Arginase: an old enzyme with new tricks

Abstract

Arginase has roots in early life-forms. It converts L-arginine to urea and ornithine. The former provides protection against NH3; the latter serves to stimulate cell growth and other physiological functions. Excessive arginase activity in mammals has been associated with cardiovascular and nervous system dysfunction and disease. Two relevant aspects of this elevated activity may be involved in these disease states. First, excessive arginase activity reduces the supply of L-arginine needed by nitric oxide (NO) synthase to produce NO. Second, excessive production of ornithine leads to vascular structural problems and neural toxicity. Recent research has identified inflammatory agents and reactive oxygen species (ROS) as drivers of this pathologic elevation of arginase activity and expression. We review the involvement of arginase in cardiovascular and nervous system dysfunction, and discuss potential therapeutic interventions targeting excess arginase.

Keywords: arginase; neurodegeneration; nitric oxide; oxidative stress; peroxynitrite; polyamine; superoxide; vascular dysfunction.

Figure 1

Scheme for arginase catabolism of L-arginine to L-ornithine/urea or L-citrulline/NO, production of polyamines and anabolism and catabolism of proline. Also shown are the pathway for synthesis of L-arginine from L-glutamine, the reversible pathway between L-ornithine and L-glutamine, and the recycling of L-citrulline into L-arginine. Abbreviations: ASL, aminosuccinate lyase; ASS, aminosuccinate synthase; NOS, nitric oxide synthase; OAT; ornithine aminotransferase; ODC, ornithine decarboxylase; OTC, ornithine transcarbamylase. Arginase (bottom, left) is the final enzyme in the urea cycle within the liver, which restarts the cycle through the synthesis of L-citrulline from carbamoyl-phosphate (1) and L-ornithine (2) by OTC (center). It should be noted that that these reactions do not all occur within any given cell. In particular, the urea cycle is independent of the other reactions; i.e., L-arginine produced within the urea cycle is not a substrate for NOS and L-ornithine produced within the urea cycle is not a substrate for OAT or ODC

Figure 2

Scheme for endothelial nitric oxide synthase (eNOS) catabolism of L-arginine to NO and L-citrulline, which can be recycled back to L-arginine. Abbreviations: ASL, aminosuccinate lyase; ASS, aminosuccinate synthase; BH4, tetrahydrobiopterin; CAT-1, cationic amino acid transporter-1; FAD, flavin adenine dinucleotide; FMN, flavin mononucleotide; NADP, nicotinamide adenine dinucleotide phosphate.

Figure 3

Physiologic and pathophysiologic activities of endothelial nitric oxide synthase (eNOS) and arginase. Under physiologic conditions eNOS maintains a healthy vasculature with production of NO and arginase produces ornithine, polyamines and proline, for tissue growth and collagen formation, respectively. Under pathologic stimulation by RhoA/ROCK, increased arginase expression/activity putatively depletes eNOS of its substrate, L-arginine. When eNOS does not have sufficient substrate it can be uncoupled, becoming more a producer of superoxide (O₂^․−) rather than NO. Increased production of polyamines and proline can also lead to pathologic vascular remodeling and stiffness.

Figure 4

Flow chart of the ornithine pathway showing formation of polyamines and polyamine oxidation. Abbreviations: MDL, MDL-72,527 [N,N'-bis(2,3-butadienyl)-1,4-butanediamine]; ODC, ornithine decarboxylase; OAT, ornithine aminotransferase; SMO, spermine oxidase; APAO, N (1)-acetyl polyamine oxidase; SSAT, spermine spermidine acetyl transferase.