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人胆绿素IXβ还原酶的结构,一种早期胎儿胆红素IXβ生成酶。

Structure of human biliverdin IXbeta reductase, an early fetal bilirubin IXbeta producing enzyme.

作者信息

Pereira P J, Macedo-Ribeiro S, Párraga A, Pérez-Luque R, Cunningham O, Darcy K, Mantle T J, Coll M

机构信息

Instituto de Biologia Molecular de Barcelona, Consejo Superior de Investigaciones Científicas, Jordi Girona, 18-26, 08034 Barcelona, Spain.

出版信息

Nat Struct Biol. 2001 Mar;8(3):215-20. doi: 10.1038/84948.

Abstract

Biliverdin IXbeta reductase (BVR-B) catalyzes the pyridine nucleotide-dependent production of bilirubin-IXbeta, the major heme catabolite during early fetal development. BVR-B displays a preference for biliverdin isomers without propionates straddling the C10 position, in contrast to biliverdin IXalpha reductase (BVR-A), the major form of BVR in adult human liver. In addition to its tetrapyrrole clearance role in the fetus, BVR-B has flavin and ferric reductase activities in the adult. We have solved the structure of human BVR-B in complex with NADP+ at 1.15 A resolution. Human BVR-B is a monomer displaying an alpha/beta dinucleotide binding fold. The structures of ternary complexes with mesobiliverdin IValpha, biliverdin IXalpha, FMN and lumichrome show that human BVR-B has a single substrate binding site, to which substrates and inhibitors bind primarily through hydrophobic interactions, explaining its broad specificity. The reducible atom of both biliverdin and flavin substrates lies above the reactive C4 of the cofactor, an appropriate position for direct hydride transfer. BVR-B discriminates against the biliverdin IXalpha isomer through steric hindrance at the bilatriene side chain binding pockets. The structure also explains the enzyme's preference for NADP(H) and its B-face stereospecificity.

摘要

胆绿素IXβ还原酶(BVR - B)催化依赖吡啶核苷酸生成胆红素IXβ,这是胎儿早期发育过程中的主要血红素分解代谢产物。与成人肝脏中BVR的主要形式胆绿素IXα还原酶(BVR - A)不同,BVR - B对C10位无丙酸酯的胆绿素异构体表现出偏好。除了在胎儿中具有四吡咯清除作用外,BVR - B在成人中还具有黄素和铁还原酶活性。我们已在1.15埃分辨率下解析了与NADP + 结合的人BVR - B的结构。人BVR - B是一种单体,呈现α/β二核苷酸结合折叠。与中胆绿素IValpha、胆绿素IXalpha、FMN和光色素形成的三元复合物结构表明,人BVR - B具有单一底物结合位点,底物和抑制剂主要通过疏水相互作用结合于此,这解释了其广泛的特异性。胆绿素和黄素底物的可还原原子位于辅因子反应性C4上方,这是直接氢化物转移的合适位置。BVR - B通过双三烯侧链结合口袋处的空间位阻来区分胆绿素IXalpha异构体。该结构还解释了该酶对NADP(H)的偏好及其B面立体特异性。

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