Enzymatic Methylation of Arsenic Compounds. VII. Monomethylarsonous Acid (MMAIII) Is the Substrate for MMA Methyltransferase of Rabbit Liver and Human Hepatocytes

Zakharyan, Roksana; Ayala-Fierro, Felix; Wr, Cullen; Carter, DM; Hv, Aposhian

doi:10.1006/taap.1999.8687

Cited by 97 publications

(65 citation statements)

References 23 publications

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“…These results are consistent with evidence that trivalent arsenicals are the preferred substrate for this enzyme and that the pentavalent arsenicals must be reduced enzymatically or nonenzymatically before methylation (7,11,41). Based on estimated molecular weights, the protein purified from rat liver cytosol (ϳ42.000) is probably not identical with the enzyme purified from rabbit liver cytosol (ϳ60,000) that catalyzes the methylation of arsenite and methylarsonous acid (10,11). S-Adenosyl-Lmethionine:arsenic(III) methyltransferase from rat liver differs kinetically from arsenic methyltransferases purified from rabbit or hamster liver cytosol.…”

Section: Discussionsupporting

confidence: 89%

“…Cullen and co-workers (4) summarized the conversion of inorganic arsenic into these methylated products in a reaction scheme which incorporates oxidative methylation and the cycling of arsenic between the pentavalent (As V ) 1 Because reduction of arsenic to trivalency is a prerequisite for its oxidative methylation, pentavalent arsenicals are reduced by endogenous thiols such as glutathione (GSH) (5,6) or by As V reductases (7)(8)(9). A protein has been purified from rabbit liver cytosol that catalyzes the methylation of both arsenite and methylarsonous acid (10,11); however, this protein has not been sequenced. These activities are designated arsenite methyltransferase (EC 2.1.1.137) and methylarsonite methyltransferase (EC 2.1.1.138), respectively.…”

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confidence: 99%

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A Novel S-Adenosyl-l-methionine:Arsenic(III) Methyltransferase from Rat Liver Cytosol

Lin

Shi

Nix

et al. 2002

Journal of Biological Chemistry

318

216

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S-Adenosyl-L-methionine (AdoMet):arsenic(III) methyltransferase, purified from liver cytosol of adult male Fischer 344 rats, catalyzes transfer of a methyl group from AdoMet to trivalent arsenicals producing methylated and dimethylated arsenicals. The kinetics of production of methylated arsenicals in reaction mixtures containing enzyme, AdoMet, dithiothreitol, glutathione (GSH), and arsenite are consistent with a scheme in which monomethylated arsenical produced from arsenite is the substrate for a second methylation reaction that yields dimethylated arsenical. The mRNA for this protein predicts a 369-amino acid residue protein (molecular mass 41056) that contains common methyltransferase sequence motifs. Its sequence is similar to Cyt19, a putative methyltransferase, expressed in human and mouse tissues. Reverse transcription-polymerase chain reaction detects S-adenosyl-L-methionine:arsenic(III) methyltransferase mRNA in rat tissues and in HepG2 cells, a human cell line that methylates arsenite and methylarsonous acid. S-Adenosyl-L-methionine:arsenic-(III) methyltransferase mRNA is not detected in UROtsa cells, an immortalized human urothelial cell line that does not methylate arsenite. Because methylation of arsenic is a critical feature of its metabolism, characterization of this enzyme will improve our understanding of this metalloid's metabolism and its actions as a toxin and a carcinogen.In many species, including humans, exposure to inorganic arsenic results in urinary excretion of methylated and dimethylated arsenicals (1-3). Cullen and co-workers (4) summarized the conversion of inorganic arsenic into these methylated products in a reaction scheme which incorporates oxidative methylation and the cycling of arsenic between the pentavalent (As V ) 1 and trivalent (As III ) oxidation states,Because reduction of arsenic to trivalency is a prerequisite for its oxidative methylation, pentavalent arsenicals are reduced by endogenous thiols such as glutathione (GSH) (5, 6) or by As V reductases (7-9). A protein has been purified from rabbit liver cytosol that catalyzes the methylation of both arsenite and methylarsonous acid (10, 11); however, this protein has not been sequenced. These activities are designated arsenite methyltransferase (EC 2.1.1.137) and methylarsonite methyltransferase (EC 2.1.1.138), respectively. This protein (estimated molecular mass 60 kDa) uses S-adenosyl-L-methionine (AdoMet) as the methyl group donor. The methylation of arsenite by this protein is stimulated by a monothiol (GSH) and the methylation of methylarsonous acid is highly stimulated by a dithiol, dithiothreitol (DTT). The methylation of arsenic has been commonly regarded as a mechanism for its detoxification (12). However, recent research has shown that methylated arsenicals that contain As III are important intermediates in the metabolism of inorganic arsenic. Methylated arsenicals that contain As III are found in the urine of individuals who chronically consume drinking water that contains inorganic arsenic and in cells cu...

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Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

A Novel S-Adenosyl-l-methionine:Arsenic(III) Methyltransferase from Rat Liver Cytosol

Lin

Shi

Nix

et al. 2002

Journal of Biological Chemistry

318

216

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“…Arsenite methyltransferase activity has been studied and partially purified in various animal tissues (14,118,258). Methylarsonite transferases have been purified from rabbit liver and Chang human hepatocytes (248,260). Reviews describing them are available (14,15,227).…”

Section: Enzymes Catalyzing Methyl Group Transfersmentioning

confidence: 99%

Microbial Methylation of Metalloids: Arsenic, Antimony, and Bismuth

Bentley

Chasteen

2002

Microbiol Mol Biol Rev

502

316

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A significant 19th century public health problem was that the inhabitants of many houses containing wallpaper decorated with green arsenical pigments experienced illness and death. The problem was caused by certain fungi that grew in the presence of inorganic arsenic to form a toxic, garlic-odored gas. The garlic odor was actually put to use in a very delicate microbiological test for arsenic. In 1933, the gas was shown to be trimethylarsine. It was not until 1971 that arsenic methylation by bacteria was demonstrated. Further research in biomethylation has been facilitated by the development of delicate techniques for the determination of arsenic species. As described in this review, many microorganisms (bacteria, fungi, and yeasts) and animals are now known to biomethylate arsenic, forming both volatile (e.g., methylarsines) and nonvolatile (e.g., methylarsonic acid and dimethylarsinic acid) compounds. The enzymatic mechanisms for this biomethylation are discussed. The microbial conversion of sodium arsenate to trimethylarsine proceeds by alternate reduction and methylation steps, with S-adenosylmethionine as the usual methyl donor. Thiols have important roles in the reductions. In anaerobic bacteria, methylcobalamin may be the donor. The other metalloid elements of the periodic table group 15, antimony and bismuth, also undergo biomethylation to some extent. Trimethylstibine formation by microorganisms is now well established, but this process apparently does not occur in animals. Formation of trimethylbismuth by microorganisms has been reported in a few cases. Microbial methylation plays important roles in the biogeochemical cycling of these metalloid elements and possibly in their detoxification. The wheel has come full circle, and public health considerations are again important

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“…In rats, that activity is expressed in a variety of organs, and a similar activity is expressed in the human liver, kidney, and brain (21). The cloning of a rat cDNA, encoded by a gene that was originally annotated as "Cyt19," and the subsequent demonstration that the encoded protein was an "arsenic methyltransferase" (20), opened the way for studies of the possible contribution of variation in this gene (subsequently annotated as As3mt) to individual differences in arsenic methylation.…”

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confidence: 94%

Human Arsenic Methyltransferase (AS3MT) Pharmacogenetics

Wood

Salavagionne

Mukherjee

et al. 2006

Journal of Biological Chemistry

122

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Arsenic contaminates ground water worldwide. Methylation is an important reaction in the biotransformation of arsenic. We set out to study the pharmacogenetics of human arsenic methyltransferase (AS3MT, previously CYT19). After cloning the human AS3MT cDNA, we annotated the human gene and resequenced its 5-flanking region, exons, and splice junctions using 60 DNA samples from African-American (AA) and 60 samples from Caucasian-American (CA) subjects. We

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Enzymatic Methylation of Arsenic Compounds. VII. Monomethylarsonous Acid (MMAIII) Is the Substrate for MMA Methyltransferase of Rabbit Liver and Human Hepatocytes

Cited by 97 publications

References 23 publications

A Novel S-Adenosyl-l-methionine:Arsenic(III) Methyltransferase from Rat Liver Cytosol

A Novel S-Adenosyl-l-methionine:Arsenic(III) Methyltransferase from Rat Liver Cytosol

Microbial Methylation of Metalloids: Arsenic, Antimony, and Bismuth

Human Arsenic Methyltransferase (AS3MT) Pharmacogenetics

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