Files and links (1)
Accepted (AM)Open Access (License Unspecified), Open
Journal article
Binding of alpha,alpha-Disubstituted Amino Acids to Arginase Suggests New Avenues for Inhibitor Design
Journal of medicinal chemistry, v 54(15), pp 5432-5443
11 Aug 2011
PMID: 21728378
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Arginase is a binuclear manganese metalloenzyme that hydrolyzes L-arginine to form L-ornithine and urea, and aberrant arginase activity is implicated in various diseases such as erectile dysfunction, asthma, atherosclerosis, and cerebral malaria. Accordingly, arginase inhibitors may be therapeutically useful. Continuing our efforts to expand the chemical space of arginase inhibitor design and inspired by the binding of 2-(difluoromethyl)-L-ornithine to human arginase I, we now report the first study of the binding of a., alpha-disubstituted amino acids to arginase. Specifically, we report the design, synthesis, and assay of racemic 2-amino-6-borono-2-methylhexanoic acid and racemic 2-amino-6-borono-2-(difluoromethyl)hexanoic acid. X-ray crystal structures of human arginase I and Plasmodium falciparum arginase complexed with these inhibitors reveal the exclusive binding of the L-stereoisomer; the additional alpha-substituent of each inhibitor is readily accommodated and makes new intermolecular interactions in the outer active site of each enzyme. Therefore, this work highlights a new region of the protein surface that can be targeted for additional affinity interactions, as well as the first comparative structural insights on inhibitor discrimination between a human and a parasitic arginase.
Metrics
Details
- Title
- Binding of alpha,alpha-Disubstituted Amino Acids to Arginase Suggests New Avenues for Inhibitor Design
- Creators
- Monica Ilies - Drexel UniversityLuigi Di Costanzo - Rutgers State Univ, Dept Chem & Chem Biol, RCSB Prot Data Bank, Piscataway, NJ 08854 USADaniel P. Dowling - Massachusetts Institute of TechnologyKatherine J. Thorn - Episcopal AcademyDavid W. Christianson - University of Pennsylvania
- Publication Details
- Journal of medicinal chemistry, v 54(15), pp 5432-5443
- Publisher
- American Chemical Society; Washington, DC
- Number of pages
- 12
- Grant note
- GM49758 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA DE-AC02-06CH11357 / U.S. Department of Energy, Office of Basic Energy Sciences; United States Department of Energy (DOE) P41RR015301 / NATIONAL CENTER FOR RESEARCH RESOURCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) R01GM049758 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) RR-15301 / National Center for Research Resources at the National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemistry
- Web of Science ID
- WOS:000293419400015
- Scopus ID
- 2-s2.0-79961238056
- Other Identifier
- 991019168090004721
UN Sustainable Development Goals (SDGs)
This publication has contributed to the advancement of the following goals:
InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Chemistry, Medicinal