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An oxidative N-demethylase reveals PAS transition from ubiquitous sensor to enzyme

DOI: 10.1038/nature20159 DOI Help

Authors: Mary Ortmayer (University of Manchester) , Pierre Lafite (University of Manchester) , Binuraj R. K. Menon (University of Manchester) , Tewes Tralau (University of Manchester) , Karl Fisher (Manchester Institute of Biotechnology) , Lukas Denkhaus (University of Manchester) , Nigel S. Scrutton (University of Manchester) , Stephen E. J. Rigby (University of Manchester) , Andrew W. Munro (University of Manchester) , Sam Hay (University of Manchester) , David Leys (University of Manchester)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature , VOL 539 , PAGES 593 - 597

State: Published (Approved)
Published: November 2016
Diamond Proposal Number(s): 8997

Abstract: The universal Per-ARNT-Sim (PAS) domain functions as a signal transduction module involved in sensing diverse stimuli such as small molecules, light, redox state and gases. The highly evolvable PAS scaffold can bind a broad range of ligands, including haem, flavins and metal ions. However, although these ligands can support catalytic activity, to our knowledge no enzymatic PAS domain has been found. Here we report characterization of the first PAS enzyme: a haem-dependent oxidative N-demethylase. Unrelated to other amine oxidases, this enzyme contains haem, flavin mononucleotide, 2Fe-2S and tetrahydrofolic acid cofactors, and specifically catalyses the NADPH-dependent oxidation of dimethylamine. The structure of the ? subunit reveals that it is a haem-binding PAS domain, similar in structure to PAS gas sensors. The dimethylamine substrate forms part of a highly polarized oxygen-binding site, and directly assists oxygen activation by acting as both an electron and proton donor. Our data reveal that the ubiquitous PAS domain can make the transition from sensor to enzyme, suggesting that the PAS scaffold can support the development of artificial enzymes.

Journal Keywords: heme dependent oxidative N-demethylase

Subject Areas: Biology and Bio-materials
Collaborations: Diamond Manchester

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)