this tissue. No inhibition of this enzyme is observed in the brain of methionine treated animals. Nor are S-adenosylmethionine concentrations increased significantly in brain. Serine hydroxymethyltransferase activity responds to methionine-loading by decreasing in brain and increasing in liver.

Animals↗
PubMed1976

The serine hydroxymethyltransferase of Plasmodium lophurae.

Plasmodium lophurae serine hydroxymethyltransferase (EC 2.1.2.1) was partially purified and characterized by (NH4)2SO4 fractionation and chromatography on Sephadex G-100. The enzyme, precipitated by 3.0.3.3 M (NH4)2SO4, had a molecular weight of 68,300 as estimated by exclusion chromatography on G-100. The pH optimum of the enzyme was 6.8-7.6 in sodium phosphate-citrate buffer. Citrate stabilized the enzyme during storage in phosphate buffer at 4 C. The Km was 4.3 X 10(-3) M for L-serine and 2.5 X 10(-4) M for tetrahydrofolate.

Ammonium Sulfate↗
PubMed1979

Regional assignment of human genes TPI1, GAPDH, LDHB, SHMT, and PEPB on chromosome 12.

Karyological analysis was performed on a series of human-Chinese hamster cell hybrids containing deletions of human chromosome 12. Chromosome breakage was produced by treatment of the cells with either X-rays or 5-bromodeoxyuridine and near-visible light. The hybrid clones were analyzed for the presence or absence of the following five human gene markers known to be located on chromosome 12: triosephosphate isomerase-1 (TPI1), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), lactate dehydrogenase-B (LDHB), serine hydroxymethyltransferase (SHMT), and peptidase-B (PEPB). Based on the correlation between the isozyme markers and karyological analysis of these clones, a regional map of the five human genes on chromosome 12 was established. The linear order for these genes is: pter-TPI1-GAPDH-LDHB-centromere-SHMT-PEPB-qter. The locations of these genes are: TPI1, GAPDH, LDHB: pter leads to p12; SHMT: q12 leads to q14; PEPB: q14 leads to qter. Statistical analysis similar to that of Goss and Harris (1975, 1977a, b) has been performed on the segregation data in the hybrid clones. The statistical map, in general, agrees with the cytogenetic map and further localizes PEPB to 12q21.

Animals↗
PubMed1975

Regulation of enzymes of serine and one-carbon metabolism by testosterone in rat prostate, liver, and kidney.

A significant decrease in the specific activity of 3 enzymes of serine and one-carbon metabolism (3-phosphoglycerate dehydrgenase, phosphoserine phosphatase, and serine hydroxy-methyltransferase) was found in the rat prostate gland with castration. A single injection of testosterone propionate to rats 3 days after castration resulted in a significant increase in the 3 enzyme activities within 24 h. This increase in specific activity was maximal 72 h after injection of testosterone in the case of 3-phosphoglycerate dehydrogenase and serine hydroxymethyltransferase. When cycloheximide was administered in conjunction with testosterone, the increase in 3-phosphoglycerate dehydrogenase and serine hydroxy-methyltransferase activity was significantly reduced compared to injection of testosterone alone. N6, O2'-dibutyryl adenosine-3',5'-cyclic monophosphate [(Bu)2 cAMP] and theophylline injected at 8 h intervals to rats 3 days after castration failed to mimic the action of testosterone on these 3 enzymes 24 and 72 h after beginning injections. Castration had no effect on the specific activity of these enzymes in the kidney; however, 3-phosphoglycerate dehydrogenase was significantly diminished in the liver 6 days after castration. A single injection of testosterone to rats 3 days after castration restored the activity to sham-operated levels. Serine hydroxy-methyltransferase and phosphoserine phosphatase activity in the liver were unaffected 6 days after castration. Thus testosterone exerts a regulatory role on serine and one-carbon metabolism in the prostate and liver which (Bu), cAMP is unable to minic.

Alcohol Oxidoreductases↗
PubMed2026

Epitranscriptomic Regulation of ALDOA by SHMT2-Mediated m6A Modification Drives Gastric Cancer Malignancy.

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with limited therapeutic advancements despite progress in early detection. Serine hydroxymethyltransferase 2 (SHMT2), a key metabolic enzyme, and fructose-1,6-bisphosphate aldolase A (ALDOA), a glycolytic enzyme, are implicated in tumor progression. However, the molecular mechanisms linking SHMT2 and ALDOA in GC remain unclear. This study investigates how SHMT2 regulates ALDOA expression via m6A RNA modification to drive GC malignancy. Bioinformatic analyses (TCGA, LinkedOmics, and SRAMP) were used to assess SHMT2 expression in GC patients and identify its correlated genes. In vitro experiments (CCK-8, EdU, Transwell, and wound healing) evaluated the effects of SHMT2 overexpression or knockdown on GC cell proliferation, migration, invasion, and glycolysis. m6A modification of ALDOA was analyzed via MeRIP-PCR and dual-luciferase assays, while RNA stability was assessed using actinomycin D treatment. Xenograft models validated SHMT2's role in vivo. SHMT2 was upregulated in GC tissues and cell lines, correlating with advanced tumor stages and poor prognosis. SHMT2 knockdown suppressed GC cell viability, migration, invasion, and glycolysis, while overexpression enhanced these traits. Mechanistically, SHMT2 increased S-adenosylmethionine levels, promoting ALDOA m6A modification, likely mediated through the predicted site 1 (position 291). This modification stabilized ALDOA mRNA via IGF2BP1 recognition, an m6A reader. ALDOA overexpression reversed the tumor-suppressive effects of SHMT2 knockdown. In vivo, SHMT2 depletion reduced tumor growth and Ki67 expression in xenograft models. In conclusion, SHMT2 drives GC progression by enhancing ALDOA expression through m6A modification and IGF2BP1-mediated stabilization. Targeting the SHMT2-ALDOA axis represents a promising therapeutic strategy for gastric cancer.

Humans↗
PubMed1978

Hyperglycinuria and hyperglycinemia in two siblings with mild developmental delays.

Two preschool-age siblings with similar histories of encephalopathy were examined for developmental retardation and found to have elevated levels of urinary and blood glycine. Their inability to convert glycine into serine in the absence of elevated blood and urinary ketone levels was suggestive of a defect in the glycine-cleavage enzyme system (or serine hydroxymethyl transferase). These patients differ significantly from the majority of reported cases of nonketotic hyperglycinemia in that they did not manifest life-threatening neonatal illness, severe mental retardation, or neurological deficits. However, during an oral glycine load, alterations in the electroencephalographic pattern occurred that suggested a relationship between elevated blood glycine levels and pathological involvement of the central nervous system. The ratio of CSF-blood glycine was found to be in the range expected for nonketotic hyperglycinemia.

Amino Acid Metabolism, Inborn Errors↗