The 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).
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.
