Med Res Rev. 2016 Nov 15. doi: 10.1002/med.21419. [Epub ahead of print]
- 1PEPITE - EA4267, University Bourgogne Franche-Comté, Besançon, France.
Abstract
Arginase
(EC 3.5.3.1) is the bimanganese enzyme that converts L-arginine into
ornithine and urea. This enzyme was discovered more than a century ago
and early α-amino acids were identified as weak inhibitors. It was only
during the 90s, after nitric oxide (NO) was reported as one of the most
important biological mediators and when tight interrelation of arginase
and NO synthase was found, that the development of arginase inhibitors
was accelerated. The regulation of arginase activity by the
N-hydroxy-L-arginine (3, NOHA) intermediate of the NO synthesis was the
starting point of the N-hydroxy-nor-arginine (21, nor-NOHA) that proved
to be the first micromolar inhibitor. The previously known manganese and
arginase binding by borate inspired the 2(S)-amino-6-boronohexanoic
acid (39, ABH) and S-(2-boronoethyl)-L-cysteine (40, BEC) now both
considered as reference compounds in arginase inhibition. The
high-resolution crystal structure of arginase and molecular modeling has
rendered possible the recent design of (53) the strongest
α,α-disubstituted derivatives of ABH. Simultaneously, traditional medicinal plants
have contributed as a source of molecular diversity to the discovery of
arginase inhibitors. This rational, step-by-step approach serves as
guide in the present review where emphasis is placed on structure
activity relationships. Highlights exhaustive review on arginase
inhibitors highlight is made on rational approach to conception and
structure activity relationships evaluation model is systematically
mentioned with results.
© 2016 Wiley Periodicals, Inc.
KEYWORDS:
arginase; inhibitor; structure activity relationships
