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Knockout of arsenic (+3 oxidation state) methyltransferase results in sex-dependent changes in phosphatidylcholine metabolism in mice.

ABSTRACT: Arsenic (+3 oxidation state) methyltransferase is the key enzyme in the methylation pathway for inorganic arsenic. We have recently shown that As3mt knockout (KO) has a profound effect on metabolomic profiles in mice. Phosphatidylcholine species (PCs) were the largest group of metabolites altered in both plasma and urine. The present study used targeted analysis to investigate the KO-associated changes in PC profiles in the liver, the site of PC synthesis. Results show that As3mt KO has a systemic effect on PC metabolism and that this effect is sex dependent.

SUBMITTER: Huang MC

PROVIDER: S-EPMC5358322 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Knockout of arsenic (+3 oxidation state) methyltransferase results in sex-dependent changes in phosphatidylcholine metabolism in mice.

Huang Madelyn C MC Douillet Christelle C CC Stýblo Miroslav M

Archives of toxicology 20160903 12

Arsenic (+3 oxidation state) methyltransferase is the key enzyme in the methylation pathway for inorganic arsenic. We have recently shown that As3mt knockout (KO) has a profound effect on metabolomic profiles in mice. Phosphatidylcholine species (PCs) were the largest group of metabolites altered in both plasma and urine. The present study used targeted analysis to investigate the KO-associated changes in PC profiles in the liver, the site of PC synthesis. Results show that As3mt KO has a system ...[more]

PMID: 27591999

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Project description:Arsenic (As) occurs as monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) in humans, and the methylation pattern demonstrates large interindividual differences. The fraction of urinary MMA is a marker for susceptibility to As-related diseases.We evaluated the impact of polymorphisms in five methyltransferase genes on As metabolism in two populations, one in South America and one in Southeast Asia. The methyltransferase genes were arsenic(+III oxidation state) methyltransferase (AS3MT), DNA-methyltransferase 1a and 3b (DNMT1a and DNMT3b, respectively), phosphatidylethanolamine N-methyltransferase (PEMT), and betaine-homocysteine methyltransferase (BHMT). AS3MT expression was analyzed in peripheral blood.Subjects were women exposed to As in drinking water in the Argentinean Andes [n = 172; median total urinary As (U-As), 200 µg/L] and in rural Bangladesh (n = 361; U-As, 100 µg/L; all in early pregnancy). Urinary As metabolites were measured by high-pressure liquid chromatography/inductively coupled plasma mass spectrometry. Polymorphisms (n = 22) were genotyped with Sequenom, and AS3MT expression was measured by quantitative real-time polymerase chain reaction using TaqMan expression assays.Six AS3MT polymorphisms were significantly associated with As metabolite patterns in both populations (p ? 0.01). The most frequent AS3MT haplotype in Bangladesh was associated with a higher percentage of MMA (%MMA), and the most frequent haplotype in Argentina was associated with a lower %MMA and a higher percentage of DMA. Four polymorphisms in the DNMT genes were associated with metabolite patterns in Bangladesh. Noncoding AS3MT polymorphisms affected gene expression of AS3MT in peripheral blood, demonstrating that one functional impact of AS3MT polymorphisms may be altered levels of gene expression.Polymorphisms in AS3MT significantly predicted As metabolism across these two very different populations, suggesting that AS3MT may have an impact on As metabolite patterns in populations worldwide.

Project description:Residues Tyr59, Gly78, Ser79, Met103, Gln107, Ile136 and Glu137 in human arsenic (+3 oxidation state) methyltransferase (hAS3MT) were deduced to form a potential hydrogen bond network around S-adenosylmethionine (SAM) from the sequence alignment between Cyanidioschyzon merolae arsenite S-adenosylmethyltransferase (CmArsM) and hAS3MT. Herein, seven mutants Y59A, G78A, S79A, M103A, Q107A, I136A and E137A were obtained. Their catalytic activities and conformations were characterized and models were built. Y59A and G78A were completely inactive. Only 7.0%, 10.6% and 13.8% inorganic arsenic (iAs) was transformed to monomethylated arsenicals (MMA) when M103A, Q107A and I136A were used as the enzyme. The Vmax (the maximal velocity of the reaction) values of M103A, Q107A, I136A and E137A were decreased to 8%, 22%, 15% and 50% of that of WT-hAS3MT, respectively. The KM(SAM) (the Michaelis constant for SAM) values of mutants M103A, I136A and E137A were 15.7, 8.9 and 5.1 fold higher than that of WT-hAS3MT, respectively, indicating that their affinities for SAM were weakened. The altered microenvironment of SAM and the reduced capacity of binding arsenic deduced from KM(As) (the Michaelis constant for iAs) value probably synergetically reduced the catalytic activity of Q107A. The catalytic activity of S79A was higher than that of WT despite of the higher KM(SAM) , suggesting that Ser79 did not impact the catalytic activity of hAS3MT. In short, residues Tyr59 and Gly78 significantly influenced the catalytic activity of hAS3MT as well as Met103, Ile136 and Glu137 because they were closely associated with SAM-binding, while residue Gln107 did not affect SAM-binding regardless of affecting the catalytic activity of hAS3MT. Modeling and our experimental results suggest that the adenine ring of SAM is sandwiched between Ile136 and Met103, the amide group of SAM is hydrogen bonded to Gly78 in hAS3MT and SAM is bonded to Tyr59 with van der Waals, cation-? and hydrogen bonding contacts.

Dataset Information

Knockout of arsenic (+3 oxidation state) methyltransferase results in sex-dependent changes in phosphatidylcholine metabolism in mice.

Publications

Knockout of arsenic (+3 oxidation state) methyltransferase results in sex-dependent changes in phosphatidylcholine metabolism in mice.

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