Structural and mechanistic insights into C-P bond hydrolysis by phosphonoacetate hydrolase

Vinayak Agarwal, Svetlana A. Borisova, William W. Metcalf, Wilfred A. Van Der Donk, Satish K. Nair

Research output: Contribution to journalArticlepeer-review

Abstract

Bacteria have evolved pathways to metabolize phosphonates as a nutrient source for phosphorus. In Sinorhizobium meliloti 1021, 2-aminoethylphosphonate is catabolized to phosphonoacetate, which is converted to acetate and inorganic phosphate by phosphonoacetate hydrolase (PhnA). Here we present detailed biochemical and structural characterization of PhnA that provides insights into the mechanism of C-P bond cleavage. The 1.35 resolution crystal structure reveals a catalytic core similar to those of alkaline phosphatases and nucleotide pyrophosphatases but with notable differences, such as a longer metal-metal distance. Detailed structure-guided analysis of active site residues and four additional cocrystal structures with phosphonoacetate substrate, acetate, phosphonoformate inhibitor, and a covalently bound transition state mimic provide insight into active site features that may facilitate cleavage of the C-P bond. These studies expand upon the array of reactions that can be catalyzed by enzymes of the alkaline phosphatase superfamily.

Original languageEnglish (US)
Pages (from-to)1230-1240
Number of pages11
JournalChemistry and Biology
Volume18
Issue number10
DOIs
StatePublished - Oct 28 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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