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Mol Cell. 2014 Jul 17;55(2):264-76. doi: 10.1016/j.molcel.2014.05.028. Epub 2014 Jun 26.

Akt phosphorylation and regulation of transketolase is a nodal point for amino acid control of purine synthesis.

Author information

1
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
2
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
3
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: rpilz@ucsd.edu.
4
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: gboss@ucsd.edu.

Abstract

The phosphatidylinositol 3-kinase (PI3K)/Akt pathway integrates environmental clues to regulate cell growth and survival. We showed previously that depriving cells of a single essential amino acid rapidly and reversibly arrests purine synthesis. Here we demonstrate that amino acids via mammalian target of rapamycin 2 and IκB kinase regulate Akt activity and Akt association and phosphorylation of transketolase (TKT), a key enzyme of the nonoxidative pentose phosphate pathway (PPP). Akt phosphorylates TKT on Thr382, markedly enhancing enzyme activity and increasing carbon flow through the nonoxidative PPP, thereby increasing purine synthesis. Mice fed a lysine-deficient diet for 2 days show decreased Akt activity, TKT activity, and purine synthesis in multiple organs. These results provide a mechanism whereby Akt coordinates amino acid availability with glucose utilization, purine synthesis, and RNA and DNA synthesis.

PMID:
24981175
PMCID:
PMC4104231
DOI:
10.1016/j.molcel.2014.05.028
[Indexed for MEDLINE]
Free PMC Article

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