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Inhibition of dog and human gastric lipases by enantiomeric phosphonate inhibitors: A structure-activity study

机译：对映体膦酸酯抑制剂对狗和人胃脂肪酶的抑制作用：结构活性研究

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The crystal structures of gastric lipases in the apo form [Roussel, A., et al. (1999) J. Biol. Chem. 274, 16995-17002] or in complex with the (R-p)-undecyl butyl phosphonate [C11Y4(+)] [Roussel, A., et al. (2002) J. Biol. Chem. 277, 2266-2274] have improved our understanding of the structure-activity relationships of acid lipases. In this report, we have performed a kinetic study with dog and human gastric lipases (DGL and HGL, respectively) using several phosphonate inhibitors by varying the absolute configuration of the phosphorus atom and the chain length of the alkyl/alkoxy substitutents. Using the two previously determined structures and that of a new crystal structure obtained with the other (S-p)-phosphonate enantiomer [C11Y4(-)], we constructed models of phosphonate inhibitors fitting into the active site crevices of DGL and HGL. All inhibitors with a chain length of fewer than 12 carbon atoms were found to be completely buried in the catalytic crevice, whereas longer alkyl/alkoxy chains were found to point out of the cavity. The main stereospecific determinant explaining the stronger inhibition of the S-p enantiomers is the presence of a hydrogen bond involving the catalytic histidine as found in the DGL-C11Y4(-) complex. On the basis of these results, we have built a model of the first tetrahedral intermediate corresponding to the tristearoyl-lipase complex. The triglyceride molecule completely fills the active site crevice of DGL, in contrast with what is observed with other lipases such as pancreatic lipases which have a shallower and narrower active site. For substrate hydrolysis, the supply of water molecules to the active site might be achieved through a lateral channel identified in the protein core. [References: 27]
机译：载脂蛋白形式的胃脂肪酶的晶体结构[Roussel，A.，et al。 （1999）生物化学杂志。化学274，16995-17002]或与（R-p）-十一烷基丁基膦酸酯[C11Y4（+）]配合使用[Roussel，A.，等人。 （2002）J.Biol。化学[277，2266-2274]增进了我们对酸性脂肪酶的构效关系的理解。在本报告中，我们通过改变磷原子的绝对构型和烷基/烷氧基取代基的链长，使用几种膦酸酯抑制剂对狗和人的胃脂肪酶（分别为DGL和HGL）进行了动力学研究。使用两个先前确定的结构以及使用其他（S-p）-膦酸酯对映体[C11Y4（-）]获得的新晶体结构，我们构建了适用于DGL和HGL活性位缝的膦酸酯抑制剂模型。发现所有链长小于12个碳原子的抑制剂都完全掩埋在催化缝隙中，而更长的烷基/烷氧基链则指向空腔。解释S-p对映体的更强抑制作用的主要立体特异性决定因素是在DGL-C11Y4（-）复合物中发现的涉及催化组氨酸的氢键的存在。基于这些结果，我们建立了对应于三硬脂酰脂肪酶复合物的第一个四面体中间体的模型。甘油三酸酯分子完全填充了DGL的活性位点缝隙，这与其他脂肪酶（例如具有较浅和较窄活性位点的胰脂肪酶）所观察到的相反。对于底物水解，可以通过蛋白质核心中确定的侧向通道实现向活性位点的水分子供应。 [参考：27]

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