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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Interkingdom pharmacology of angiotensin-I converting enzyme inhibitor phosphonates produced by actinomycetes
ACS Medicinal Chemistry Letters, Volume 5, No. 4, Year 2014
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Description
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. © 2014 American Chemical Society.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC4027624/bin/ml4004588_si_001.zip
Authors & Co-Authors
Kramer, Glenna J.
United States, Nashville
Vanderbilt University
Mohd, Akif
United Kingdom, Bath
University of Bath
India, Hyderabad
University of Hyderabad
Schwager, Sylva L.U.
South Africa, Cape Town
University of Cape Town
Masuyer, Geoffrey
United Kingdom, Bath
University of Bath
Ravi Acharya, K.
United Kingdom, Bath
University of Bath
Sturrock, Edward D.
South Africa, Cape Town
University of Cape Town
Bachmann, Brian O.
United States, Nashville
Vanderbilt University
Statistics
Citations: 24
Authors: 7
Affiliations: 4
Identifiers
Doi:
10.1021/ml4004588
e-ISSN:
19485875
Study Design
Cohort Study