CBCB faculty Eytan Ruppin’s group co-authors a paper in Nature on the diversion of aspartate in ASS1-deficient tumours, a study led by Ayelet Erez from the Weizmann Institute

Keren Yizhak from Eytan Ruppin’s group co-authored a paper titled “Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis”, published in Nature on November 11, 2015.

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.

In this study, the authors 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. 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 ASS1is downregulated. Their results demonstrate that ASS1downregulation is a novel mechanism supporting cancerous proliferation, and that ASS1 downregulation provides a metabolic link between the urea cycle enzymes and pyrimidine synthesis.

“Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis” article: http://www.nature.com/nature/journal/vaop/ncurrent/pdf/nature15529.pdf