Modulation of the Arginase Pathway in the Context of Microbial Pathogenesis: A Metabolic Enzyme Moonlighting as an Immune Modulator

Abstract

Arginine is a crucial amino acid that serves to modulate the cellular immune response during infection. Arginine is also a common substrate for both inducible nitric oxide synthase (iNOS) and arginase. The generation of nitric oxide from arginine is responsible for efficient immune response and cytotoxicity of host cells to kill the invading pathogens. On the other hand, the conversion of arginine to ornithine and urea via the arginase pathway can support the growth of bacterial and parasitic pathogens. The competition between iNOS and arginase for arginine can thus contribute to the outcome of several parasitic and bacterial infections. There are two isoforms of vertebrate arginase, both of which catalyze the conversion of arginine to ornithine and urea, but they differ with regard to tissue distribution and subcellular localization. In the case of infection with Mycobacterium, Leishmania, Trypanosoma, Helicobacter, Schistosoma, and Salmonella spp., arginase isoforms have been shown to modulate the pathology of infection by various means. Despite the existence of a considerable body of evidence about mammalian arginine metabolism and its role in immunology, the critical choice to divert the host arginine pool by pathogenic organisms as a survival strategy is still a mystery in infection biology.

Re-thinking the functions of IgA+plasma cells

“…113,114 L-Arg is a central intestinal metabolite, functioning both as a constituent of protein synthesis and as a regulatory molecule limiting intestinal alterations and maintaining immune-physiological functions. 115,116 While the cytosolic Arg1 is abundant in liver as part of the urea cycle, Arg2 is mostly abundant in extra-hepatic tissues such as the kidney, brain and gut.…”

“…In contrast NOS catalyzes the production of NO and L-Cit from L-Arg. 113 L-Arg is derived from the diet, turnover of proteins and endogenous production through synthesis from L-citrulline (L-Cit) and enzymes of the urea cycle. Although synthesis of LArg from L-Cit can occur in many cell types, a major part of endogenous synthesis occurs via "the intestinal-renal axis" involving IEC of the small intestine and proximal tubule cells of the kidney.…”

“…113 Infection-associated L-Arg deficiency has been shown to contribute to immunopathology and predisposes to co-infections, 119 and clinical trials involving L-Arg administration have shown substantial decreases in inflammation and infectious complications.…”

Immunosuppressive Effects of Arginine Deiminase From Streptococcus Pyogenes

“…Еще одной важной вехой в изучении метаболиз-ма аргинина явилась расшифровка механизмов иммуносупрессии у онкологических больных, связанных с деплецией аргинина в результате аргиназной активности миелоидных супрессор-ных клеток [29]. На важность метаболизма этой аминокислоты в осуществлении защитных ре-акций указывает тот факт, что многие патогены используют метаболические пути аргинина ор-ганизма-хозяина для своей успешной инвазии и диссеминации [20]. Одним из ферментов, мета-болизирующих аргинин, является бактериальная аргининдеиминаза (АД).…”

A Role of Arginine Deiminase From Streptococcus Pyogenes M49-16 in Promoting Infection and Inhibition of Endothelial Cell Proliferation

“…Многие патогенные микроорганизмы ис-пользуют метаболические пути аргинина орга-низма-хозяина в качестве стратегии выживания [8]. Одним из бактериальных ферментов, ката-лизирующих гидролиз аргинина, является арги-ниндеиминаза (АД) [23].…”