The mammalian target of rapamycin (mTOR) regulates cell metabolism and proliferation, and deregulation of the mTOR signalling network is associated with several diseases. mTOR forms two distinct complexes, C1 and C2 — the C1 complex can be inhibited by rapamycin. Although direct substrates and downstream effectors of mTOR, such as S6 kinase, are well studied, the broad physiological role of mTOR implies that there are still downstream pathways to be identified.

Now, Hall and colleagues (Science http://doi.org/krg; 2013) and Manning and colleagues (Science http://doi.org/krh; 2013) have identified another target of mTORC1, the pyrimidine synthesis pathway. Hall and colleagues used a phosphoproteomics approach to identify unknown mTOR effectors, whereas Manning and colleagues screened for metabolites regulated by mTORC1. Both studies showed that mTORC1, through S6 kinase, phosphorylates CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase and dihydroorotase), an enzyme that catalyses the three first steps of pyrimidine synthesis. mTORC1 activation led to an increase in de novo pyrimidine synthesis, but nutrient deprivation or inhibition of mTORC1 showed the opposite effect.

Furthermore, Hall and colleagues revealed that phosphorylation of CAD leads to oligomerization of the CAD proteins and cell cycle progression through S phase. These articles provide evidence of a further role for mTOR in orchestrating anabolic cell growth by stimulating nucleotide synthesis.