Inhibitors of human neutrophil cathepsin G: structural and biochemical studies.
The interaction of a series of sulfonate and phosphate esters derived from N-hydroxysuccinimide with human leukocyte cathepsin G was investigated. The synthesized compounds were found to be time-dependent inhibitors of the enzyme. The composite interplay of steric and electronic effects leads to the formation of acyl enzymes of variable stability, ultimately resulting in partial or full recovery of enzymatic activity. Compounds acting via phosphorylation of the active site serine inactivated the enzyme rapidly and irreversibly.
Groutas
W C
WC
Department of Chemistry, Wichita State University, Kansas 67208.
Brubaker
M J
MJ
Venkataraman
R
R
Epp
J B
JB
Stanga
M A
MA
McClenahan
J J
JJ
D000215:Acylation; D001665:Binding Sites; D056649:Cathepsin G; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D006801:Humans; D007700:Kinetics; D015394:Molecular Structure; D009504:Neutrophils / Q000201:enzymology*; D010710:Phosphates / Q000737:chemistry / Q000494:pharmacology*; D010768:Phosphoserine / Q000378:metabolism; D012697:Serine Endopeptidases; D013329:Structure-Activity Relationship; D013388:Succinimides / Q000737:chemistry; D013451:Sulfonic Acids / Q000737:chemistry / Q000494:pharmacology*
D010710:Phosphates; D013388:Succinimides; D013451:Sulfonic Acids; D010768:Phosphoserine; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; C001426:N-hydroxysuccinimide