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Mechanism of regulation of pantothenate biosynthesis by the PanD-PanZ.AcCoA complex reveals an additional mode of action for the antimetabolite N-pentyl pantothenamide (N5-Pan)

DOI: 10.1021/acs.biochem.7b00509 DOI Help

Authors: Zoe L. P. Arnott (University of Leeds) , Shingo Nozaki (National Institute of Genetics) , Diana C. F. Monteiro (University of Leeds) , Holly E. Morgan (University of Leeds) , Arwen R. Pearson (Institute of Nanostructure and Solid State Physics, University of Hamburg) , Hironori Niki (National Institute of Genetics) , Michael E. Webb (University of Leeds)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Biochemistry

State: Published (Approved)
Published: August 2017

Abstract: The antimetabolite pentyl pantothenamide has broad spectrum antibiotic activity but exhibits enhanced activity against Escherichia coli. The PanDZ complex has been proposed to regulate the pantothenate biosynthetic pathway in E. coli by limiting the supply of β-alanine in response to coenzyme A concentration. We show that formation of this complex between activated aspartate decarboxylase (PanD) and PanZ leads to sequestration of the pyruvoyl cofactor as a ketone hydrate and demonstrate that both PanZ overexpression-linked β-alanine auxotrophy and pentyl pantothenamide toxicity are due to formation of this complex. This both demonstrates that the PanDZ complex regulates pantothenate biosynthesis in a cellular context and validates the complex as a target for antibiotic development.

Journal Keywords: Metabolic regulation; antimetabolites; antibiotics; vitamin biosynthesis; pyruvoyldependent; enzymes

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I03-Macromolecular Crystallography