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  • 1
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    Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-11-13
    Description: Cancer cells hijack and remodel existing metabolic pathways for their benefit. Argininosuccinate synthase (ASS1) is a urea cycle enzyme that is essential in the conversion of nitrogen from ammonia and aspartate to urea. A decrease in nitrogen flux through ASS1 in the liver causes the urea cycle disorder citrullinaemia. In contrast to the well-studied consequences of loss of ASS1 activity on ureagenesis, the purpose of its somatic silencing in multiple cancers is largely unknown. Here we show that decreased activity of ASS1 in cancers supports proliferation by facilitating pyrimidine synthesis via CAD (carbamoyl-phosphate synthase 2, aspartate transcarbamylase, and dihydroorotase complex) activation. Our studies were initiated by delineating the consequences of loss of ASS1 activity in humans with two types of citrullinaemia. We find that in citrullinaemia type I (CTLN I), which is caused by deficiency of ASS1, there is increased pyrimidine synthesis and proliferation compared with citrullinaemia type II (CTLN II), in which there is decreased substrate availability for ASS1 caused by deficiency of the aspartate transporter citrin. Building on these results, we demonstrate that ASS1 deficiency in cancer increases cytosolic aspartate levels, which increases CAD activation by upregulating its substrate availability and by increasing its phosphorylation by S6K1 through the mammalian target of rapamycin (mTOR) pathway. Decreasing CAD activity by blocking citrin, the mTOR signalling, or pyrimidine synthesis decreases proliferation and thus may serve as a therapeutic strategy in multiple cancers where ASS1 is downregulated. Our results demonstrate that ASS1 downregulation is a novel mechanism supporting cancerous proliferation, and they provide a metabolic link between the urea cycle enzymes and pyrimidine synthesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655447/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655447/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rabinovich, Shiran -- Adler, Lital -- Yizhak, Keren -- Sarver, Alona -- Silberman, Alon -- Agron, Shani -- Stettner, Noa -- Sun, Qin -- Brandis, Alexander -- Helbling, Daniel -- Korman, Stanley -- Itzkovitz, Shalev -- Dimmock, David -- Ulitsky, Igor -- Nagamani, Sandesh C S -- Ruppin, Eytan -- Erez, Ayelet -- 1 U54 HD083092/HD/NICHD NIH HHS/ -- England -- Nature. 2015 Nov 19;527(7578):379-83. doi: 10.1038/nature15529. Epub 2015 Nov 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Regulation, Weizmann Institute of Science, Rehovot 7610001, Israel. ; The Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv 69978, Israel. ; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA. ; Biological Services, Weizmann Institute of Science, Rehovot 69978, Israel. ; Human and Molecular Genetic and Biochemistry Center, Medical College Wisconsin, Milwaukee, Wisconsin 53226, USA. ; Genetic and Metabolic Center, Hadassah Medical Center, Jerusalem 91120, Israel. ; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 69978, Israel. ; Texas Children's Hospital, Houston, Texas 77030, USA. ; The Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. ; Center for Bioinformatics and Computational Biology &Department of Computer Science, University of Maryland, College Park, Maryland 20742, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26560030" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Argininosuccinate Synthase/*deficiency/metabolism ; Aspartate Carbamoyltransferase/metabolism ; Aspartic Acid/*metabolism ; Calcium-Binding Proteins/antagonists & inhibitors/metabolism ; Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Citrullinemia/metabolism ; Cytosol/metabolism ; Dihydroorotase/metabolism ; Down-Regulation ; Enzyme Activation ; Humans ; Male ; Mice ; Mice, SCID ; Neoplasms/enzymology/*metabolism/pathology ; Organic Anion Transporters/antagonists & inhibitors/metabolism ; Phosphorylation ; Pyrimidines/*biosynthesis ; TOR Serine-Threonine Kinases/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Alu-mediated diverse and complex pathogenic copy-number variants within human chromosome 17 at p13.3 (2015)
    Oxford University Press
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    Publication Date: 2015-06-23
    Description: Alu repetitive elements are known to be major contributors to genome instability by generating Alu -mediated copy-number variants (CNVs). Most of the reported Alu -mediated CNVs are simple deletions and duplications, and the mechanism underlying Alu – Alu -mediated rearrangement has been attributed to non-allelic homologous recombination (NAHR). Chromosome 17 at the p13.3 genomic region lacks extensive low-copy repeat architecture; however, it is highly enriched for Alu repetitive elements, with a fraction of 30% of total sequence annotated in the human reference genome, compared with the 10% genome-wide and 18% on chromosome 17. We conducted mechanistic studies of the 17p13.3 CNVs by performing high-density oligonucleotide array comparative genomic hybridization, specifically interrogating the 17p13.3 region with ~150 bp per probe density; CNV breakpoint junctions were mapped to nucleotide resolution by polymerase chain reaction and Sanger sequencing. Studied rearrangements include 5 interstitial deletions, 14 tandem duplications, 7 terminal deletions and 13 complex genomic rearrangements (CGRs). Within the 17p13.3 region, Alu – Alu -mediated rearrangements were identified in 80% of the interstitial deletions, 46% of the tandem duplications and 50% of the CGRs, indicating that this mechanism was a major contributor for formation of breakpoint junctions. Our studies suggest that Alu repetitive elements facilitate formation of non-recurrent CNVs, CGRs and other structural aberrations of chromosome 17 at p13.3. The common observation of Alu -mediated rearrangement in CGRs and breakpoint junction sequences analysis further demonstrates that this type of mechanism is unlikely attributed to NAHR, but rather may be due to a recombination-coupled DNA replicative repair process.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 3
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    Human recombinant arginase enzyme reduces plasma arginine in mouse models of arginase deficiency (2015)
    Oxford University Press
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    Publication Date: 2015-10-23
    Description: Arginase deficiency is caused by deficiency of arginase 1 (ARG1), a urea cycle enzyme that converts arginine to ornithine. Clinical features of arginase deficiency include elevated plasma arginine levels, spastic diplegia, intellectual disability, seizures and growth deficiency. Unlike other urea cycle disorders, recurrent hyperammonemia is typically less severe in this disorder. Normalization of plasma arginine levels is the consensus treatment goal, because elevations of arginine and its metabolites are suspected to contribute to the neurologic features. Using data from patients enrolled in a natural history study conducted by the Urea Cycle Disorders Consortium, we found that 97% of plasma arginine levels in subjects with arginase deficiency were above the normal range despite conventional treatment. Recently, arginine-degrading enzymes have been used to deplete arginine as a therapeutic strategy in cancer. We tested whether one of these enzymes, a pegylated human recombinant arginase 1 (AEB1102), reduces plasma arginine in murine models of arginase deficiency. In neonatal and adult mice with arginase deficiency, AEB1102 reduced the plasma arginine after single and repeated doses. However, survival did not improve likely, because this pegylated enzyme does not enter hepatocytes and does not improve hyperammonemia that accounts for lethality. Although murine models required dosing every 48 h, studies in cynomolgus monkeys indicate that less frequent dosing may be possible in patients. Given that elevated plasma arginine rather than hyperammonemia is the major treatment challenge, we propose that AEB1102 may have therapeutic potential as an arginine-reducing agent in patients with arginase deficiency.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 4
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    Branched-chain amino acid metabolism: from rare Mendelian diseases to more common disorders (2014)
    Oxford University Press
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    Publication Date: 2014-03-20
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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