title: Akt phosphorylation and regulation of transketolase is a nodal point for amino acid control of purine synthesis.
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.
authors: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Arindam
authors: A
authors: Saha
authors: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors: Stephen
authors: S
authors: Connelly
authors: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Jingjing
authors: J
authors: Jiang
authors: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Shunhui
authors: S
authors: Zhuang
authors: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Deron T
authors: DT
authors: Amador
authors: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Tony
authors: T
authors: Phan
authors: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: rpilz@ucsd.edu.
authors: Renate B
authors: RB
authors: Pilz
authors: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: gboss@ucsd.edu.
authors: Gerry R
authors: GR
authors: Boss
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000502:physiology*; D000818:Animals; D017124:Conserved Sequence; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D008297:Male; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism; D010084:Oxidation-Reduction; D010754:Phosphoribosyl Pyrophosphate / Q000096:biosynthesis; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011687:Purines / Q000096:biosynthesis*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014174:Transketolase / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D046912:Multiprotein Complexes; D011687:Purines; D010754:Phosphoribosyl Pyrophosphate; D014174:Transketolase; C494918:AKT1 protein, human; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051550:I-kappa B Kinase