Inhibition and structure-activity studies of methionine hydroxamic acid derivatives with bacterial peptide deformylase.
The posttranslational deformylation of N-formyl-Met-polypeptides by the metalloenzyme, peptide deformylase, is essential for bacterial growth. Methionine hydroxamic acid derivatives were found to inhibit recombinant Escherichia coli peptide deformylase activity containing either zinc or cobalt. The binding of methionine hydroxamate and hydrazide inhibitors to cobalt-substituted deformylase caused spectral changes consistent with the formation of a pentacoordinate metal complex similar to that of actinonin, a psuedopeptide hydroxamate inhibitor. The spectral and kinetic data support the binding of these N-substituted L-methionine derivatives in a reverse orientation with respect to N-formyl-Met-peptide substrates within the active site. Based on this hypothesis a second generation of N-substituted methionyl hydroxamic acids were evaluated and found to possess greater inhibitory potency. These results may provide the basis for the design of more potent and selective deformylase inhibitors as potential antibacterial agents.
Grant
S K
SK
Department of HTS and Automation, Merck & Co., Rahway, New Jersey 07065, USA. stephan_grant@merck.com
Green
B G
BG
Kozarich
J W
JW
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D003035:Cobalt / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology*; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*; D008715:Methionine / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013997:Time Factors; D015032:Zinc / Q000737:chemistry
D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D003035:Cobalt; D008715:Methionine; D000581:Amidohydrolases; C084507:peptide deformylase; D015032:Zinc