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 such a 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.
Highlights
The antimetabolite pentyl pantothenamide 1 [N5-Pan (Scheme 1a)] was first described in 1970.1 Like other pantothenamides, it has broad spectrum antibiotic activity but, uniquely, shows an order of magnitude improvement against Escherichia coli, with a minimum inhibitory concentration (MIC) of 2 μg mL−1
Relationship between Pentyl Pantothenamide (N5-Pan) and Regulation of Pantothenate Biosynthesisa a(a) N5-Pan 1 is metabolized by pantothenate kinase (PanK), CoaD, and CoaE to generate ethyl dethiacoenzyme A (EtdtCoA, 2). (b) Pathway from L-aspartate to coenzyme A. β-Alanine 4 is produced by decarboxylation of Laspartate 3 by aspartate α-decarboxylase (PanD). β-Alanine forms pantothenate 5, which is subsequently metabolized by PanK, CoaB, CoaC, CoaD, and CoaE to form coenzyme A 3
We investigated whether the enhanced toxicity of pentyl pantothenamide is due to accumulation of EtdtCoA, leading to downregulation of pantothenate biosynthesis mediated by this complex
Summary
The antimetabolite pentyl pantothenamide 1 [N5-Pan (Scheme 1a)] was first described in 1970.1 Like other pantothenamides, it has broad spectrum antibiotic activity but, uniquely, shows an order of magnitude improvement against Escherichia coli, with a minimum inhibitory concentration (MIC) of 2 μg mL−1. While low-level expression of PanZ relieves the β-alanine auxotrophy caused by panZ deletion, overexpression of PanZ leads to inhibition of the pantothenate biosynthesis pathway due to inhibition of catalysis by activated PanD.[8] At physiological concentrations of PanZ, we hypothesized that the protein−protein interaction provides a negative feedback mechanism for the pantothenate biosynthesis pathway in response to cellular CoA concentration (Scheme 1b). Given this regulatory mechanism, we investigated whether the enhanced toxicity of pentyl pantothenamide is due to accumulation of EtdtCoA, leading to downregulation of pantothenate biosynthesis mediated by this complex
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