Stereoselectivity of isozyme C of glutathione S-transferase toward arene and azaarene oxides.
Stereoselectivity of isozyme C of glutathione S-transferase toward arene and azaarene oxides.
复制标题
谷胱甘肽 S-转移酶同工酶 C 对芳烃和氮杂芳烃氧化物的立体选择性。
DOI：
10.1021/bi00273a015
复制
发表时间：
1983
期刊：
影响因子：
2.9
通讯作者：
Armstrong,RN
中科院分区：
文献类型：
--
作者：
Cobb,D;Boehlert,C;Lewis,D;Armstrong,RN
Diane Cobb、Charles Boehlert、Deborah刘易斯和Richard N.阿姆斯特朗 * 摘要：谷胱甘肽5-转移酶（EC 2.5。1.18）（同工酶A、B和C）以不同程度的效率和立体选择性催化谷胱甘肽与菲9，10-氧化物的加成。同工酶C对该底物的效率分别是同工酶A和B的2倍和35倍，并给出两种可能的非对映体产物的20：1的比例。同工酶A（~ 1 ∶ 1）和B（3 ∶ 1）的空间选择性较低。通过圆二色光谱推断同工酶C的主要产物非对映体具有95，1 OS绝对构型，这意味着谷胱甘肽对R绝对构型上的环氧乙烷碳的攻击。同工酶C在其他K-区芳烃氧化物如芘4，5-氧化物和烯-（3，4-二氢吡喃-5-转移酶（EC 2.5）之间显示出很小的动力学区分。1.18）催化谷胱甘肽的硫醇加成到具有亲脂取代基的亲电化合物上，这是一种在烷基化剂（如芳烃氧化物、烷基卤化物等）的解毒中相当重要的反应（Chasseaud，1979）。从大鼠和人肝细胞质中分离的GSH转移酶1的同工酶显示出相当广泛的重叠底物特异性[最近的综述，见Jakoby和Habig（1980）]。催化异生物质生物转化反应的酶通常表现出低程度的底物选择性，这对于作用于结构多样性和潜在毒性化合物所需的催化剂是明显的优势。相反，异生素化合物的酶促加工可以并且经常以高度的立体选择性进行，其中代谢途径中的酶进行的立体化学选择影响母体化合物或其代谢物的生物活性。例如，细胞色素P-450在芳烃的前手性中心催化的氧化可以立体选择性地进行，以主要得到一种对映体芳烃氧化物（Levin等人，1980; Armstrong等人，1981 a;货车Bladeren等人，1982年）。最初的立体选择可以影响随后生物转化的动力学、立体化学和最终生物学结果，如通过细胞色素P-450、环氧化物水解酶和细胞色素P-450对苯并[a]芘的连续和立体选择性作用所证实的，主要产生苯并[a]芘-7，8-二醇9，10-环氧化物的单一的高度致瘤性立体异构体（Levin et al.，1980年）。
Diane Cobb, Charles Boehlert, Deborah Lewis, and Richard N. Armstrong* abstract: Three of the isozymes of glutathione 5-transferase (EC 2.5. 1.18) from rat liver (isozymes A, B, and C) catalyze the addition of glutathione to phenanthrene 9, 10-oxide with varying degrees of efficiency and stereoselectivity. Isozyme C is 2-fold and 35-fold more efficient toward thissubstrate than are isozymes A and B, respectively, and gives a 20 to 1 ratio of the two possible diastereomeric products. The ste-reoselectivities of isozymes A (~ 1 to 1) and B (3 to 1) are considerably lower. The major product diastereomer from isozyme C is deduced to have the 95, 1 OS absolute configuration by circular dichroism spectroscopy, implying attack of glutathione on the oxirane carbon on R absolute configuration. Isozyme C shows little kinetic discrimination between other K-region arene oxides such as pyrene 4, 5-oxide and the en-(jTlutathione 5-transferases (EC 2.5. 1.18) catalyze the ad-dition of the thiol of glutathione to electrophilic compounds with lipophilic substituents, a reaction of considerable im-portance in the detoxication of alkylating agents such as arene oxides, alkyl halides, and others (Chasseaud, 1979). Isozymes of GSH transferase1 isolated from rat and human liver cytosol show a rather broad overlapping substrate specificity [for a recent review, see Jakoby & Habig (1980)]. Enzymes that catalyze biotransformation reactions of xenobiotics often ex-hibit a low degree of substrate selectivity, which is an obvious advantage for a catalyst required to act on structurally diverse and potentially toxic compounds. In contrast, the enzymatic processing of a xenobiotic compound can, and often does, proceed with a high degree of stereoselectivity in which ste-reochemical choices made by enzymes in the metabolic pathway affect the biological activity of the parent compound or its metabolites. For instance, cytochrome P-450 catalyzed oxidation at a prochiral center of an aromatic hydrocarbon can proceed stereoselectively to give predominantly one en-antiomeric arene oxide (Levin et al., 1980; Armstrong et al., 1981a; van Bladeren et al., 1982). The initial stereoselection can influence the kinetic, stereochemical, and ultimate toxi-cological outcome of subsequent biotransformations as exem-plified by the serial and stereoselective action of cytochrome P-450, epoxide hydrolase, and cytochrome P-450 on benzo-[ú] pyrene to give predominantly a single, highly tumorogenic stereoisomer of benzo [a] pyrene-7, 8-diol 9, 10-epoxide (Levin et al., 1980).