Department of Medical Biochemistry and Biophysics, Division of Chemistry II, Karolinska Institute, S-171 77 Stockholm, Sweden.
FEBS Lett. 2010 Aug 4;584(15):3446-51. doi: 10.1016/j.febslet.2010.06.044. Epub 2010 Jul 4.
Leukotriene A4 hydrolase (LTA4H) is a key enzyme in the inflammatory process of mammals. It is an epoxide hydrolase and an aminopeptidase of the M1 family of the MA clan of Zn-metallopeptidases. We have solved the crystal structure of LTA4H in complex with N-[3(R)-[(hydroxyamino)carbonyl]-2-benzyl-1-oxopropyl]-L-alanine, a potent inhibitor of several Zn-metalloenzymes, both endopeptidases and aminopeptidases. The inhibitor binds along the sequence signature for M1 aminopeptidases, GXMEN. It exhibits bidentate chelation of the catalytic zinc and binds to LTA4H's enzymatically essential carboxylate recognition site. The structure gives clues to the binding of this inhibitor to related enzymes and thereby identifies residues of their S1' sub sites as well as strategies for design of inhibitors.
白细胞三烯 A4 水解酶（LTA4H）是哺乳动物炎症过程中的关键酶。它是一种环氧化物水解酶和 M1 家族的 Zn 金属肽酶的氨基肽酶 MA 族。我们已经解决了 LTA4H 与 N-[3(R)-[(羟基氨基)羰基]-2-苄基-1-氧代丙基]-L-丙氨酸的复合物的晶体结构，N-[3(R)-[(羟基氨基)羰基]-2-苄基-1-氧代丙基]-L-丙氨酸是几种 Zn 金属酶的强效抑制剂，包括内肽酶和氨基肽酶。抑制剂沿着 M1 氨基肽酶的序列特征 GXMEN 结合。它表现出对催化锌的双齿螯合，并结合到 LTA4H 的酶必需的羧酸盐识别位点。该结构为该抑制剂与相关酶的结合提供了线索，从而确定了它们的 S1'亚位点的残基以及抑制剂设计的策略。
