Disease relevance of ARG1

• Arginase in glomerulonephritis [1].
• Ornithine transcarbamylase and arginase I deficiency are responsible for diminished urea cycle function in the human hepatoblastoma cell line HepG2 [2].
• Hyperargininemia due to liver arginase deficiency [3].
• Expression tests of these mutant arginases in Escherichia coli indicated that the mutant arginase of W122X did not remain a stable product [4].
• Argininemia is caused by a hereditary deficiency of liver-type arginase (E.C.3.5.3.1) and is characterized by psychomotor retardation and spastic tetraplegia [4].

Psychiatry related information on ARG1

• Therefore, human penile arginase is a potential target for therapeutic intervention in the treatment of erectile dysfunction [5].
• Therefore, arginase is a potential therapeutic target for the treatment of sexual arousal disorders in men and women [6].
• Arginase deficiency is an urea cycle disorder that generally presents with mental retardation and spasticity, yet uncommonly with episodes of hyperammonemia [7].
• These results indicate that psychological stress causes an increase of NO level and a decrease of arginase activity in the L-arginine-NO pathway [8].
• Measurement of arginase activity made by varying the arginine concentration and the reaction time clarified that the amount of urea formed by arginase peaked at the substrate concentration of 150 mmol/l, and increased linearly by 20 minutes [9].

High impact information on ARG1

• Human carbonic anhydrase II and rat liver arginase serve as well-studied paradigms of zinc and manganese metalloenzymes, respectively [10].
• Toadfish synthesize urea using enzymes and subcellular distributions similar to those of elasmobranchs: glutamine-dependent carbamoyl phosphate synthethase (CPS III) and mitochondrial arginase [11].
• Gcn5p also enhances H3-K4 trimethylation in the ARG1 ORF and bulk histones [12].
• Unexpectedly, H3 acetylation in ARG1 coding sequences does not increase during induction due to the opposing activities of multiple HDAs associated with the ORF [12].
• In particular, sildenafil, down-regulates arginase 1 and nitric oxide synthase-2 expression, thereby reducing the suppressive machinery of CD11b(+)/Gr-1(+) myeloid-derived suppressor cells (MDSCs) recruited by growing tumors [13].

Chemical compound and disease context of ARG1

• L-arginine supplementation or arginase blockade may counteract endothelial dysfunction in the setting of acute arterial thrombosis [14].
• Plasma l-arginine concentration was diminished in psoriasis patients and the arginase product l-ornithine was significantly increased compared to healthy controls [15].
• The map is based on the segregation of 142 restriction fragment length polymorphism (RFLP) markers, two auxotrophic genes (arg1, nic1), mating type (matA+/matA-), female sterility (ste1), spore-killer (Sk), and a gene governing the production of the mycotoxin fumonisin B1 (fum1) among 121 random ascospore progeny from a single cross [16].
• The differential contribution of arginase and transamidinase to ornithine biosynthesis in two achromic human melanoma cell lines [17].
• Arginase deficiency with lethal neonatal expression: evidence for the glutamine hypothesis of cerebral edema [18].

Biological context of ARG1

• The gene for human liver arginase (ARG1) is assigned to chromosome band 6q23 [19].
• RESULTS: ARG1 SNPs and haplotypes were not associated with asthma, but all 4 ARG1 SNPs were associated with the number of positive skin tests (P = .007-.018) [20].
• OBJECTIVES: To examine the association between genetic variation in ARG1 and ARG2 and childhood asthma and atopy risk [20].
• The RAB20 gene is a member of the Ras gene superfamily and ARG1 promotes cellular proliferation [21].
• Arginase and asthma: novel insights into nitric oxide homeostasis and airway hyperresponsiveness [22].

Anatomical context of ARG1

• To determine whether arginases modulate the endothelial NO synthesis, we investigated the effects of the competitive arginase inhibitor N(omega)-hydroxy-nor-L-arginine (Nor-NOHA) on the activity of NOS, arginases, and L-arginine transporter and on NO release at surface of human umbilical vein endothelial cells (HUVECs) [23].
• We measured both arginase activity and NO production in SF macrophages and synovial membrane fibroblasts from patients with rheumatoid arthritis (RA) [24].
• Identification of arginase in human placental villi [25].
• And elevated arginase activity in the early gestational period may be responsible for proliferation of trophoblasts by increasing polyamines production [25].
• METHODS: Arginase activity was measured in synovial fluid (SF) cells from patients with different forms of arthritis, either directly or after in vitro stimulation with cytokines [24].

Associations of ARG1 with chemical compounds

• Based on these observations, we propose that a relative deficiency of NO caused by increased arginase activity and altered L-arginine homeostasis is a major factor in the pathology of asthma [22].
• To restore the urea cycle, HepG2 cells were transfected with full length Ornithine Transcarbamylase and Arginase I cDNA constructs under a CMV promoter [2].
• Gene expression data from HepG2 cells revealed that although expression of three urea cycle genes Carbamoyl Phosphate Synthase I, Arginosuccinate Synthetase and Arginosuccinate Lyase was evident, Ornithine Transcarbamylase and Arginase I expression were completely absent [2].
• Arginase catalyzes the conversion of arginine to urea and ornithine, the latter recycled to continue the cycle [3].
• Determination of the distribution and kinetics of induction of mRNAs transcribed from the five auxin-regulated genes of mung bean, which include Aux22s and SAUR as well as ARG1 and ARG2, shows that they are heterogeneous in their mode of gene expression [26].
• Activated neutrophils coreleased ARG1 and gelatinase to the extracellular environment on stimulation with phorbol-12-myristate 13-acetate (PMA), formyl-methionyl-leucyl-phenylalanine (fMLP), or tumor necrosis factor alpha (TNF-alpha) [27].

Regulatory relationships of ARG1

• Pegylated Recombinant Human Arginase (rhArg-peg5,000mw) Inhibits the In vitro and In vivo Proliferation of Human Hepatocellular Carcinoma through Arginine Depletion [28].
• We conclude that mitochondrial Arg II negatively regulates NOS1 activity, most likely by limiting substrate availability in its microdomain [29].
• IL-13-induced expression of arginase I correlated directly with increased synthesis of urea and with reduced synthesis of NO [30].
• Whereas, the enhanced overall arginase activity at term gestation seems to be because of the induced functional arginase I in concert with the attenuated arginase II expression [31].
• All cytokines except IL-10 also induced arginase I protein and mRNA [32].

Other interactions of ARG1

• Arginase is encoded by two recently discovered genes (Arginase I and Arginase II) [1].
• In a previous study, deletion mapping of 6q identified two smallest regions of overlap (SROs) of heterozygous deletions: one interstitial, spanning 12-16 cM, bordered by D6S268 (6q16.3-q21) and ARG1 (6q22.3-q23.1), and one distal to IFNGR1 (6q23-q24), spanning more than 30 cM [33].
• Human placenta expresses endothelial NOS (eNOS) in syncytiotrophoblasts, but the expression of arginase has not been fully elucidated [25].
• Known regulators of nitric oxide synthase and arginase are agonists at the human G-protein-coupled receptor GPRC6A [34].
• When CYP2D6 index and anti-arginase antibodies were combined, 55.3% of AIH patients were positive for either one or both antibodies [35].

Analytical, diagnostic and therapeutic context of ARG1

• These results were confirmed by Western blot for arginase I, where no protein was detected [2].
• Immunohistochemistry showed different distribution patterns of the arginase isoforms during gestation: A-I was observed only in cytotrophoblasts, while A-II was observed in both cytotrophoblasts and syncytiotrophoblasts [25].
• We have explored the molecular pathology in 28 individuals homozygous or heterozygous for liver arginase deficiency (hyperargininemia) by a combination of Southern analysis, western blotting, DNA sequencing, and PCR [36].
• The human liver arginase gene, whose deficiency is responsible for argininemia (McKusick no. 20780), has been assigned to 6q23 through a combination of somatic cell hybrid analysis and in situ hybridization using a 1,550-base pair (bp) human DNA probe for this gene [19].
• Insights into the interaction of human liver arginase with tightly and weakly bound manganese ions by chemical modification and site-directed mutagenesis studies [37].

References