Structure, functional characterization, and evolution of the dihydroorotase domain of human CAD.

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Grande-Garcia A, Lallous N, Diaz-Tejada C, Ramon-Maiques S

Structure, functional characterization, and evolution of the dihydroorotase domain of human CAD.

Structure. 2014 Feb 4;22(2):185-98. doi: 10.1016/j.str.2013.10.016. Epub 2013 Dec 12.

PubMed ID

24332717 [ View in PubMed

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Abstract

Upregulation of CAD, the multifunctional protein that initiates and controls the de novo biosynthesis of pyrimidines in animals, is essential for cell proliferation. Deciphering the architecture and functioning of CAD is of interest for its potential usage as an antitumoral target. However, there is no detailed structural information about CAD other than that it self-assembles into hexamers of approximately 1.5 MDa. Here we report the crystal structure and functional characterization of the dihydroorotase domain of human CAD. Contradicting all assumptions, the structure reveals an active site enclosed by a flexible loop with two Zn(2)(+) ions bridged by a carboxylated lysine and a third Zn coordinating a rare histidinate ion. Site-directed mutagenesis and functional assays prove the involvement of the Zn and flexible loop in catalysis. Comparison with homologous bacterial enzymes supports a reclassification of the DHOase family and provides strong evidence against current models of the architecture of CAD.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Aspartic acid	CAD protein	Protein	Humans	Unknown	Substrate	Details

Polypeptides

Name	UniProt ID
CAD protein	P27708	Details