Li Jiaojiao, Packianathan Charles, Rossman Toby G, Rosen Barry P
Department of Cellular Biology and Pharmacology, Herbert Wertheim College of Medicine, Florida International University , Miami, Florida 33199, United States.
The Nelson Institute of Environmental Medicine , NYU-Langone School of Medicine, Tuxedo, New York 10987, United States.
Chem Res Toxicol. 2017 Jul 17;30(7):1481-1491. doi: 10.1021/acs.chemrestox.7b00113. Epub 2017 Jun 19.
Arsenic methylation, the primary biotransformation in the human body, is catalyzed by the enzyme As(III) S-adenosylmethionine (SAM) methyltransferases (hAS3MT). This process is thought to be protective from acute high-level arsenic exposure. However, with long-term low-level exposure, hAS3MT produces intracellular methylarsenite (MAs(III)) and dimethylarsenite (DMAs(III)), which are considerably more toxic than inorganic As(III) and may contribute to arsenic-related diseases. Several single nucleotide polymorphisms (SNPs) in putative regulatory elements of the hAS3MT gene have been shown to be protective. In contrast, three previously identified exonic SNPs (R173W, M287T, and T306I) may be deleterious. The goal of this study was to examine the effect of single amino acid substitutions in hAS3MT on the activity of the enzyme that might explain their contributions to adverse health effects of environmental arsenic. We identified five additional intragenic variants in hAS3MT (H51R, C61W, I136T, W203C, and R251H). We purified the eight polymorphic hAS3MT proteins and characterized their enzymatic properties. Each enzyme had low methylation activity through decreased affinity for substrate, lower overall rates of catalysis, or lower stability. We propose that amino acid substitutions in hAS3MT with decreased catalytic activity lead to detrimental responses to environmental arsenic and may increase the risk of arsenic-related diseases.
砷甲基化是人体主要的生物转化过程，由砷（III）S-腺苷甲硫氨酸（SAM）甲基转移酶（hAS3MT）催化。该过程被认为对急性高剂量砷暴露具有保护作用。然而，长期低剂量暴露时，hAS3MT会产生细胞内亚甲基胂（MAs(III)）和二甲基亚胂（DMAs(III)），它们的毒性比无机砷（III）大得多，可能会导致与砷相关的疾病。hAS3MT基因推定调控元件中的几个单核苷酸多态性（SNP）已被证明具有保护作用。相比之下，先前鉴定出的三个外显子SNP（R173W、M287T和T306I）可能有害。本研究的目的是研究hAS3MT中单个氨基酸取代对酶活性的影响，这可能解释它们对环境砷不良健康影响的作用。我们在hAS3MT中又鉴定出五个基因内变体（H51R、C61W、I136T、W203C和R251H）。我们纯化了这八种多态性hAS3MT蛋白并对其酶学性质进行了表征。每种酶的甲基化活性都较低，原因是对底物的亲和力降低、总体催化速率较低或稳定性较差。我们认为，hAS3MT中催化活性降低的氨基酸取代会导致对环境砷的有害反应，并可能增加患砷相关疾病的风险。
