Poduch Ewa, Wei Lianhu, Pai Emil F, Kotra Lakshmi P
Center for Molecular Design and Preformulations, Toronto General Research Institute, Toronto General Hospital, Toronto, ON, Canada.
J Med Chem. 2008 Feb 14;51(3):432-8. doi: 10.1021/jm700968x. Epub 2008 Jan 9.
Orotidine monophosphate decarboxylase (ODCase) generally accepts pyrimidine-based mononucleotides as ligands, but other nucleotides are also known to bind to this enzyme. We investigated the kinetic properties of eight common and endogenous nucleotides with ODCases from three species: Methanobacterium thermoautotrophicum, Plasmodium falciparum, and Homo sapiens. UMP and XMP exhibited higher affinities as compared to the other nucleotides tested. The product of ODCase catalyzed decarboxylation, UMP, displayed inhibition constants (K(i)) of 330 microM against the Mt enzyme and of 210 and 220 microM against the Pf and Hs ODCases, respectively. The K(i) values for XMP were 130 microM and 43 microM, respectively, for Mt and Pf ODCases. Interestingly, XMP's affinity for human ODCase (K(i) = 0.71 microM) is comparable and even slightly better than that of the substrate OMP. Binding of various nucleotides and their structural features in the context of ODCase inhibition and inhibitor design are discussed.
乳清苷单磷酸脱羧酶（ODCase）通常将基于嘧啶的单核苷酸作为配体，但已知其他核苷酸也能与这种酶结合。我们研究了八种常见的内源性核苷酸与来自三种物种（嗜热自养甲烷杆菌、恶性疟原虫和智人）的ODCase的动力学特性。与测试的其他核苷酸相比，UMP和XMP表现出更高的亲和力。ODCase催化脱羧反应的产物UMP对Mt酶的抑制常数（K(i)）为330微摩尔，对Pf和Hs ODCase的抑制常数分别为210和220微摩尔。XMP对Mt和Pf ODCase的K(i)值分别为130微摩尔和43微摩尔。有趣的是，XMP对人ODCase的亲和力（K(i)=0.71微摩尔）与底物OMP相当，甚至略好。讨论了在ODCase抑制和抑制剂设计背景下各种核苷酸的结合及其结构特征。
