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Title

Quinone biogenesis: Structure and mechanism of PqqC, the final catalyst in the production of pyrroloquinoline quinone

AuthorsMagnusson, Olafur Th.; Toyama, Hirohide; Saeki, Megumi; Rojas, A. M. ; Reed, John C.; Liddington, Robert C.; Klinman, Judith P.; Schwarzenbacher, Robert
Issue Date2004
PublisherNational Academy of Sciences (U.S.)
CitationProceedings of the National Academy of Sciences 101(21): 7913–7918 (2004)
AbstractThe biosynthesis of pyrroloquinoline quinone (PQQ), a vitamin and redox cofactor of quinoprotein dehydrogenases, is facilitated by an unknown pathway that requires the expression of six genes, pqqA to -F. PqqC, the protein encoded by pqqC, catalyzes the final step in the pathway in a reaction that involves ring cyclization and eight-electron oxidation of 3a-(2-amino-2-carboxyethyl)-4,5-dioxo-4,5,6,7,8,9-hexahydroquinoline-7,9-dicarboxylic-acid to PQQ. Herein, we describe the crystal structures of PqqC and its complex with PQQ and determine the stoichiometry of H2O2 formation and O2 uptake during the reaction. The PqqC structure(s) reveals a compact seven-helix bundle that provides the scaffold for a positively charged active site cavity. Product binding induces a large conformational change, which results in the active site recruitment of amino acid side chains proposed to play key roles in the catalytic mechanism. PqqC is unusual in that it transfers redox equivalents to molecular oxygen without the assistance of a redox active metal or cofactor. The structure of the enzyme-product complex shows additional electron density next to R179 and C5 of PQQ, which can be modeled as O2 or H2O2, indicating a site for oxygen binding. We propose a reaction sequence that involves base-catalyzed cyclization and a series of quinone-quinol tautomerizations that are followed by cycles of O2/H2O2-mediated oxidations. Pyrroloquinoline quinone [4,5-dihydro-4,5-dioxo-1H-pyrrolo-[2,3-f]quinoline-2,7,9-tricarboxylic acid; PQQ (Fig. 1)] is an aromatic, tricyclic ortho-quinone that serves as the redox cofactor for several bacterial dehydrogenases. Among the best known examples are methanol dehydrogenase and glucose dehydrogenase (1, 2). PQQ belongs to the family of quinone cofactors that has been recognized as the third class of redox cofactors following pyridine nucleotide- and flavin-dependent cofactors (3). Although plants and animals do not produce PQQ themselves, PQQ has invoked considerable interest because of its presence in human milk and its remarkable antioxidant properties (4–6). Recently, the first potential eukaryotic PQQ-dependent enzyme [aminoadipic 6-semialdehyde-dehydrogenase (AASDH; U26)] has been identified, indicating that PQQ may function as a vitamin in mammals as well (7).
Publisher version (URL)http://doi.org/10.1073/pnas.0402640101
URIhttp://hdl.handle.net/10261/153718
DOI10.1073/pnas.0402640101
ISSN1091-6490
Appears in Collections:(IBIS) Artículos
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