ATP-CITRATE LYASE AS A TARGET FOR HYPOLIPIDEMIC INTERVENTION - SULFOXIMINE AND 3-HYDROXY-BETA-LACTAM CONTAINING ANALOGS OF CITRIC-ACID AS POTENTIAL TIGHT-BINDING INHIBITORS
ATP-CITRATE LYASE AS A TARGET FOR HYPOLIPIDEMIC INTERVENTION - SULFOXIMINE AND 3-HYDROXY-BETA-LACTAM CONTAINING ANALOGS OF CITRIC-ACID AS POTENTIAL TIGHT-BINDING INHIBITORS
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DOI：
10.1021/jm00104a014
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发表时间：
1992-12-25
影响因子：
7.3
通讯作者：
GROOT, PHE
中科院分区：
文献类型：
--
作者：
DOLLE, RE;MCNAIR, D;GROOT, PHE
柠檬酸类似物（+/-）-12a，b和（+/-）-17a，b，其中一个伯羧酸酯分别被磺基亚氨酰基和3-（3-羟基-β-内酰胺基）部分取代，已被合成并被评价为ATP-柠檬酸裂解酶抑制剂。这些抑制剂的设计是基于蛋氨酸亚砜亚胺和tabtoxinine β-内酰胺，谷氨酰胺合成酶的强效紧密结合抑制剂。ATP-柠檬酸裂解酶和谷氨酰胺合成酶都使用磷酸-羧酸酐作为催化过程中羧酸活化的方法。只有一种非对映异构体（+/-）-12a显示出弱的可逆抑制，而其余的柠檬酸盐类似物（+/-）-12b和（+/-）-17a，b对裂解酶无活性。未观察到酶的时间依赖性失活。
Citric acid analogues (+/-)-12a,b and (+/-)-17a,b, where one of the primary carboxylates has been replaced by a sulfoximinoyl and a 3-(3-hydroxy-beta-lactamyl) moiety, respectively, have been synthesized and evaluated as inhibitors of ATP-citrate lyase. The design of these inhibitors was based on methionine sulfoximine and tabtoxinine beta-lactam, potent, tight-binding inhibitors of glutamine synthetase. Both ATP-citrate lyase and glutamine synthetase employ phosphate-carboxylate anhydrides as a method for carboxylate activation during catalysis. Only one diastereomer, (+/-)-12a, displayed weak, reversible inhibition, while the remaining citrate analogues (+/-)-12b and (+/-)-17a,b were inactive against the lyase. No time-dependent inactivation of the enzyme was observed.