Homoarginine and inhibition of human arginase activity: kinetic characterization and biological relevance

Tommasi, S., Elliot, D.J., Da Boit, M., Gray, S.R. , Lewis, B.C. and Mangoni, A.A. (2018) Homoarginine and inhibition of human arginase activity: kinetic characterization and biological relevance. Scientific Reports, 8, 3697. (doi:10.1038/s41598-018-22099-x) (PMID:29487337) (PMCID:PMC5829263)

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Abstract

The inhibition of arginase, resulting in higher arginine (ARG) availability for nitric oxide synthesis, may account for the putative protective effect of homoarginine (HOMOARG) against atherosclerosis and cardiovascular disease. However, uncertainty exists regarding the significance of HOMOARG-induced arginase inhibition in vivo. A novel UPLC-MS method, measuring the conversion of ARG to ornithine (ORN), was developed to determine arginase 1 and arginase 2 inhibition by HOMOARG, lysine (LYS), proline (PRO), agmatine (AG), asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and NG-Monomethyl-L-arginine (L-NMMA). Plasma HOMOARG, ARG and ORN concentrations were further measured in 50 healthy older adults >65 years (27 males and 23 females). HOMOARG inhibited arginase 1 with IC50 and Ki values of 8.14 ± 0.52 mM and 6.1 ± 0.50 mM, and arginase 2 with IC50 and Ki values of 2.52 ± 0.01 mM and 1.73 ± 0.10 mM, respectively. Both arginase isoforms retained 90% activity vs. control when physiological HOMOARG concentrations (1–10 µM) were used. In partial correlation analysis, plasma HOMOARG was not associated with ARG (P = 0.38) or ARG/ORN ratio (P = 0.73) in older adults. Our results suggest that arginase inhibition is unlikely to play a significant role in the reported cardio-protective effects of HOMOARG.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Gray, Dr Stuart
Authors: Tommasi, S., Elliot, D.J., Da Boit, M., Gray, S.R., Lewis, B.C., and Mangoni, A.A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Scientific Reports
Publisher:Nature Publishing Group
ISSN:2045-2322
ISSN (Online):2045-2322
Published Online:27 February 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Scientific Reports 8:3697
Publisher Policy:Reproduced under a Creative Commons License

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