Recent advances in arginine metabolism: roles and regulation of the arginases

Abstract

As arginine can serve as precursor to a wide range of compounds, including nitric oxide, creatine, urea, polyamines, proline, glutamate and agmatine, there is considerable interest in elucidating mechanisms underlying regulation of its metabolism. It is now becoming apparent that the two isoforms of arginase in mammals play key roles in regulation of most aspects of arginine metabolism in health and disease. In particular, work over the past several years has focused on the roles and regulation of the arginases in vascular disease, pulmonary disease, infectious disease, immune cell function and cancer. As most of these topics have been considered in recent review articles, this review will focus more closely on results of recent studies on expression of the arginases in endothelial and vascular smooth muscle cells, post-translational modulation of arginase activity and applications of arginase inhibitors in vivo.

Figures

Figure 1

Overview of mammalian arginine metabolism. Sources of the free arginine pool are indicated, as well as the various end products of arginine metabolism. In addition to arginine, the methylated arginine derivatives asymmetric dimethyl-L-arginine (ADMA), symmetric dimethyl-L-arginine (SDMA) and NG-monomethyl-L-arginine (NMMA) are released upon the turnover of post-translationally methylated proteins. Enzymes that use arginine as substrate are: (a) arginyl-tRNA synthetase; (b) NO synthases; (c) arginases; (d) arginine:glycine amidinotransferase; and (e) arginine decarboxylase. Not shown are the various transporters that are required for movement of arginine across plasma and mitochondrial membranes.

Figure 2

Consequences of increased arginase activity. Up and down arrows indicate increases or decreases in amount or rate of synthesis of the indicated biochemical products. Depending on the specific protein, reduced arginine availability may result in either decreased translational efficiency (e.g. iNOS) or increased translational efficiency (e.g. CAT-1) of the corresponding mRNA (reviewed in Morris, 2007).

Figure 3

Structures of arginine and arginase inhibitors. Values of Ki for these inhibitors are in the sub-micromolar to micromolar range (Christianson, 2005). ABH, 2(S)-amino-6-boronohexanoic acid; BEC, S-(2-boronoethyl)-L-cysteine; NOHA, NG-hydroxy-L-arginine; nor-NOHA, Nω-hydroxyl-nor-L-arginine.