Interkingdom pharmacology of angiotensin-I converting enzyme inhibitor phosphonates produced by actinomycetes

Glenna J. Kramer, Akif Mohd, Sylva L U Schwager, Geoffrey Masuyer, K. Ravi Acharya, Edward D. Sturrock, Brian O. Bachmann

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)346-351
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume5
Issue number4
DOIs
Publication statusPublished - 10 Apr 2014

Keywords

  • ACE inhibitor
  • Angiotensin-I converting enzyme (ACE)
  • bacterial dicarboxypeptidase
  • K-26

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Biochemistry

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