Carbethoxylating agents as inhibitors of aldehyde dehydrogenase.
Carbethoxylating agents as inhibitors of aldehyde dehydrogenase.
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作为乙醛脱氢酶抑制剂的乙氧基化剂。
DOI：
10.1021/jm00011a006
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发表时间：
1995
影响因子：
7.3
通讯作者：
Shirota,FN
中科院分区：
文献类型：
--
作者：
Nagasawa,HT;DeMaster,EG;Goon,DJ;Kawle,SP;Shirota,FN
IV, 0-Dicarbethoxy-4-chlorobenzenesulfohydroxamate (lc) and O-carbethoxy-ZV-hydroxysaccharin (6), both potential carbethoxylating agents, inhibited yeast aldehyde dehydrogenase (A1DH) with ICso’s of 24 and 56 «, respectively. The esterase activity of the enzyme was commensurably inhibited. A1DH activity was only partially restored on incubation with mercaptoethanol (20 mM) for 1 h. On incubation with rat plasma, lc liberated nitroxyl, a potent inhibitor of A1DH. Under the same conditions, nitroxyl generation from 6 was minimal, a result compatible with a previous observation thatnitroxyl generation from IV-hydroxysac-charin (7), the product of the hydrolysis of the carbethoxy group of 6, was minimal at physiological pH. Since chemical carbethoxylating agents represented by the O-carbethoxylated IV-hydroxyphthalimide, 1-hydroxybenzotriazole, and IV-hydroxysuccinimide (8, 9, and 10, respectively) likewise inhibited yeast A1DH, albeit with ICso’s 1 order of magnitude higher, we postulate that lc and 6 act as irreversible inhibitors of A1DH bycarbethoxylating the active site of the enzyme.The active site of the enzymealdehyde dehydrogenase (A1DH, EC 1.2. 1.3) has been shown to be Cys 302, 1 a sulfhydryl amino acid which is preserved in all known AlDH’s. 2 AlDH’s catalyze the oxidationof alcohols to aldehydes, the most relevant alcohol being ethanol which is converted to acetaldehyde. The enzyme also functions as an esterase3 (possibly aided by a neighbor-ing histidine group4), andmechanistic considerations would suggest that this sulfhydryl group at the active site is altered when the enzyme is inactivated. We have previously reported5 that IV, 0-diacylated 4-chlorobenzenesulfohydroxamates la are hydrolyzed at the ester linkage by the intrinsic esterase activity of yeast A1DH to give an IV-acylated arenesulfohydrox-amate (2). The latter, being unstable, spontaneously disproportionates to an arenesulfinic acid (3) and an acyl nitroso intermediate (4) that ultimately solvolyzes to nitroxyl (HN= 0) and the corresponding carboxylic acid 5 (Scheme 1). The liberated nitroxyl is a potent inhibi-tor of A1DH, and lb was found to inhibit yeast A1DH
