Exploring the interplay between the purinosome, a multienzyme, purine biosynthetic machine, and the Rheb-mTORC1 signaling axis.

Pharmacologic agents that interfere with nucleotide metabolism constitute an important class of anticancer agents. Recent studies demonstrated that mTOR complex 1 (mTORC1) inhibitors suppress de novo biosynthesis of pyrimidine and purine nucleotides. We have previously demonstrated that mTORC1 itself is suppressed by drugs that reduce intracellular purine nucleotide pools. Cellular treatment with AG2037, an inhibitor of the purine biosynthetic enzyme, GARFT, profoundly inhibits mTORC1 activity via a reduction in the level of GTP-bound Rheb, an obligate upstream activator of mTORC1, in part due to a reduction in intracellular guanine nucleotides. Purines are synthesized intracellularly in dynamic metabolic structures known as the purinosome. Our emerging data suggest that Rheb associates with the purinosome and treatment with AG2037 disrupts this interaction. We hypothesize that Rheb senses the availability of purines at the site of the purinosome and communicates purine sufficiency to activate mTORC1. The results of this project will increase our understanding of the regulation of purine biosynthesis and mTORC1 activation, two key processes in cell proliferation and cancer. Citation Format: Natasha Emmanuel, Elyssa Bernfeld, Shoba Ragunathan, Fang Wang, Qin Shan, Andreas Giannakou, Nanni Huser, Guixian Jin, Jeremy Myers, Keziban Unsal-Kacmaz, Robert T. Abraham. Exploring the interplay between the purinosome, a multienzyme, purine biosynthetic machine, and the Rheb-mTORC1 signaling axis [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr A10.