title: The structure of the PanD/PanZ protein complex reveals negative feedback regulation of pantothenate biosynthesis by coenzyme A.
abstract: Coenzyme A (CoA) is an ubiquitous and essential cofactor, synthesized from the precursor pantothenate. Vitamin biosynthetic pathways are normally tightly regulated, including the pathway from pantothenate to CoA. However, no regulation of pantothenate biosynthesis has been identified. We have recently described an additional component in the pantothenate biosynthetic pathway, PanZ, which promotes the activation of the zymogen, PanD, to form aspartate α-decarboxylase (ADC) in a CoA-dependent manner. Here we report the structure of PanZ in complex with PanD, which reveals the structural basis for the CoA dependence of this interaction and activation. In addition, we show that PanZ acts as a CoA-dependent inhibitor of ADC catalysis. This inhibitory effect can effectively regulate the biosynthetic pathway to pantothenate, and thereby also regulate CoA biosynthesis. This represents a previously unobserved mode of metabolic regulation whereby a cofactor-utilizing protein negatively regulates the biosynthesis of the same cofactor.
authors.affiliation: Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK; School of Chemistry, University of Leeds, Leeds LS2 9JT, UK; Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Diana C F
authors.initials: DCF
authors.lastname: Monteiro
authors.affiliation: Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK; Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Vijay
authors.initials: V
authors.lastname: Patel
authors.affiliation: Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK; Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Bartlett
authors.affiliation: Microbial Genetics Laboratory, Genetic Strains Research Center, National Institute of Genetics, 1111 Yata, Mishima, Shizuoka 411-8540, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Nozaki
authors.affiliation: Hauptmann-Woodward Medical Research Institute, Buffalo, NY 14203, USA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Grant
authors.affiliation: Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK; School of Chemistry, University of Leeds, Leeds LS2 9JT, UK; Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: James A
authors.initials: JA
authors.lastname: Gowdy
authors.affiliation: Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK; Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Thompson
authors.affiliation: Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK; Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Arnout P
authors.initials: AP
authors.lastname: Kalverda
authors.affiliation: Hauptmann-Woodward Medical Research Institute, Buffalo, NY 14203, USA.
authors.forename: Edward H
authors.initials: EH
authors.lastname: Snell
authors.affiliation: Microbial Genetics Laboratory, Genetic Strains Research Center, National Institute of Genetics, 1111 Yata, Mishima, Shizuoka 411-8540, Japan; Department of Genetics, Graduate University for Advanced Studies (Sokendai), 1111 Yata, Mishima, Shizuoka 411-8540, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Niki
authors.affiliation: Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK; Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK. Electronic address: arwen.pearson@cfel.de.
authors.forename: Arwen R
authors.initials: AR
authors.lastname: Pearson
authors.affiliation: Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK; School of Chemistry, University of Leeds, Leeds LS2 9JT, UK. Electronic address: m.e.webb@leeds.ac.uk.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Webb
mesh_terms: D000595:Amino Acid Sequence; D055162:Biocatalysis; D003065:Coenzyme A / Q000737:chemistry / Q000378:metabolism*; D005968:Glutamate Decarboxylase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010205:Pantothenic Acid / Q000096:biosynthesis*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D053838:Scattering, Small Angle; D016415:Sequence Alignment; D014961:X-Ray Diffraction
chemical_list: D010205:Pantothenic Acid; C019104:aspartate-alpha-decarboxylase; D005968:Glutamate Decarboxylase; D003065:Coenzyme A