HGNC Approved Gene Symbol: ARG2
Cytogenetic location: 14q24.1 Genomic coordinates (GRCh38): 14:67,619,920-67,651,708 (from NCBI)
Spector et al. (1980) presented evidence for the existence of 2 arginases. The one found in liver and red cells (ARG1; 608313) is severely deficient in argininemia (207800). In patients with this disorder, some urea is produced, presumably because the arginase of kidney, brain, and gastrointestinal tract is less affected; 'liver-type' enzyme constitutes only about half the enzyme in these tissues. In argininemia, kidney enzyme is about 3 times normal. Spector et al. (1980, 1983) demonstrated immunologic differences between liver and kidney enzymes by means of rabbit anti-human liver arginase. In addition to the immunologic differences and differences in tissue location, the second enzyme differs in electrophoretic mobility in polyacrylamide gels, in its quantitatively different requirement for divalent manganese activation, and in its differential inhibition by proline and isoleucine; it is localized to the mitochondrial matrix, whereas arginase 1 is cytoplasmic.
Vockley et al. (1996) found several EST database sequences with 40 to 60% homology to ARG1 and used these sequences to clone the human ARG2 gene from a Jurkat cDNA library. The ARG2 gene encodes a 355-amino acid polypeptide. Comparing the amino acid sequences of ARG1 and ARG2, Vockley et al. (1996) noted 6 short regions of 92% identity in conserved regions and about 42% identity throughout the remainder of the sequences. Using Northern blot analysis and RT-PCR, Vockley et al. (1996) found that ARG2 is expressed as a 1.5-kb mRNA in a wide variety of tissues, with highest levels in prostate, brain, and kidney. The authors also observed 2 other transcripts of 2.0 and 4.0 kb in prostate tissue. Gotoh et al. (1996) cloned the human ARG2 gene. They noted that it contained a mitochondrial import sequence, and showed that in transfected COS-7 cells the protein is imported into the mitochondria with appropriate proteolysis.
Morris et al. (1997) found that the predicted sequence of human type 2 arginase is 58% identical to the sequence of human type 1 arginase but is 71% identical to the sequence of Xenopus type 2 arginase, suggesting that duplication of the arginase gene occurred before mammals and amphibians diverged. Seven residues known to be essential for activity are conserved in all arginases. Type 2 arginase mRNA was detected in virtually all human and mouse RNA samples tested, whereas type 1 arginase mRNA was found only in liver. Morris et al. (1997) speculated that multiple type 2 arginase mRNAs in humans may arise from differential RNA processing or usage of alternative promoters.
Vockley et al. (1996) stated that ARG2 may be inducible and may be essential in the regulation of nitric oxide synthesis by modulating local arginine concentrations. Gotoh et al. (1996) showed that ARG2 mRNA and nitric oxide synthase (NOS) mRNA were coinduced by lipopolysaccharide in a macrophage-like cell line. This coinduction was enhanced by dexamethasone and dibutyryl cAMP, and was prevented by interferon-gamma (147570).
In a review and discussion of the human arginases and arginase deficiency, Iyer et al. (1998) provided a brief history leading up to the cloning of the ARG2 gene. They pointed out that the mitochondrial location of ARG2 and its coinduction with ornithine aminotransferase (613349) and involvement with proline biosynthesis in lactating rat mammary gland had led to the inference that ARG2 is involved in biosynthetic functions, as opposed to the metabolic ones of the urea cycle. The many metabolic fates of arginine and its immediate product ornithine were diagrammed in their Figure 4. They presented evidence for the role of ARG2 in nitric oxide and polyamine metabolism.
McGovern et al. (2017) showed that subsets of antigen-presenting cells can be identified in fetal tissues and are related to adult populations of antigen-presenting cells. Similar to adult dendritic cells, fetal dendritic cells migrate to lymph nodes and respond to toll-like receptor (see TLR1, 601194) ligation; however, they differ markedly in their response to allogeneic antigens, strongly promoting regulatory T-cell induction and inhibiting TNFA production through ARG2 activity. McGovern et al. (2017) concluded that their results revealed a role of dendritic cells within the developing fetus and indicated that they mediate homeostatic immune-suppressive responses during gestation.
By PCR analysis of somatic cell hybrid panels, fluorescence in situ hybridization, and radiation hybrid analysis, Gotoh et al. (1997) mapped the ARG2 gene to 14q24.1-q24.3.
Deignan et al. (2006) generated mice with individual and combined knockout of Arg1 and Arg2. Arg1 knockout animals died by 14 days of age from hyperammonemia, whereas Arg2 knockout mice had no obvious phenotype. The double Arg1/Arg2 knockout mice exhibited the phenotype of the Arg1-knockout mice, with the additional absence of Arg2 not exacerbating the phenotype. Plasma amino acid measurements in the double knockout mice showed arginine levels increased roughly 100-fold and ornithine decreased roughly 10-fold compared with wildtype. Arginine and ornithine levels were also altered in liver, kidney, brain, and small intestine in the double knockout mice.
Deignan, J. L., Livesay, J. C., Yoo, P. K., Goodman, S. I., O'Brien, W. E., Iyer, R. K., Cederbaum, S. D., Grody, W. W. Ornithine deficiency in the arginase double knockout mouse. Molec. Genet. Metab. 89: 87-96, 2006. [PubMed: 16753325] [Full Text: https://doi.org/10.1016/j.ymgme.2006.04.007]
Gotoh, T., Araki, M., Mori, M. Chromosomal localization of the human arginase II gene and tissue distribution of its mRNA. Biochem. Biophys. Res. Commun. 233: 487-491, 1997. [PubMed: 9144563] [Full Text: https://doi.org/10.1006/bbrc.1997.6473]
Gotoh, T., Sonoki, T., Nagasaki, A., Terada, K., Takiguchi, M., Mori, M. Molecular cloning of cDNA for nonhepatic mitochondrial arginase (arginase II) and comparison of its induction with nitric oxide synthase in a murine macrophage-like cell line. FEBS Lett. 395: 119-122, 1996. [PubMed: 8898077] [Full Text: https://doi.org/10.1016/0014-5793(96)01015-0]
Iyer, R., Jenkinson, C. P., Vockley, J. G., Kern, R. M., Grody, W. W., Cederbaum, S. The human arginases and arginase deficiency. J. Inherit. Metab. Dis. 21 (suppl. 1): 86-100, 1998. [PubMed: 9686347] [Full Text: https://doi.org/10.1023/a:1005313809037]
McGovern, N., Shin, A., Low, G., Low, D., Duan, K., Yao, L. J., Msallam, R., Low, I., Shadan, N. B., Sumatoh, H. R., Soon, E., Lum, J., and 26 others. Human fetal dendritic cells promote prenatal T-cell immune suppression through arginase-2. Nature 546: 662-666, 2017. [PubMed: 28614294] [Full Text: https://doi.org/10.1038/nature22795]
Morris, S. M., Jr., Bhamidipati, D., Kepka-Lenhart, D. Human type II arginase: sequence analysis and tissue-specific expression. Gene 193: 157-161, 1997. [PubMed: 9256072] [Full Text: https://doi.org/10.1016/s0378-1119(97)00099-1]
Spector, E. B., Rice, S. C. H., Cederbaum, S. D. Evidence for two genes encoding human arginase. (Abstract) Am. J. Hum. Genet. 32: 55A only, 1980.
Spector, E. B., Rice, S. C. H., Cederbaum, S. D. Immunologic studies of arginase in tissues of normal human adult and arginase-deficient patients. Pediat. Res. 17: 941-944, 1983. [PubMed: 6419196] [Full Text: https://doi.org/10.1203/00006450-198312000-00003]
Vockley, J. G., Jenkinson, C. P., Shukla, H., Kern, R. M., Grody, W. W., Cederbaum, S. D. Cloning and characterization of the human type II arginase gene. Genomics 38: 118-123, 1996. [PubMed: 8954792] [Full Text: https://doi.org/10.1006/geno.1996.0606]