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Crystal structure of human mARC1 reveals its exceptional position among eukaryotic molybdenum enzymes

Christian Kubitza,F. Bittner,Carsten Ginsel,Antje Havemeyer,B. Clement,A. Scheidig

Published 2018 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance The involvement of biotransformation enzymes in drug metabolism is one of the most crucial objectives during preclinical research, since they ultimately determine the bioavailability of medicinal drugs. The mARC N-reductive enzyme system was found to be a highly effective counterpart to one of the most prominent biotransformation enzymes, CYP450, and is involved in activation of amidoxime prodrugs as well as inactivation of other drugs containing N-hydroxylated functional groups. Owing to its potent N-reductive capacity toward a broad range of compounds, including mutagenic N-oxygenated nucleobase analogs, mARC plays a crucial role in pharmacology. Our crystal structure of human mARC forms the basis for predictions on the metabolism of drug candidates and structure–activity relationships. Moreover, it indicates the evolutionary development of different molybdoenzyme families. Biotransformation enzymes ensure a viable homeostasis by regulating reversible cycles of oxidative and reductive reactions. The metabolism of nitrogen-containing compounds is of high pharmaceutical and toxicological relevance because N-oxygenated metabolites derived from reactions mediated by cytochrome P450 enzymes or flavin-dependent monooxygenases are in some cases highly toxic or mutagenic. The molybdenum-dependent mitochondrial amidoxime-reducing component (mARC) was found to be an extremely efficient counterpart, which is able to reduce the full range of N-oxygenated compounds and thereby mediates detoxification reactions. However, the 3D structure of this enzyme was unknown. Here we present the high-resolution crystal structure of human mARC. We give detailed insight into the coordination of its molybdenum cofactor (Moco), the catalytic mechanism, and its ability to reduce a wide range of N-oxygenated compounds. The identification of two key residues will allow future discrimination between mARC paralogs and ensure correct annotation. Since our structural findings contradict in silico predictions that are currently made by online databases, we propose domain definitions for members of the superfamily of Moco sulfurase C-terminal (MOSC) domain-containing proteins. Furthermore, we present evidence for an evolutionary role of mARC for the emergence of the xanthine oxidase protein superfamily. We anticipate the hereby presented crystal structure to be a starting point for future descriptions of MOSC proteins, which are currently poorly structurally characterized.

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