Altered Metabolism of Polycyclic Aromatic Hydrocarbons by UDP-Glycosyltransferase 3A2 Missense Variants,Chemical Research in Toxicology

当前位置： X-MOL 学术 › Chem. Res. Toxicol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Altered Metabolism of Polycyclic Aromatic Hydrocarbons by UDP-Glycosyltransferase 3A2 Missense Variants
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2020-09-30 , DOI: 10.1021/acs.chemrestox.0c00233
Ana G Vergara ₁ , Christy J W Watson ₁ , Jeffrey M Watson ₂ , Gang Chen ₁ , Philip Lazarus ₁

Affiliation

The UDP-glycosyltransferase (UGT) family of enzymes are important in the metabolism of a variety of exogenous substances including polycyclic aromatic hydrocarbons (PAHs), a potent class of environmental carcinogens. As compared to the majority of UGT enzymes, which utilize UDP-glucuronic acid as a cosubstrate, UGT3A2 utilizes alternative cosubstrates (UDP-glucose and UDP-xylose). UGT3A2 is expressed in aerodigestive tract tissues and was highly active against multiple PAHs with both cosubstrates. The goal of the present study was to assess the functional effects of UGT3A2 missense variants (MAF ≥ 0.005) on PAH metabolism and the utilization of cosubstrates. The glycosylation activity (V_max/K_m) of all variants against simple PAHs using both cosubstrates was significantly (P < 0.05) decreased by 42–100% when compared to wild-type UGT3A2. When utilizing UDP-glucose, the variant isoforms exhibited up to a 362-fold decrease in V_max/K_m when compared to wild-type UGT3A2, with a 3.1- to 14-fold decrease for D140N, A344T, and S435Y, a 24- and 43-fold decrease for A436T and R445C, respectively, and a 147- and 362-fold decrease for Y474C and Y74N, respectively. When utilizing UDP-xylose, the variants exhibited up to a 4.0-fold decrease in V_max/K_m when compared to wild-type UGT3A2; Y74N did not exhibit activity, and Y474C did not reach saturation (K_m > 4000 μM). Additionally, both wild-type and variant UGT3A2 exhibited a significant (P < 0.05) difference in their utilization of UDP-glucose vs UDP-xylose as cosubstrates using 1-OH-pyrene as substrate. These data suggest that UGT3A2 missense variants decrease the detoxification of PAHs, potentially resulting in altered individual risk for PAH-related cancers.

中文翻译：

UDP-糖基转移酶 3A2 错义变体改变多环芳烃的代谢

UDP-糖基转移酶 (UGT) 酶家族在多种外源性物质的代谢中很重要，包括多环芳烃 (PAH)，这是一种强效的环境致癌物。与使用 UDP-葡萄糖醛酸作为共底物的大多数 UGT 酶相比，UGT3A2 使用替代共底物（UDP-葡萄糖和 UDP-木糖）。UGT3A2 在呼吸消化道组织中表达，并且对具有两种共底物的多种 PAH 具有高度活性。本研究的目的是评估 UGT3A2 错义变体（MAF ≥ 0.005）对 PAH 代谢和共底物利用的功能影响。糖基化活性（V _max / K _m)与野生型 UGT3A2 相比，使用两种共底物针对简单多环芳烃的所有变体的 ) 显着 ( P < 0.05) 降低了 42-100%。当使用 UDP-葡萄糖时，与野生型 UGT3A2 相比，变异亚型的V _max / K _m降低了 362倍，D140N、A344T 和 S435Y 降低了 3.1 到 14 倍，24 - 和 A436T 和 R445C 分别降低了 43 倍，Y474C 和 Y74N 分别降低了 147 和 362 倍。当利用UDP木糖，所述变体显示出高达4.0倍的降低V_最大/ ķ_米相比于野生型UGT3A2时; Y74N 没有表现出活性，Y474C 没有达到饱和（K _m > 4000 μM）。此外，野生型和变体 UGT3A2在使用 UDP-葡萄糖与 UDP-木糖作为共底物使用 1-OH-芘作为底物时表现出显着（P < 0.05）差异。这些数据表明，UGT3A2 错义变异会降低多环芳烃的解毒能力，从而可能导致多环芳烃相关癌症的个体风险改变。

更新日期：2020-11-16

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11