argininosuccinate synthase


Summary: An enzyme of the urea cycle that catalyzes the formation of argininosuccinic acid from citrulline and aspartic acid in the presence of ATP. Absence or deficiency of this enzyme causes the metabolic disease CITRULLINEMIA in humans. EC

Top Publications

  1. Goodwin B, Solomonson L, Eichler D. Argininosuccinate synthase expression is required to maintain nitric oxide production and cell viability in aortic endothelial cells. J Biol Chem. 2004;279:18353-60 pubmed
    ..To support this proposal, RNA interference analysis was used to selectively reduce the expression of argininosuccinate synthase (AS), because the only known metabolic role for AS in endothelial cells is in the regeneration of l-..
  2. Kim R, Bold R, Kung H. ADI, autophagy and apoptosis: metabolic stress as a therapeutic option for prostate cancer. Autophagy. 2009;5:567-8 pubmed
    ..Thus, targeting multiple cell death pathways, either through autophagy modulation or non-canonical apoptosis, may find expanded use as adjuvant chemotherapies, providing additional avenues for cancer treatment. ..
  3. Delage B, Fennell D, Nicholson L, McNeish I, Lemoine N, Crook T, et al. Arginine deprivation and argininosuccinate synthetase expression in the treatment of cancer. Int J Cancer. 2010;126:2762-72 pubmed publisher
    ..This review examines the prospects for novel approaches in the prevention, diagnosis and treatment of malignant disease based on ASS1 pathophysiology and its rate-limiting product, arginine. ..
  4. Bowles T, Kim R, Galante J, Parsons C, Virudachalam S, Kung H, et al. Pancreatic cancer cell lines deficient in argininosuccinate synthetase are sensitive to arginine deprivation by arginine deiminase. Int J Cancer. 2008;123:1950-5 pubmed publisher
    ..Therefore, these findings suggest that arginine deprivation by ADI could provide a beneficial strategy for the treatment of pancreatic cancer, a malignancy in which new therapy is desperately needed. ..
  5. Lemke C, Howell P. The 1.6 A crystal structure of E. coli argininosuccinate synthetase suggests a conformational change during catalysis. Structure. 2001;9:1153-64 pubmed
    ..Sequence similarity between the bacterial and human enzymes has been used for providing insight into the structural and functional effects of observed clinical mutations. ..
  6. Brasse Lagnel C, Lavoinne A, Fairand A, Vavasseur K, Husson A. IL-1beta stimulates argininosuccinate synthetase gene expression through NF-kappaB in Caco-2 cells. Biochimie. 2005;87:403-9 pubmed
    ..Using gel shift assay and double-strand oligonucleotide sequence of the identified putative NF-kappaB binding site of the ASS promoter, we provide evidence that NF-kappaB may functionally interact with this element. ..
  7. Husson A, Brasse Lagnel C, Fairand A, Renouf S, Lavoinne A. Argininosuccinate synthetase from the urea cycle to the citrulline-NO cycle. Eur J Biochem. 2003;270:1887-99 pubmed
    ..In most cases, regulation of ASS gene expression is exerted at a transcriptional level, but molecular mechanisms are still poorly understood. ..
  8. Engel K, Hohne W, Haberle J. Mutations and polymorphisms in the human argininosuccinate synthetase (ASS1) gene. Hum Mutat. 2009;30:300-7 pubmed publisher
    ..Enzymatic studies have been done in bacterial and human cell systems. However, the prognostic value of genetic aberrations with respect to their effect on protein function and clinical manifestation remains uncertain. ..
  9. Nicholson L, Smith P, Hiller L, Szlosarek P, Kimberley C, Sehouli J, et al. Epigenetic silencing of argininosuccinate synthetase confers resistance to platinum-induced cell death but collateral sensitivity to arginine auxotrophy in ovarian cancer. Int J Cancer. 2009;125:1454-63 pubmed publisher
    ..The collateral sensitivity of cells lacking endogenous ASS1 to arginine depletion suggests novel therapeutic strategies for the management of relapsed ovarian cancer. ..

More Information


  1. Haberle J, Pauli S, Schmidt E, Schulze Eilfing B, Berning C, Koch H. Mild citrullinemia in Caucasians is an allelic variant of argininosuccinate synthetase deficiency (citrullinemia type 1). Mol Genet Metab. 2003;80:302-6 pubmed
    ..According to the mutations found in this study, mild citrullinemia seems to be primarily related to the human ASS gene, at least in patients of caucasian origin...
  2. Köhler E, Sankaranarayanan S, van Ginneken C, Van Dijk P, Vermeulen J, Ruijter J, et al. The human neonatal small intestine has the potential for arginine synthesis; developmental changes in the expression of arginine-synthesizing and -catabolizing enzymes. BMC Dev Biol. 2008;8:107 pubmed publisher
    ..The perinatal human intestine therefore resembles that of rodents and pigs. Enteral ASS behaves as a typical suckling enzyme because its expression all but disappears in the putative weaning period of human infants. ..
  3. Goto M, Nakajima Y, Hirotsu K. Crystal structure of argininosuccinate synthetase from Thermus thermophilus HB8. Structural basis for the catalytic action. J Biol Chem. 2002;277:15890-6 pubmed publisher
    ..The reaction mechanism so far proposed seems to be consistent with the locations of ATP and the substrate analogues. The reaction may proceed without the large conformational change of the enzyme proposed for the catalytic process...
  4. Feun L, You M, Wu C, Kuo M, Wangpaichitr M, Spector S, et al. Arginine deprivation as a targeted therapy for cancer. Curr Pharm Des. 2008;14:1049-57 pubmed
    ..This article reviews our laboratory and clinical experience as well as that from others with ADI-PEG20 as an antineoplastic agent. Future direction in utilizing this agent is also discussed. ..
  5. Bizzoco E, Faussone Pellegrini M, Vannucchi M. Activated microglia cells express argininosuccinate synthetase and argininosuccinate lyase in the rat brain after transient ischemia. Exp Neurol. 2007;208:100-9 pubmed
    ..Therefore, local factors such as the NO produced by nNOS/ASS/ASL-positive neurons, could influence ASS/ASL-positive microglia cells avoiding or allowing the induction, in these cells, of iNOS. ..
  6. Wheatley D. Arginine deprivation and metabolomics: important aspects of intermediary metabolism in relation to the differential sensitivity of normal and tumour cells. Semin Cancer Biol. 2005;15:247-53 pubmed
  7. Perez C, Jaubert J, Guenet J, Barnhart K, Ross Inta C, Quintanilla V, et al. Two hypomorphic alleles of mouse Ass1 as a new animal model of citrullinemia type I and other hyperammonemic syndromes. Am J Pathol. 2010;177:1958-68 pubmed publisher
  8. Berning C, Bieger I, Pauli S, Vermeulen T, Vogl T, Rummel T, et al. Investigation of citrullinemia type I variants by in vitro expression studies. Hum Mutat. 2008;29:1222-7 pubmed publisher
    ..This study should guide clinicians as well as patients with mild citrullinemia toward a lifelong awareness of the disorder...
  9. Shaheen N, Kobayashi K, Terazono H, Fukushige T, Horiuchi M, Saheki T. Characterization of human wild-type and mutant argininosuccinate synthetase proteins expressed in bacterial cells. Enzyme Protein. 1994;48:251-64 pubmed
    ..190 mmol/l) than in wild-type ASS (0.056 mmol/l). The results confirm that these mutations are responsible for ASS deficiency and also indicate that these amino acid residues are important for the function and structure of ASS protein. ..
  10. Flam B, Eichler D, Solomonson L. Endothelial nitric oxide production is tightly coupled to the citrulline-NO cycle. Nitric Oxide. 2007;17:115-21 pubmed
    ..As further support, alpha-methyl-DL-aspartate, an inhibitor of argininosuccinate synthase (AS), a component of the citrulline-NO cycle, inhibited NO production in a dose-dependent manner...
  11. Goto M, Omi R, Miyahara I, Sugahara M, Hirotsu K. Structures of argininosuccinate synthetase in enzyme-ATP substrates and enzyme-AMP product forms: stereochemistry of the catalytic reaction. J Biol Chem. 2003;278:22964-71 pubmed publisher
    ..The stereochemistry of the catalysis of the enzyme is clarified on the basis of the structures of tAsS (argininosuccinate synthetase from T. thermophilus HB8) complexes...
  12. Wu G, Jaeger L, Bazer F, Rhoads J. Arginine deficiency in preterm infants: biochemical mechanisms and nutritional implications. J Nutr Biochem. 2004;15:442-51 pubmed
    ..g., pyrroline-5-carboxylate synthase, argininosuccinate synthase and lyase), thereby contributing to hypoargininemia...
  13. Goodwin B, Pendleton L, Levy M, Solomonson L, Eichler D. Tumor necrosis factor-alpha reduces argininosuccinate synthase expression and nitric oxide production in aortic endothelial cells. Am J Physiol Heart Circ Physiol. 2007;293:H1115-21 pubmed
    ..not only eNOS expression but also the availability of arginine via the coordinate suppression of argininosuccinate synthase (AS) expression in aortic endothelial cells...
  14. Guerreiro J, Lameu C, Oliveira E, Klitzke C, Melo R, Linares E, et al. Argininosuccinate synthetase is a functional target for a snake venom anti-hypertensive peptide: role in arginine and nitric oxide production. J Biol Chem. 2009;284:20022-33 pubmed publisher
    ..Therefore, we propose the activation of AsS as a new mechanism for the anti-hypertensive effect of Bj-BPP-10c in SHR and AsS as a novel target for the therapy of hypertension-related diseases. ..
  15. Savaraj N, You M, Wu C, Wangpaichitr M, Kuo M, Feun L. Arginine deprivation, autophagy, apoptosis (AAA) for the treatment of melanoma. Curr Mol Med. 2010;10:405-12 pubmed
  16. Leung T, Lu Y, Yan W, MORON CONCEPCION J, Ward S, Ge X, et al. Argininosuccinate synthase conditions the response to acute and chronic ethanol-induced liver injury in mice. Hepatology. 2012;55:1596-1609 pubmed publisher
    b>Argininosuccinate synthase (ASS) is the rate-limiting enzyme in both the urea and the L-citrulline/nitric oxide (NO·) cycles regulating protein catabolism, ammonia levels, and NO· generation...
  17. Haberle J, Pauli S, Linnebank M, Kleijer W, Bakker H, Wanders R, et al. Structure of the human argininosuccinate synthetase gene and an improved system for molecular diagnostics in patients with classical and mild citrullinemia. Hum Genet. 2002;110:327-33 pubmed
  18. Qualls J, Subramanian C, Rafi W, Smith A, Balouzian L, DeFreitas A, et al. Sustained generation of nitric oxide and control of mycobacterial infection requires argininosuccinate synthase 1. Cell Host Microbe. 2012;12:313-23 pubmed publisher
    ..Accumulated intracellular citrulline is thought to fuel arginine synthesis catalyzed by argininosuccinate synthase (Ass1) and argininosuccinate lyase (Asl), which would lead to abundant NO production...
  19. Begum L, Jalil M, Kobayashi K, Iijima M, Li M, Yasuda T, et al. Expression of three mitochondrial solute carriers, citrin, aralar1 and ornithine transporter, in relation to urea cycle in mice. Biochim Biophys Acta. 2002;1574:283-92 pubmed
  20. Lemke C, Howell P. Substrate induced conformational changes in argininosuccinate synthetase. J Biol Chem. 2002;277:13074-81 pubmed
    ..Combined, these structures also provide structural explanations of some of the observed kinetic properties of the enzyme and have enabled a detailed enzymatic mechanism of AS catalysis to be proposed. ..
  21. de Jonge W, Dingemanse M, de Boer P, Lamers W, Moorman A. Arginine-metabolizing enzymes in the developing rat small intestine. Pediatr Res. 1998;43:442-51 pubmed
  22. Tsai W, Aiba I, Long Y, Lin H, Feun L, Savaraj N, et al. Activation of Ras/PI3K/ERK pathway induces c-Myc stabilization to upregulate argininosuccinate synthetase, leading to arginine deiminase resistance in melanoma cells. Cancer Res. 2012;72:2622-33 pubmed publisher
  23. Van Vliet F, Crabeel M, Boyen A, Tricot C, Stalon V, Falmagne P, et al. Sequences of the genes encoding argininosuccinate synthetase in Escherichia coli and Saccharomyces cerevisiae: comparison with methanogenic archaebacteria and mammals. Gene. 1990;95:99-104 pubmed
    ..EMBO J. 1 (1982) 945-951] and are therefore candidates for ATP-binding sites. The third region shows some similarity to a short portion of the N-proximal part of the PurA enzyme which catalyses an analogous reaction. ..
  24. Corbin K, Pendleton L, Solomonson L, Eichler D. Phosphorylation of argininosuccinate synthase by protein kinase A. Biochem Biophys Res Commun. 2008;377:1042-6 pubmed publisher
    b>Argininosuccinate synthase (AS) is essential for endothelial nitric oxide (NO) production and its regulation in this capacity has been studied primarily at the transcriptional level...
  25. Kim J, Kim J, Yu Y, Kim D, Min B, Kim K. Anti-tumor activity of arginine deiminase via arginine deprivation in retinoblastoma. Oncol Rep. 2007;18:1373-7 pubmed
    ..These results indicate that arginine deprivation via ADI could be another treatment option for retinoblastoma due to low ASS activity in retinoblastoma cells. ..
  26. Morris C, Reeve J. Conservation of structure in the human gene encoding argininosuccinate synthetase and the argG genes of the archaebacteria Methanosarcina barkeri MS and Methanococcus vannielii. J Bacteriol. 1988;170:3125-30 pubmed
  27. Yoon C, Shim Y, Kim E, Lee J, Won N, Kim J, et al. Renal cell carcinoma does not express argininosuccinate synthetase and is highly sensitive to arginine deprivation via arginine deiminase. Int J Cancer. 2007;120:897-905 pubmed
    ..Therefore, these findings suggest that arginine deprivation by ADI could provide a beneficial strategy for the treatment of RCC in ways of inhibitions of arginine availability and neovascularization. ..
  28. Kobayashi E, Masuda M, Nakayama R, Ichikawa H, Satow R, Shitashige M, et al. Reduced argininosuccinate synthetase is a predictive biomarker for the development of pulmonary metastasis in patients with osteosarcoma. Mol Cancer Ther. 2010;9:535-44 pubmed publisher
    ..Our data indicate that in patients with osteosarcoma, reduced expression of ASS is not only a novel predictive biomarker for the development of metastasis, but also a potential target for pharmacologic intervention. ..
  29. Pendleton L, Goodwin B, Solomonson L, Eichler D. Regulation of endothelial argininosuccinate synthase expression and NO production by an upstream open reading frame. J Biol Chem. 2005;280:24252-60 pubmed
    b>Argininosuccinate synthase (AS) catalyzes the rate-limiting step in the recycling of citrulline to arginine, which in endothelial cells, is tightly coupled to the production of nitric oxide (NO)...
  30. Patejunas G, Bradley A, Beaudet A, O Brien W. Generation of a mouse model for citrullinemia by targeted disruption of the argininosuccinate synthetase gene. Somat Cell Mol Genet. 1994;20:55-60 pubmed
    ..Because the phenotype of the mutant mice closely resembles that of humans who lack the ASS enzyme, we expect that these mice will serve as a useful model for exploring new treatments for citrullinemia including somatic gene therapy. ..
  31. Xie L, Gross S. Argininosuccinate synthetase overexpression in vascular smooth muscle cells potentiates immunostimulant-induced NO production. J Biol Chem. 1997;272:16624-30 pubmed
    ..In accord with the reported "channeling" of substrates by urea cycle enzymes, we hypothesize that the Arg/Cit cycle sequesters a discrete pool of recyclable substrate that sustains high-output NO synthesis. ..
  32. Guei T, Liu M, Yang C, Su T. Identification of a liver-specific cAMP response element in the human argininosuccinate synthetase gene. Biochem Biophys Res Commun. 2008;377:257-61 pubmed publisher
    ..Our results show that liver-specific enhancement of ASS gene expression is mediated in part by the cAMP signaling pathway through a distal CRE site. ..
  33. Ensor C, Holtsberg F, Bomalaski J, Clark M. Pegylated arginine deiminase (ADI-SS PEG20,000 mw) inhibits human melanomas and hepatocellular carcinomas in vitro and in vivo. Cancer Res. 2002;62:5443-50 pubmed
  34. Solomonson L, Flam B, Pendleton L, Goodwin B, Eichler D. The caveolar nitric oxide synthase/arginine regeneration system for NO production in endothelial cells. J Exp Biol. 2003;206:2083-7 pubmed
    ..In support of this hypothesis, the recycling enzymes, argininosuccinate synthase (AS) and argininosuccinate lyase (AL), have been shown to colocalize with eNOS in caveolae, a ..
  35. Szlosarek P, Klabatsa A, Pallaska A, Sheaff M, Smith P, Crook T, et al. In vivo loss of expression of argininosuccinate synthetase in malignant pleural mesothelioma is a biomarker for susceptibility to arginine depletion. Clin Cancer Res. 2006;12:7126-31 pubmed
    ..A phase II clinical trial is planned to evaluate the role of arginine depletion in patients with AS-negative MPM. ..
  36. Dillon B, Prieto V, Curley S, Ensor C, Holtsberg F, Bomalaski J, et al. Incidence and distribution of argininosuccinate synthetase deficiency in human cancers: a method for identifying cancers sensitive to arginine deprivation. Cancer. 2004;100:826-33 pubmed
    ..Based on these results, human clinical trials using arginine-degrading enzyme therapy to treat patients with advanced melanoma or hepatocellular carcinoma have been initiated. ..
  37. Tsai W, Aiba I, Lee S, Feun L, Savaraj N, Kuo M. Resistance to arginine deiminase treatment in melanoma cells is associated with induced argininosuccinate synthetase expression involving c-Myc/HIF-1alpha/Sp4. Mol Cancer Ther. 2009;8:3223-33 pubmed publisher
    ..Inability of AS induction in A375 cells under arginine depletion conditions was correlated by the failure of c-Myc to interact with the AS promoter. ..
  38. Kelly M, Jungbluth A, Wu B, Bomalaski J, Old L, Ritter G. Arginine deiminase PEG20 inhibits growth of small cell lung cancers lacking expression of argininosuccinate synthetase. Br J Cancer. 2012;106:324-32 pubmed publisher
    ..These results suggest a role for ADI-PEG20 in the treatment of SCLC, and a clinical trial exploring this therapeutic approach in patients with ASS-negative SCLC by IHC has now been initiated. ..
  39. Ye X, Whiteman B, Jerebtsova M, Batshaw M. Correction of argininosuccinate synthetase (AS) deficiency in a murine model of citrullinemia with recombinant adenovirus carrying human AS cDNA. Gene Ther. 2000;7:1777-82 pubmed
  40. Brasse Lagnel C, Fairand A, Lavoinne A, Husson A. Glutamine stimulates argininosuccinate synthetase gene expression through cytosolic O-glycosylation of Sp1 in Caco-2 cells. J Biol Chem. 2003;278:52504-10 pubmed
    ..Collectively, the results constitute the first demonstration of a functional relationship between a regulating signal (glutamine), a transcription factor (Sp1), and the transcription of the ASS gene. ..
  41. Kim R, Coates J, Bowles T, McNerney G, Sutcliffe J, Jung J, et al. Arginine deiminase as a novel therapy for prostate cancer induces autophagy and caspase-independent apoptosis. Cancer Res. 2009;69:700-8 pubmed publisher
    ..Finally, a tissue microarray of 88 prostate tumor samples lacked expression of ASS, indicating ADI-PEG20 is a potential novel therapy for the treatment of prostate cancer ..
  42. Karlberg T, Collins R, van den Berg S, Flores A, Hammarström M, Högbom M, et al. Structure of human argininosuccinate synthetase. Acta Crystallogr D Biol Crystallogr. 2008;64:279-86 pubmed publisher
    ..In addition, the structure also provides new insights into the function of the numerous clinical mutations identified in patients with type I citrullinaemia (also known as classic citrullinaemia). ..
  43. Shen L, Lin W, Beloussow K, Shen W. Resistance to the anti-proliferative activity of recombinant arginine deiminase in cell culture correlates with the endogenous enzyme, argininosuccinate synthetase. Cancer Lett. 2003;191:165-70 pubmed
    ..Our results indicate that resistance to rADI-treatment may correlate with cellular AS activity, either constitutive or inducible, allowing cell survival by conversion of the product of the rADI reaction, i.e. citrulline to arginine. ..
  44. Gao H, Kobayashi K, Tabata A, Tsuge H, Iijima M, Yasuda T, et al. Identification of 16 novel mutations in the argininosuccinate synthetase gene and genotype-phenotype correlation in 38 classical citrullinemia patients. Hum Mutat. 2003;22:24-34 pubmed
  45. Goodwin B, Corbin K, Pendleton L, Levy M, Solomonson L, Eichler D. Troglitazone up-regulates vascular endothelial argininosuccinate synthase. Biochem Biophys Res Commun. 2008;370:254-8 pubmed publisher
    ..of endothelial nitric oxide synthase (eNOS), but also regulation of caveolar-localized endothelial argininosuccinate synthase (AS), which catalyzes the rate-limiting step of the cycle...
  46. Lichter P, Richards J, Downs C, Stringham H, Boehnke M, Farley F. Cosegregation of open-angle glaucoma and the nail-patella syndrome. Am J Ophthalmol. 1997;124:506-15 pubmed
    ..To evaluate two families ascertained only for the presence of glaucoma in which both nail-patella syndrome and glaucoma occur in several generations and to determine whether the two diseases are genetically related...
  47. Carritt B. Somatic cell genetic evidence for the presence of a gene for citrullinemia on human chromosome 9. Cytogenet Cell Genet. 1977;19:44-8 pubmed
  48. Nakata M, Yada T, Nakagawa S, Kobayashi K, Maruyama I. Citrulline-argininosuccinate-arginine cycle coupled to Ca2+-signaling in rat pancreatic beta-cells. Biochem Biophys Res Commun. 1997;235:619-24 pubmed
    ..L-citrulline also stimulated NO production in HIT cells, which was inhibited by NMMA. In conclusion, L-citrulline is metabolized by ASS-ASL-NOS cycle to produce NO, which in turn increases [Ca2+]i in beta-cells. ..
  49. Patel H, Kim J, Huncke T. General anesthesia in a patient with citrullinemia using Precedex as an adjunct to prevent delayed emergence. J Clin Anesth. 2016;33:403-5 pubmed publisher
    ..type I is a rare autosomal recessive genetic condition that causes reduced activity of the enzyme, argininosuccinate synthase, which is needed for proper urea metabolism...
  50. Mishra R, Tseng T, Chen M, Chen P, Lee T. Bacterial toxins activation of abbreviated urea cycle in porcine cerebral vascular smooth muscle cells. Vascul Pharmacol. 2016;87:110-120 pubmed publisher
    ..This cycle indicates that argininosuccinate synthase (ASS) catalyzes l-citrulline (l-cit) conversion to form argininosuccinate (AS), and subsequent AS ..
  51. Mueller E, Palenchar P. Using genomic information to investigate the function of ThiI, an enzyme shared between thiamin and 4-thiouridine biosynthesis. Protein Sci. 1999;8:2424-7 pubmed
  52. Moradi H, Kwok V, Vaziri N. Effect of chronic renal failure on arginase and argininosuccinate synthetase expression. Am J Nephrol. 2006;26:310-8 pubmed
    ..The latter, in turn, attenuates L-arg catabolism and urea production and, thereby, mitigates the fall in plasma L-arg. ..
  53. Mun G, Boo Y. A regulatory role of Kruppel-like factor 4 in endothelial argininosuccinate synthetase 1 expression in response to laminar shear stress. Biochem Biophys Res Commun. 2012;420:450-5 pubmed publisher
    ..The ectopic expression of KLF4 led to the increase of ASS1 expression and NO production. The present study demonstrated a key regulatory role of KLF4 in the endothelial ASS1 expression and NO production in response to LSS. ..