title: Interkingdom pharmacology of Angiotensin-I converting enzyme inhibitor phosphonates produced by actinomycetes.
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.
authors.affiliation: Vanderbilt University Department of Chemistry, 7300 Stevenson Center, Nashville, Tennessee 37204, United States.
authors.forename: Glenna J
authors.initials: GJ
authors.lastname: Kramer
authors.affiliation: University of Bath , Department of Biology & Biochemistry, Bath BA2 7AY, United Kingdom.
authors.forename: Akif
authors.initials: A
authors.lastname: Mohd
authors.affiliation: University of Cape Town , The Division of Medical Biochemistry, Institute of Infectious Disease and Molecular Medicine, Observatory 7925, South Africa.
authors.forename: Sylva L U
authors.initials: SL
authors.lastname: Schwager
authors.affiliation: University of Bath , Department of Biology & Biochemistry, Bath BA2 7AY, United Kingdom.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Masuyer
authors.affiliation: University of Bath , Department of Biology & Biochemistry, Bath BA2 7AY, United Kingdom.
authors.forename: K Ravi
authors.initials: KR
authors.lastname: Acharya
authors.affiliation: University of Cape Town , The Division of Medical Biochemistry, Institute of Infectious Disease and Molecular Medicine, Observatory 7925, South Africa.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Sturrock
authors.affiliation: Vanderbilt University Department of Chemistry, 7300 Stevenson Center, Nashville, Tennessee 37204, United States.
authors.forename: Brian O
authors.initials: BO
authors.lastname: Bachmann
keywords: ACE inhibitor; Angiotensin-I converting enzyme (ACE); K-26; bacterial dicarboxypeptidase