N- versus C-domain selectivity of catalytic inactivation of human angiotensin converting enzyme by lisinopril-coupled transition metal chelates.
The N- and C-terminal domains of human somatic angiotensin I converting enzyme (sACE-1) demonstrate distinct physiological functions, with resulting interest in the development of domain-selective inhibitors for specific therapeutic applications. Herein, the activity of lisinopril-coupled transition metal chelates was tested for both reversible binding and irreversible catalytic inactivation of each domain of sACE-1. C/N domain binding selectivity ratios ranged from 1 to 350, while rates of irreversible catalytic inactivation of the N- and C-domains were found to be significantly greater for the N-domain, suggesting a more optimal orientation of M-chelate-lisinopril complexes within the active site of the N-domain of sACE-1. Finally, the combined effect of binding selectivity and inactivation selectivity was assessed for each catalyst (double-filter selectivity factors), and several catalysts were found to cause domain-selective catalytic inactivation. The results of this study demonstrate the ability to optimize the target selectivity of catalytic metallopeptides through both binding and catalytic factors (double-filter effect).
Evans Laboratory of Chemistry, The Ohio State University , 100 West 18th Avenue, Columbus, Ohio 43210, United States.
Lalintip
L
Hocharoen
Jeff C
JC
Joyner
J A
JA
Cowan
D055162:Biocatalysis; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D017706:Lisinopril / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D013329:Structure-Activity Relationship; D028561:Transition Elements / Q000737:chemistry*
D002614:Chelating Agents; D004791:Enzyme Inhibitors; D028561:Transition Elements; D017706:Lisinopril; C488034:ACE protein, human; D007703:Peptidyl-Dipeptidase A