Argininosuccinate synthetase from the urea cycle to the citrulline–NO cycle

Abstract

Argininosuccinate synthetase (ASS, EC 6.3.4.5) catalyses the condensation of citrulline and aspartate to form argininosuccinate, the immediate precursor of arginine. First identified in the liver as the limiting enzyme of the urea cycle, ASS is now recognized as a ubiquitous enzyme in mammalian tissues. Indeed, discovery of the citrulline–NO cycle has increased interest in this enzyme that was found to represent a potential limiting step in NO synthesis. Depending on arginine utilization, location and regulation of ASS are quite different. In the liver, where arginine is hydrolyzed to form urea and ornithine, the ASS gene is highly expressed, and hormones and nutrients constitute the major regulating factors: (a) glucocorticoids, glucagon and insulin, particularly, control the expression of this gene both during development and adult life; (b) dietary protein intake stimulates ASS gene expression, with a particular efficiency of specific amino acids like glutamine. In contrast, in NO‐producing cells, where arginine is the direct substrate in the NO synthesis, ASS gene is expressed at a low level and in this way, proinflammatory signals constitute the main factors of regulation of the gene expression. In most cases, regulation of ASS gene expression is exerted at a transcriptional level, but molecular mechanisms are still poorly understood.

Brain nitric oxide production by a proline-rich decapeptide from Bothrops jararaca venom improves baroreflex sensitivity of spontaneously hypertensive rats

“…11 ASS is the rate-limiting enzyme of the citrulline-NO cycle that regulates the supply of L-arginine as a substrate for NOS. 6 We showed that Bj-PRO-10c administration results in augmented NO production in SHR brain tissues as well as in primary cultures of postnatal SHR brain neurons. Bj-PRO-10c-induced NO production in neuronal cells was abolished by pretreatment of cells with ASS and NOS inhibitors (data not shown).…”

“…ASS is an ubiquitous enzyme that is expressed in all tissues, including the brain. 6 This enzyme catalyzes the conjugation reaction of citrulline with aspartate to generate argininosuccinate, which in turn is converted by argininosuccinate lyase into fumarate and L-arginine. L-arginine is cleaved into citrulline and NO, completing the cycle.…”

“…L-arginine is cleaved into citrulline and NO, completing the cycle. 6,7 Our group has recently shown that a decapeptide that is rich in proline residues binds to ASS. This molecule, named Bj- or BPP-10c, belongs to a class of peptides isolated from Bothrops jararaca snake venom.…”

“…17 Changes in neural-cardiovascular integration due to NO deficiency may be the main cause of autonomic abnormalities in several models of experimental hypertension 2 as a consequence of impaired arterial baroreflex. 3,18 As a result of augmented ASS activity, an enzyme also expressed in the CNS, 6 and central effects on the control of blood pressure 11,14 in the presence of Bj-PRO-10c, we expected to observe increased NO production in the brain and improved arterial baroreflex function in conscious SHRs. Therefore, this study was designed to examine the effects of Bj-PRO-10c on baroreflex sensitivity in SHRs and to elucidate involved mechanisms.…”

Glutamine Stimulates Argininosuccinate Synthetase Gene Expression through Cytosolic O-Glycosylation of Sp1 in Caco-2 Cells

“…), the key enzyme of arginine synthesis, we observed that the mechanism involved might depend on the cell type studied. Indeed, we previously reported that the glutamine-induced cell swelling was involved in hepatocytes because hypo-osmolarity totally mimicked the glutamine stimulating effect on the mRNA level (10); but this was not the case in Caco-2 cells, a human intestinal cell line (17). The present work was therefore begun to specify the molecular mechanism involved in the stimulating effect of glutamine on ASS gene expression in Caco-2 cells.…”