122699-13-2Relevant articles and documents
Lys314 is a nucleophile in non-classical reactions of orotidine-5′- monophosphate decarboxylase
Heinrich, Daniel,Diederichsen, Ulf,Rudolph, Markus Georg
, p. 6619 - 6625 (2009)
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 wildtype 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. Structurebased mechanisms for the reaction of 6-substituted UMP derivatives are extracted in accordance with results from mutagenesis, mass spectrometry, and OMPD enzyme activity. The Lys314based mechanisms explain the chemodiversity of OMPD, and offer a strategy to design mechanism-based inhibitors that could be used for antineoplastic purposes for example.
Alternative nucleic acid molecules and uses thereof
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, (2015/11/09)
The present disclosure provides alternative nucleosides, nucleotides, and nucleic acids, and methods of using them.
MODIFIED NUCLEIC ACID MOLECULES AND USES THEREOF
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, (2014/07/07)
The present disclosure provides modified nucleosides, nucleotides, and nucleic acids, and methods of using them.
