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Lysine relay mechanism coordinates intermediate transfer in vitamin B6 biosynthesis

DOI: 10.1038/nchembio.2273 DOI Help

Authors: Matthew J Rodrigues (University of Southampton; Diamond Light Source) , Volker Windeisen (University of Southampton; Heidelberg University Biochemistry Center (BZH)) , Yang Zhang (Cornell University) , Gabriela Guédez (Heidelberg University Biochemistry Center (BZH)) , Stefan Weber (Heidelberg University Biochemistry Center (BZH)) , Marco Strohmeier (Heidelberg University Biochemistry Center (BZH)) , Jeremiah W Hanes (Pacific Biosciences) , Antoine Royant (Université Grenoble Alpes) , Gwyndaf Evans (Diamond Light Source) , Irmgard Sinning (Heidelberg University Biochemistry Center (BZH)) , Steven E. Ealick (Cornell University) , Tadhg P. Begley (Texas A&M University) , Ivo Tews (University of Southampton; Heidelberg University Biochemistry Center (BZH))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Chemical Biology

State: Published (Approved)
Published: January 2017
Diamond Proposal Number(s): 8891

Abstract: Substrate channeling has emerged as a common mechanism for enzymatic intermediate transfer. A conspicuous gap in knowledge concerns the use of covalent lysine imines in the transfer of carbonyl-group-containing intermediates, despite their wideuse in enzymatic catalysis. Here we show how imine chemistry operates in the transfer of covalent intermediates in pyridoxal 5′-phosphate biosynthesis by the Arabidopsis thaliana enzyme Pdx1. An initial ribose 5-phosphate lysine imine is converted to the chromophoric I320 intermediate, simultaneously bound to two lysine residues and partially vacating the active site, which creates space for glyceraldehyde 3-phosphate to bind. Crystal structures show how substrate binding, catalysis and shuttling are coupled to conformational changes around strand β6 of the Pdx1 (βα)8-barrel. The dual-specificity active site and imine relay mechanism for migration of carbonyl intermediates provide elegant solutions to the challenge of coordinating a complex sequence of reactions that follow a path of over 20 Å between substrate- and product-binding sites.

Journal Keywords: Enzyme mechanisms; Enzymes; X-ray crystallography; Robert A. Welch Foundation

Subject Areas: Biology and Bio-materials, Chemistry

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