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Interkingdom Pharmacology of Angiotensin-I Converting Enzyme Inhibitor Phosphonates Produced by Actinomycetes

DOI: 10.1021/ml4004588 DOI Help
PMID: 24900839 PMID Help

Authors: Glenna J. Kramer (Vanderbilt University Department of Chemistry) , Akif Mohd (University of Bath) , Sylva L. U. Schwager (University of Cape Town) , Geoffrey Masuyer (University of Bath) , Ravi Acharya (University of Bath) , Edward D. Sturrock (University of Cape Town) , Brian O. Bachmann (Vanderbilt University Department of Chemistry)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Medicinal Chemistry Letters , VOL 5 (4)

State: Published (Approved)
Published: February 2014
Diamond Proposal Number(s): 1226

Open Access Open Access

Abstract: The K-26 family of bacterial secondary metabolites are N-modified tripeptides terminated by an unusual phosphonate analog of tyrosine. These natural products, produced via three different actinomycetales, are potent inhibitors of human angiotensin-I converting enzyme (ACE). Herein we investigate the interkingdom pharmacology of the K-26 family by synthesizing these metabolites and assessing their potency as inhibitors of both the N-terminal and C-terminal domains of human ACE. In most cases, selectivity for the C-terminal domain of ACE is displayed. Co-crystallization of K-26 in both domains of human ACE reveals the structural basis of the potent inhibition and has shown an unusual binding motif that may guide future design of domain-selective inhibitors. Finally, the activity of K-26 is assayed against a cohort of microbially produced ACE relatives. In contrast to the synthetic ACE inhibitor captopril, which demonstrates broad interkingdom inhibition of ACE-like enzymes, K-26 selectively targets the eukaryotic family.

Journal Keywords: Angiotensin-I Converting Enzyme (Ace); K-26; Bacterial Dicarboxypeptidase; Ace Inhibitor

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography