Premium
Catalytic Differences Between Human Wild Type Arsenic (+3 Oxidation State) Methyltransferase And Its 287 Polymorph
Author(s) -
Xing Weibing,
Adair Blakely M.,
Drobna Zuzana,
Styblo Miroslav,
Thomas David J.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.lb52-c
Subject(s) - chemistry , glutathione , methyltransferase , methylation , wild type , catalysis , methionine , arsenic , thioredoxin , mutant , biochemistry , enzyme , gene , amino acid , organic chemistry
Arsenic (+3 oxidation state) methyltransferase (AS3MT) catalyzes AdoMet‐dependent conversion of inorganic arsenic (iAs) to methylated (MAs) and dimethylated (DMAs) arsenicals. A common polymorphism in which threonine replaces methionine 287 (M287T) occurs in about 10% of some populations. This work compared patterns of iAs metabolism catalyzed by recombinant wild type (wt) and M287T AS3MT. In assays with 1 mM AdoMet and 1 mM tris (2‐carboxylethyl) phosphine as reductant, wt and M287T proteins had similar K m 's (2.2 v. 2.5 μM iAs) but different V's (3.3 v. 6.1 pmol product/μg protein/hour). In assays with 1 mM AdoMet, 3 μM iAs(III), and a thioredoxin (Tx), Tx reductase, NADPH system as reductant, wt AS3MT produced more DMAs than M287T. Addition of up to 5 mM GSH to assays stimulated catalysis by either protein, increasing yield of methylated arsenicals. Overall, increasing GSH concentration had a larger effect on activity of wt AS3MT than on M287 activity. For wt AS3MT, the major GSH effect was on DMAs production; for M287T, the main effect was on MAs production. Hence, this mutation may alter AS3MT's capacity to catalyze formation of DMAs from MAs. Differential regulation by GSH of wt and M287T AS3MTactivites may affect phenotypes of individuals for iAs methylation and susceptibility to adverse effects of chronic iAs exposure. (This abstract does not reflect the policies of the U.S. Environmental Protection Agency.)