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AMINO ACIDS REGULATE DE NOVO PURINE SYNTHESIS VIA AKT REGULATION OF PENTOSE PHOSPHATE PATHWAY ENZYMES
Author(s) -
Saha Arindam,
Amador Deron,
Fridman Alla,
Pilz Renate,
Boss Gerry
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.918.2
Subject(s) - transketolase , pentose phosphate pathway , de novo synthesis , purine , biochemistry , amino acid , purine metabolism , protein kinase b , biology , enzyme , chemistry , glycolysis , phosphorylation
The focus of this study is to investigate how starvation for any single essential amino acid reduces de novo purine synthesis in cultured human cells. As little as 3 h of starvation for lysine reduces de novo purine synthesis by 70% in HeLa cells. Decreased purine synthesis results largely from a 45% decrease in phosphoribosylpyrophosphate (PRPP) production via the non‐oxidative pentose phosphate pathway (PPP); flux through the oxidative PPP is unchanged. The activity of two key non‐oxidative PPP enzymes transketolase (TK) and transaldolase (TA)‐decreased by 50–60% during amino acid starvation. Restoring lysine in the medium for 30 min completely returns purine synthesis, PRPP production, and TK and TA activities to control values. Expressing TK and TA individually has only a small effect on de novo purine synthesis, but expressing both enzymes simultaneously doubles the rate of purine synthesis in starved cells. Amino acid starvation causes a 50% reduction in Akt activity, a serine‐threonine kinase and a master regulator of intermediary metabolism. Constitutively active, myristoylated Akt increases TK and TA activities and completely restores de novo purine synthesis in starved cells, while kinase‐dead Akt prevents reversal by amino acid restoration. We conclude that amino acid starvation decreases de novo purine synthesis through Akt‐mediated regulation of TK and TA.