Structural insights into the dual substrate specificities of mammalian and Dictyostelium dihydropteridine reductases toward two stereoisomers of quinonoid dihydrobiopterin

초록

Up to now, D-threo-tetrahydrobiopterin (DH4, dictyopterin) was detected only in Dictyostelium discoideum, while the isomer L-erythro-tetrahydrobioterin (BH4) is common in mammals. To elucidate the mechanism of DH4 regeneration by D. discoideum dihydropteridine reductase (DicDHPR), we have determined the crystal structure of DicDHPR complexed with NAD(+) at 2.16 angstrom resolution. Significant structural differences from mammalian DHPRs are found around the coenzyme binding site, resulting in a higher K-m value for NADH (K-m = 46.51 +/- 0.4 mu M) than mammals. In addition, we have found that rat DHPR as well as DicDHPR could bind to both substrates quinonoid-BH2 and quinonoid-DH2 by docking calculations and have confirmed their catalytic activity by in vitro assay. Structured summary of protein interactions: DHPR binds to DHPR by X-ray crystallography (View interaction) (C) 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

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