3EX2

human orotidyl-5'-monophosphate decarboxylase in complex with 6-cyano-UMP

3EX2 の概要

• エントリーDOI: 10.2210/pdb3ex2/pdb
• 関連するPDBエントリー: 3EWU 3EWW 3EWX 3EWY 3EWZ 3EX0 3EX1 3EX3 3EX4 3EX5 3EX6
• 分子名称: Orotidine-5'-phosphate decarboxylase, 6-cyanouridine 5'-phosphate, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: decarboxylase, tim barrel, unusual catalysis, disease mutation, glycosyltransferase, lyase, multifunctional enzyme, pyrimidine biosynthesis, transferase
• 由来する生物種: Homo sapiens
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 57389.96

構造登録者

Heinrich, D.,Diederichsen, U.,Rudolph, M. (登録日: 2008-10-16, 公開日: 2009-04-07, 最終更新日: 2023-12-27)

主引用文献

Heinrich, D.,Diederichsen, U.,Rudolph, M.G.
Lys314 is a nucleophile in non-classical reactions of orotidine-5'-monophosphate decarboxylase
Chemistry, 15:6619-6625, 2009

PubMed Abstract: Orotidine-5'-monophosphate decarboxylase (OMPD) catalyzes the decarboxylation of orotidine-5'-monophosphate (OMP) to uridine-5'-monophosphate (UMP) in an extremely proficient manner. The reaction does not require any cofactors and proceeds by an unknown mechanism. In addition to decarboxylation, OMPD is able to catalyze other reactions. We show that several C6-substituted UMP derivatives undergo hydrolysis or substitution reactions that depend on a lysine residue (Lys314) in the OMPD active site. 6-Cyano-UMP is converted to UMP, and UMP derivatives with good leaving groups inhibit OMPD by a suicide mechanism in which Lys314 covalently binds to the substrate. These non-classical reactivities of human OMPD were characterized by cocrystallization and freeze-trapping experiments with wild-type OMPD and two active-site mutants by using substrate and inhibitor nucleotides. The structures show that the C6-substituents are not coplanar with the pyrimidine ring. The extent of this substrate distortion is a function of the substituent geometry. Structure-based mechanisms for the reaction of 6-substituted UMP derivatives are extracted in accordance with results from mutagenesis, mass spectrometry, and OMPD enzyme activity. The Lys314-based mechanisms explain the chemodiversity of OMPD, and offer a strategy to design mechanism-based inhibitors that could be used for antineoplastic purposes for example.

PubMed: 19472232
DOI: 10.1002/chem.200900397

実験手法

X-RAY DIFFRACTION (1.55 Å)