REACTION INTERMEDIATE ANALOGS FOR ENOLASE
REACTION INTERMEDIATE ANALOGS FOR ENOLASE
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DOI：
10.1021/bi00307a038
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发表时间：
1984-01-01
期刊：
影响因子：
2.9
通讯作者：
CLELAND, WW
中科院分区：
文献类型：
--
作者：
ANDERSON, VE;WEISS, PM;CLELAND, WW
许多化合物看起来像是正常碳负离子中间体的ACI形式的类似物，是酵母烯醇化酶的良好抑制剂。它们包括(3-羟基-2-硝丙基)膦(I)，其电离形式(PK=8.1)硝酸盐在5 mM镁离子存在下具有6 nm的KI，(硝乙基)膦酸盐(III)(PK=8.5；在5 mM镁离子存在下硝酸盐的KI=1微米)，膦酸乙酰羟甲酸酯(IV)(PK=10.2；KI，离子形式饱和镁2+=15 PM)和(膦乙基)硝酸盐(VII)(KI在1 mM镁+=14 NM时)。丙酮酸膦(VI)的KI为75µm，与pH无关。I、IV、VI和VII是慢结合抑制剂。所有这些化合物在类似于2-磷酸甘油酸酯的C-2的位置上都是三角的，并且都含有一个膦酸基，但是在2-磷酸甘油酸酯的C-3上的羟基与负电荷的金属配体在异构性位置上(如在IV中)似乎比硝基异构性与2-磷酸甘油酸酯的羧基(I和III)的结合作用更大。2-磷酸甘油酸酯的3-羟基显然直接与镁离子配位，然后被消除生成磷酸烯醇式丙酮酸。
A number of compounds that appear to be analogs of the aci form of the normal carbanion intermediate are good inhibitors of yeast enolase. These include (3-hydroxy-2-nitropropyl)phosphonate (I), the ionized (pK = 8.1) nitronate form of which in the presence of 5 mM Mg2+ has a Ki of 6 nM, (nitroethyl)phosphonate (III) (pK = 8.5; Ki of the nitronate in the presence of 5 mM Mg2+ = 1 .mu.M), phosphonoacetohydroxamate (IV) (pK = 10.2; Ki with saturating Mg2+ for the ionized form = 15 pM) and (phosphonoethyl)nitrolate (VII) (Ki at 1 mM Mg2+ = 14 nM). The oxime of phosphonopyruvate (VI) has a pH-independent Ki of 75 .mu.M. I, IV, VI and VII are slow binding inhibitors. All of these compounds are trigonal at the position analogous to C-2 of 2-phosphonoglycerate and contain a phosphono group, but a negatively charged metal ligand at the position isosteric with the hydroxyl attached to C-3 of 2-phosphoglycerate (as in IV) appears to contribute more to binding than a nitro group isosteric with the carboxyl of 2-phosphoglycerate (I and III). The carbanion mechanism is supported for enolase and the 3-hydroxy of 2-phosphoglycerate is apparently directly coordinated to Mg2+ prior to being eliminated to give phosphoenolpyruvate.