Disease relevance of acetylphosphonate

• Phosphonoacetaldehyde hydrolase (phosphonatase) from Bacillus cereus catalyzes hydrolytic P-C bond cleavage of phosphonoacetaldehyde (Pald) via a Schiff base intermediate formed with Lys53 [1].
• First characterization of the phosphonoacetaldehyde hydrolase gene of Pseudomonas aeruginosa [2].
• Expression of the phosphonoacetaldehyde hydrolase coding sequence in Escherichia coli under control of the E. coli tac promoter resulted in the production of enzymatically active protein with an affinity constant similar to that of the phosphonoacetaldehyde hydrolase purified from P. aeruginosa A237 [2].

High impact information on acetylphosphonate

• X-ray structure determination of the D12A mutant in the presence of the substrate phosphonoacetaldehyde showed that replacement of the loop 1 Asp, common to all HAD family members, with Ala shifts the position of Mg(II), thereby allowing innersphere coordination to Asp190 and causing a shift in the position of the substrate [3].
• The active site contains a cofactor, pyridoxal 5'-phosphate (PLP), and the product phosphonoacetaldehyde [4].
• The ability of the phosphonatase competitive inhibitor (Ki = 230 +/- 20 microM) acetonylphosphonate to protect the enzyme from phosphonoacetaldehyde/NaBH4-induced inactivation suggested that the reactive lysine residue is located in the enzyme active site [5].
• The inhibition by phosphonates and phosphate analogues of the alkaline phosphatase activity of rat intestinal brush-border membrane vesicles was studied at pH 7.5 and 30 degrees C. Phenylene-1,3-diphosphonate, 2,6-dinitrophenylphosphonate and phosphonoacetaldehyde were found to be competitive inhibitors, with Ki values in the range 16-80 microM [6].
• The phnX gene encoding the phosphonoacetaldehyde hydrolase (phosphonatase) from the Gram-negative bacterium Pseudomonas aeruginosa A237 has been cloned and its sequence determined [2].

Chemical compound and disease context of acetylphosphonate

• Methyl acetylphosphonate and acetylphosphonate are competitive inhibitors toward pyruvate with Escherichia coli pyruvate oxidase and E. coli pyruvate dehydrogenase but the value of the Ki for the oxidase is more than three orders of magnitude higher than for the dehydrogenase [7].

Biological context of acetylphosphonate

• Phosphonoacetaldehyde hydrolase (phosphonatase) catalyzes the hydrolysis of phosphonoacetaldehyde to acetaldehyde and phosphate using Mg(II) as cofactor [8].

Associations of acetylphosphonate with other chemical compounds

• The reaction proceeds via a novel bicovalent catalytic mechanism in which an active-site nucleophile abstracts the phosphoryl group from the Schiff-base intermediate formed from Lys53 and phosphonoacetaldehyde [8].
• Phosphonatase functions in the 2-aminoethylphosphonate (AEP) degradation pathway of bacteria, catalyzing the hydrolysis of the CP bond in phosphonoacetaldehyde (Pald) via formation of a bi-covalent Lys53ethylenamine/Asp12 aspartylphosphate intermediate [9].
• The X-ray crystallographic structure of wild-type phosphonatase reduced with NaBH(4) in the presence of Pald was determined at 2.4A resolution to reveal Nepsilon-ethyl-Lys53 juxtaposed with a sulfate ligand bound in the phosphate site [9].

Gene context of acetylphosphonate

• Kinetic studies with substrate analogs and group-directed chemical modification agents were carried out for the purpose of identifying the enzyme-substrate interactions required for phosphonoacetaldehyde (P-Ald) binding and catalyzed hydrolysis by P-Ald hydrolase (phosphonatase) [10].

References