The Phosphatidylinositol 3-Kinase/Akt Cassette Regulates Purine Nucleotide Synthesis

The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is highly conserved throughout evolution and regulates cell size and survival and cell cycle progression. It regulates the latter by stimulating procession through G1 and the G1/S phase transition. Entry into S phase requires an abundant supply of purine nucleotides, but the effect of the PI3K/Akt pathway on purine synthesis has not been studied. We now show that the PI3K/Akt cassette regulates both de novo and salvage purine nucleotide synthesis in insulin-responsive mouse mesenchymal cells. We found that serum and insulin stimulated de novo purine synthesis in serum-starved cells largely through PI3K/Akt signaling, and pharmacologic and genetic inhibition of PI3K/Akt reduced de novo synthesis by 75% in logarithmically growing cells. PI3K/Akt regulated early steps of de novo synthesis by modulating phosphoribosylpyrophosphate production by the non-oxidative pentose phosphate pathway and late steps by modulating activity of the bifunctional enzyme aminoimidazole-carboxamide ribonucleotide transformylase IMP cyclohydrolase, an enzyme not previously known to be regulated. The effects of PI3K/Akt on purine nucleotide salvage were likely through regulating phosphoribosylpyrophosphate availability. These studies define a new mechanism whereby the PI3K/Akt cassette functions as a master regulator of cellular metabolism and a key player in oncogenesis. The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is highly conserved throughout evolution and regulates cell size and survival and cell cycle progression. It regulates the latter by stimulating procession through G1 and the G1/S phase transition. Entry into S phase requires an abundant supply of purine nucleotides, but the effect of the PI3K/Akt pathway on purine synthesis has not been studied. We now show that the PI3K/Akt cassette regulates both de novo and salvage purine nucleotide synthesis in insulin-responsive mouse mesenchymal cells. We found that serum and insulin stimulated de novo purine synthesis in serum-starved cells largely through PI3K/Akt signaling, and pharmacologic and genetic inhibition of PI3K/Akt reduced de novo synthesis by 75% in logarithmically growing cells. PI3K/Akt regulated early steps of de novo synthesis by modulating phosphoribosylpyrophosphate production by the non-oxidative pentose phosphate pathway and late steps by modulating activity of the bifunctional enzyme aminoimidazole-carboxamide ribonucleotide transformylase IMP cyclohydrolase, an enzyme not previously known to be regulated. The effects of PI3K/Akt on purine nucleotide salvage were likely through regulating phosphoribosylpyrophosphate availability. These studies define a new mechanism whereby the PI3K/Akt cassette functions as a master regulator of cellular metabolism and a key player in oncogenesis. Insulin and a variety of other growth factors activate the PI3K 3The abbreviations used are: PI3K, phosphatidylinositol 3-kinase; AICA-riboside, 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside; AICAR, AICA-riboside monophosphate, also known as ZMP; ATIC, AICAR transformylase IMP cyclohydrolase; DMEM, Dulbecco's modified Eagle's medium; DMSO, dimethyl sulfoxide; FBS, fetal bovine serum; FGAR, formylglycinamide ribonucleotide; HPLC, high performance liquid chromatography; HEL, human erythroleukemia; PRPP, phosphoribosylpyrophosphate; TLC, thin layer chromatography; mTOR, mammalian target of rapamycin; siRNA, small interfering RNA; AOPCP, α,β-methylene adenosine diphosphate; ZDP, AICA-riboside diphosphate; ZTP, AICA-riboside triphosphate. /Akt (protein kinase B) pathway. Activated Akt regulates several intracellular processes including protein synthesis, glucose metabolism, and cell cycle progression (1Kandel E.S. Hay N. Exp. Cell Res.. 1999; 253: 210-229Google Scholar, 2Manning B.D. Cantley L.C. Cell.. 2007; 129: 1261-1274Google Scholar). Frequently regulation occurs at more than one step. (i) Akt increases protein synthesis by activating mTOR, which regulates the activities of S6 kinase-1 and 4E-BP1, two translational regulators (3Isotani S. Hara K. Tokunaga C. Inoue H. Avruch J. Yonezawa K. J. Biol. Chem.. 1999; 274: 34493-34498Google Scholar). (ii) Akt regulates glucose metabolism by inducing translocation of glucose transporters to the cell surface, by activating hexokinase, and by inhibiting glycogen synthase kinase-3 (4Rathmell J.C. Fox C.J. Plas D.R. Hammerman P.S. Cinalli R.M. Thompson C.B. Mol. Cell. Biol.. 2003; 23: 7315-7328Google Scholar). (iii) Akt stimulates the cell cycle by phosphorylating, and thereby inhibiting, the cyclin-dependent kinase inhibitors p21Cip/WAF1 and p27Kip1 and the FOXO transcription factors and through phosphorylation of glycogen synthase kinase-3, which regulates the G1 cyclins, cyclins D and E (2Manning B.D. Cantley L.C. Cell.. 2007; 129: 1261-1274Google Scholar, 5Liang J. Slingerland J.M. Cell Cycle.. 2003; 2: 339-345Google Scholar). The de novo synthesis of purines consists of 10 sequential steps, starting with phosphoribosylpyrophosphate (PRPP) and ending with IMP; the latter is converted to AMP or GMP (see Fig. 1). PRPP amidotransferase catalyzes the first committed step of the pathway (see Fig. 1, reaction 2) and is subject to feedback inhibition by purine nucleotides; therefore, it has been considered a major point of pathway regulation (6Holmes E.W. Wyngaarden J.B. Kelley W.N. J. Biol. Chem.. 1973; 248: 6035-6040Google Scholar). We showed previously that production of ribose 5-phosphate, the immediate precursor of PRPP and an end product of the pentose phosphate pathway, also contributes to the regulation of purine synthesis (7Pilz R.B. Willis R.C. Boss G.R. J. Biol. Chem.. 1984; 259: 2927-2935Google Scholar). Salvage purine nucleotide synthesis involves hypoxanthine phosphoribosyltransferase, which catalyzes the conversion of hypoxanthine or guanine to IMP, a PRPP-requiring reaction (see Fig. 1, reaction 6). Although no previous studies have assessed whether the PI3K/Akt cassette regulates purine synthesis, several lines of evidence suggest that this may indeed be the case. First, the intracellular ATP concentration is decreased in mouse embryo fibroblasts that lack Akt1 and Akt2 (8Hahn-Windgassen A. Nogueira V. Chen C.C. Skeen J.E. Sonenberg N. Hay N. J. Biol. Chem.. 2005; 280: 32081-32089Google Scholar). Second, treating keratinocytes with epidermal or keratinocyte growth factor, both of which activate PI3K and Akt, increases expression of several purine synthetic enzymes (9Gassmann M.G. Stanzel A. Werner S. Oncogene.. 1999; 18: 6667-6676Google Scholar). Third, the intracellular ATP concentration is 3 times higher in Rat1a fibroblasts that overexpress myristoylated, constitutively active Akt compared with control cells (8Hahn-Windgassen A. Nogueira V. Chen C.C. Skeen J.E. Sonenberg N. Hay N. J. Biol. Chem.. 2005; 280: 32081-32089Google Scholar, 10Gottlob K. Majewski N. Kennedy S. Kandel E. Robey R.B. Hay N. Genes Dev.. 2001; 15: 1406-1418Google Scholar). Although the concentrations of ADP and AMP were not reported, their intracellular concentrations are considerably less than ATP, and thus the increased ATP likely arose from increased purine synthesis rather than from increased ADP and AMP phosphorylation. Finally in the IL-3-dependent hematopoietic cell line FL5.12, activity of the oxidative pentose phosphate pathway is higher in cells expressing myristoylated Akt than in control cells and does not decrease on removing IL-3 as occurs in control cells (4Rathmell J.C. Fox C.J. Plas D.R. Hammerman P.S. Cinalli R.M. Thompson C.B. Mol. Cell. Biol.. 2003; 23: 7315-7328Google Scholar). Similarly increased pentose phosphate pathway activity on antigen receptor cross-linking of B lymphocytes is attenuated by LY294002, a PI3K inhibitor (11Doughty C.A. Bleiman B.F. Wagner D.J. Dufort F.J. Mataraza J.M. Roberts M.F. Chiles T.C. Blood.. 2006; 107: 4458-4465Google Scholar). Thus, it seemed possible that PI3K/Akt regulate purine synthesis. Materials—Antibodies against Akt and phospho-Akt were from Cell Signaling Technology (Danvers, MA), and an anti-tubulin antibody was from Santa Cruz Biotechnology (Santa Cruz, CA). An expression vector encoding human Akt1 with a myristoylation signal sequence was from J. R. Woodgett (Mount Sinai Hospital, Toronto, Canada) and human ATIC was produced as described previously (12Wolan D.W. Greasley S.E. Beardsley G.P. Wilson I.A. Biochemistry.. 2002; 41: 15505-15513Google Scholar). LY294002, LY303511, and wortmannin were from Calbiochem; 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICA-riboside) and AICA-riboside monophosphate (AICAR) were from Sigma-Aldrich; 5-formyltetrahydrofolate was from Schircks Laboratories (Jona, Switzerland); and AG 50 resin was from Bio-Rad. LY294002 and LY303511 were dissolved in dimethyl sulfoxide (DMSO) and when added to cells yielded a final DMSO concentration of 0.2%; cells not treated with either drug also received 0.2% DMSO, referred to as vehicle. [14C]Formate, [8-14C]adenine, [8-14C]hypoxanthine, [1-14C]glucose, and [6-14C]glucose were from Moravek (Brea, CA). Cell Culture and DNA Transfection—C2C12 mouse mesenchymal cells were from the American Tissue Culture Collection (ATCC), and tuberin-deficient mouse embryo fibroblasts were provided by D. J. Kwiatkowski (13Zhang H. Cicchetti G. Onda H. Koon H.B. Asrican K. Bajraszewski N. Vazquez F. Carpenter C.L. Kwiatkowski D.J. J. Clin. Investig.. 2003; 112: 1223-1233Google Scholar); both cell types were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS). Human erythroleukemia (HEL) cells from the ATCC were cultured in RPMI 1640 medium supplemented with 10% FBS. In some experiments, cells were transfected 48 h prior to use with a cDNA plasmid or siRNA using Lipofectamine 2000 (Invitrogen) following the manufacturer's protocol. To reduce endogenous Akt1, two siRNAs targeting different Akt1 sequences were used: Akt1 siRNA1 was from Dharmacon, and Akt1 siRNA2 had the sequence UGCCCUUCUACAACCAGGA. An siRNA targeting green fluorescent protein was used as a control. Measurement of Rates of de Novo Purine Synthesis—Rates of de novo purine synthesis were measured as described previously by following [14C]formate incorporation into all cellular purine nucleotides, i.e. the soluble purine nucleotide pool as well as purines into DNA and G.R. J. Biol. Chem.. Scholar). cells were in at in supplemented with 10% FBS. h the cells were with in of supplemented with 10% FBS, and h with 0.2% DMSO, LY294002, LY303511, or In cells were were h in some cells received either 10% or 10 insulin h in the or of the with [14C]formate was added and the cells were in in Cell were to purine from and purine nucleotides, and the were on and at The were AG 50 which were with to purine were from the in in the was measured by liquid and the are as [14C]formate incorporation into cells. in Fig. the was with to at 3 In the was with cell to at and all using were with and cell To [14C]formate incorporation into and guanine the AG 50 were in 50 of and on thin layer The were in to and guanine were and was measured by liquid In some experiments, de novo purine synthesis was measured following incorporation into purines D.W. J. Biol. Chem.. Scholar). was added to cells of h the cells were in and the were as described the on was added to the and was by The were and and guanine in the were from by as described The are as incorporation into cells. Measurement of PRPP of into by requires intracellular PRPP and be used to cellular PRPP (7Pilz R.B. Willis R.C. Boss G.R. J. Biol. Chem.. 1984; 259: 2927-2935Google Scholar). were as described de novo purine synthesis. a with the was added to the and cells were with and in The cell were on of which were times in to in nucleotides, which to the was measured by liquid Measurement of through the through the non-oxidative of the pentose phosphate pathway was measured by following [6-14C]glucose incorporation into ATP as described previously G.R. R.B. J. Biol. Chem.. Scholar). cells were as described of de novo purine synthesis [6-14C]glucose the The cells were in the were with and the were by high performance liquid on a with a from 10 to ATP were and was by liquid Although this through the oxidative of the pentose phosphate pathway, it through the non-oxidative the latter the of ribose used in purine synthesis G.R. R.B. J. Biol. Chem.. Scholar, Scholar, J. W.N. S. Res.. Scholar, S. S. W.N. 2001; Scholar). through the oxidative of the pentose phosphate pathway was measured by following from as described previously G.R. R.B. J. Biol. Chem.. Scholar). cells were in of RPMI 1640 medium supplemented with and 10% FBS. The were with a that a well a of with a with or LY294002 or LY303511, 10 of was added to the cells by a through the the end of the the well was to a and in the was measured by liquid be in a were on (HEL) cells in rather than on cells. Measurement of PRPP and ATIC 3 h in 0.2% DMSO or LY294002 were by of on and the were 10 at PRPP the and were as described by Clin. Scholar). ATIC cells were in 50 and The from 5-formyltetrahydrofolate as described by J.C. and was as described by and Biochemistry.. with the following (i) and were to and α,β-methylene adenosine was to activity G.R. Thompson J.E. J. Scholar). (ii) The IMP product was from the AICAR by on a phase with a from to The both AICAR transformylase and IMP in the cell was measured by the of and enzyme activities were measured at two Measurement of Purine purine were measured as described previously G.R. J. Biol. Chem.. Scholar). 10 cells were in were by and the were with Purine in the were by on a using the as described following [6-14C]glucose incorporation into Measurement of the and of the de Novo Purine of the early steps of the de novo purine synthesis pathway were measured by following [14C]formate incorporation into formylglycinamide ribonucleotide as described previously G.R. J. Biol. Chem.. Scholar). cells were with a 10 concentration of the this concentration ribonucleotide synthase 1, reaction but has effect on other as protein synthesis G.R. J. Biol. Chem.. Scholar, J. Biol. Chem.. Scholar, G.R. Scholar). a with [14C]formate was and h cells were with and in to were on and in a The were to and was on the on in the and in cells G.R. J. Biol. Chem.. Scholar, J.E. Scholar). on the were and in was measured by liquid Rates of the two steps of the de novo purine synthesis pathway were measured as described de novo purine synthesis 10 and AICA-riboside were added to the cells G.R. J. Biol. Chem.. Scholar, G.R. Scholar). The was to the early steps of the de novo pathway, thereby purine synthesis on the added Measurement of Purine by the Salvage synthesis by the salvage pathway was assessed by incorporation into purine as described previously G.R. J. Biol. Chem.. Scholar). The was the as described de novo purine synthesis the cells were with 10 of were as described previously using R.B. Boss G.R. J. Biol. Chem.. Scholar). were in in and to were to which were with the antibody and a and in and line are the S.E. of at in were using CA). was used and a of with a or was used with the control or of Akt on de Novo Purine whether the PI3K/Akt cassette regulates de novo purine synthesis, treated cells with LY294002 h and found that the drug reduced [14C]formate incorporation into purines by the h Rates of purine synthesis were reduced the that be i.e. the first the and reduced at 3 h Fig. all with the were at well the of the LY303511, which is to LY294002 but does not PI3K C.J. J. Biol. Chem.. had no effect on purine synthesis PI3K also reduced purine synthesis not cells serum h reduced purine synthesis, and serum or insulin purine synthesis of all LY294002 of purine synthesis We that LY294002 Akt by Akt phosphorylation on and LY303511 had no effect on Akt and serum reduced Akt phosphorylation The of purine synthesis in serum-starved cells in the of some Akt activity that serum regulates purine synthesis in through in purine synthesis by LY294002 in serum-starved cells is with this that LY294002 largely serum and insulin from purine synthesis in serum-starved cells that PI3K/Akt signaling is to serum and insulin regulation of purine synthesis. is into purines 1, 3 and decreased decrease of purine synthesis using a [14C]formate LY294002 reduced purine synthesis to a in cells as in cells evidence that LY294002 purine synthesis was that the drug incorporation into purines to a as [14C]formate incorporation The LY303511 had no effect on incorporation into and cells with which is in with not the effect of LY294002 the latter that LY294002 was not by availability. To whether regulation of purine synthesis by the PI3K/Akt cassette to PI3K, reduced Akt1 expression in cells using an siRNA of the Akt inhibitors reduced Akt activity the of different Akt1 siRNAs reduced purine synthesis, a control siRNA had no effect the control siRNA was to green fluorescent of purine synthesis with this siRNA were to in cells in Fig. a and Akt1 siRNA reduced purine synthesis to the as LY294002, which is likely to the siRNAs Akt protein and Akt Akt protein is myristoylated human Akt1 in cells treated with Akt1 siRNA1 of purine synthesis to found in cells transfected with control siRNA not be with Akt1 siRNA2 the latter was to a sequence to the mouse and human myristoylated Akt1 in cells increased of purine synthesis, but the not LY294002 more Akt than Akt1 were with LY294002 using LY303511 as a control. To whether PI3K/Akt regulate purine synthesis the kinase pathway, two of First, mouse embryo regulates activity by as a and is when by Akt (13Zhang H. Cicchetti G. Onda H. Koon H.B. Asrican K. Bajraszewski N. Vazquez F. Carpenter C.L. Kwiatkowski D.J. J. Clin. Investig.. 2003; 112: 1223-1233Google Scholar). We found that LY294002 reduced purine synthesis to the in tuberin-deficient cells as in cells cells are to the effects of Akt on the kinase pathway and S6 kinase (13Zhang H. Cicchetti G. Onda H. Koon H.B. Asrican K. Bajraszewski N. Vazquez F. Carpenter C.L. Kwiatkowski D.J. J. Clin. Investig.. 2003; 112: 1223-1233Google Scholar). Second, showed that the inhibitor reduced purine synthesis in cells and had no effect on the early or late steps of de novo purine synthesis in Fig. a and Thus, Akt to regulate purine synthesis of the kinase pathway. of Akt on PRPP ribose and PRPP production be purine synthesis (7Pilz R.B. Willis R.C. Boss G.R. J. Biol. Chem.. 1984; 259: 2927-2935Google Scholar, G.R. J. Biol. Chem.. 1984; 259: and expression of a constitutively active Akt increases through the oxidative pentose phosphate pathway (4Rathmell J.C. Fox C.J. Plas D.R. Hammerman P.S. Cinalli R.M. Thompson C.B. Mol. Cell. Biol.. 2003; 23: 7315-7328Google that PI3K/Akt regulate purine synthesis by regulating PRPP availability. We measured PRPP by cells with which is converted to AMP by phosphoribosyltransferase, a reaction PRPP (7Pilz R.B. Willis R.C. Boss G.R. J. Biol. Chem.. 1984; 259: 2927-2935Google Scholar). LY294002 decreased PRPP in cells by LY303511 had no effect reduced PRPP not to the it reduced purine synthesis, and cells with serum or insulin increased PRPP control LY294002 reduced PRPP serum-starved and largely the effects of serum or insulin cells with had no effect on PRPP of the These suggest that some of the effects of Akt and serum on purine synthesis are from a decrease in PRPP availability. To the decreased PRPP in First, measured PRPP at several glucose concentrations and found a in PRPP at concentration These suggest that decreased PRPP in cells was not from regulation of glucose a more effect on PRPP have been at glucose Second, measured through the pentose phosphate pathway. We and have that the non-oxidative of the pathway of the ribose used in purine nucleotide synthesis G.R. R.B. J. Biol. Chem.. Scholar, Scholar, J. W.N. S. Res.. Scholar, S. S. W.N. 2001; and found that LY294002 reduced through this pathway by LY294002 had no effect on through the oxidative of the pathway in it purine synthesis to a in cells as in cells The lack of an effect of LY294002 on through the oxidative pentose phosphate pathway is evidence that the effect of Akt on PRPP production was not from decreased glucose or glucose phosphorylation. Third, measured the activity of PRPP a enzyme activity is regulated by the intracellular phosphate concentration and PRPP protein Mol. Biol.. 2001; Scholar). We found that PRPP activity was the in control and and of of Thus, reduced through the non-oxidative pentose phosphate pathway to be the reduced PRPP in cells. of Akt on and of de Novo Purine early steps of de novo purine synthesis be measured by following [14C]formate incorporation into in the of 10 at this ribonucleotide synthase 1, reaction but has effect on other processes G.R. J. Biol. Chem.. Scholar, J. Biol. Chem.. Scholar, G.R. Scholar). LY294002 decreased synthesis by in LY303511 and had no effect PRPP which catalyzes the first committed step of the de novo pathway 1, reaction is by purine nucleotides, it seemed possible that Akt synthesis by nucleotide LY294002 had no effect on the intracellular concentrations of ATP, or GMP when to h the at 3 h are but were at and h of LY294002 The intracellular concentrations of purine decrease h of at which by Fig. LY294002 decreased synthesis to a as it reduced PRPP suggest that Akt the early steps of purine synthesis by PRPP availability. The two steps of de novo purine synthesis, which are by the bifunctional enzyme ATIC 1, reaction be measured by following [14C]formate incorporation into purine in the of and the on AICA-riboside, which is converted to AICAR by adenosine LY294002 purine synthesis in cells by LY303511 and had no effect To the mechanism of the decrease in purine synthesis, measured ATIC activity in cell and a decrease in enzyme activity in cells that had been treated with of protein in control and S.E. of the control and activity was in of cells treated with LY303511, and LY294002 to either ATIC or cell had no In other experiments, expressing human ATIC in cells increased of de novo purine synthesis, that endogenous ATIC was to purine and J. Clin. Investig.. a increased AICAR and ZDP, and in from of Akt on and the product of the de novo purine pathway, is converted to either AMP or GMP 1). We found that LY294002 reduced synthesis by and synthesis by LY303511 had no effect on synthesis of either nucleotide a and were found AMP and GMP synthesis, the effects of Akt inhibition on PRPP and a more of AMP and GMP synthesis. We previously found in synthesis other of reduced purine nucleotide synthesis G.R. J. Biol. Chem.. Scholar). Thus, it is possible that of reduced IMP synthesis a to a cellular mechanism to of Akt on Salvage Purine whether the PI3K/Akt cassette regulates purine nucleotide synthesis from the salvage pathway 1, reaction measured incorporation into purine the activity of hypoxanthine phosphoribosyltransferase, the major enzyme of purine LY294002 reduced salvage synthesis by LY303511 had no effect The the decrease in salvage pathway synthesis was likely from decreased PRPP the salvage pathway requires this and the in salvage synthesis was to the in PRPP availability. We have found that the PI3K/Akt cassette regulates the synthesis of purine both the de novo and salvage Akt is known to regulate and metabolism, and now show that it regulates the synthesis of major of The regulation of purine synthesis by Akt is with effects on cell growth and which a in ATP and We found that Akt regulates de novo purine synthesis at two PRPP production and conversion of AICAR to effect is to Akt regulation of glucose metabolism and protein synthesis at several (1Kandel E.S. Hay N. Exp. Cell Res.. 1999; 253: 210-229Google Scholar, J. Woodgett Scholar). In to purine synthesis, PRPP is and synthesis. Thus, by regulating PRPP Akt regulate cellular to as a master cellular regulator (2Manning B.D. Cantley L.C. Cell.. 2007; 129: 1261-1274Google Scholar). ATIC an regulation it is the enzyme in the de novo pathway. ATIC activity to be to purine synthesis, small in enzyme activity have effects on purine the decrease in ATIC activity found in cells be the the decrease in purine synthesis. AICAR be to in cells with decreased ATIC activity as occurs in with genetic ATIC S. G. M.F. J. Scholar). AICAR is a of protein kinase N. M.F. G. Scholar); the latter and and synthesis and inhibiting cell growth and N. M.F. G. Scholar, Mol. Cell Biol.. 2007; Scholar). Thus, decreased Akt growth both decreased phosphorylation of and other and protein kinase reduce synthesis, and the two have a of purine nucleotides, GMP is to and AMP is to hypoxanthine 1). and hypoxanthine are converted to IMP by hypoxanthine 1, reaction and in the of an supply of purine cells purine this salvage pathway J.E. J. Biol. Chem.. Scholar). hypoxanthine salvage activity was reduced in purine be from the cell of Akt with of de novo purine synthesis, the cell of purine Thus, the of a purine synthesis as with a PI3K or Akt inhibitor be in treating and other an abundant supply of We measured PRPP using the of PRPP is that of the of hypoxanthine PRPP R. J. Biol. Chem.. Scholar, Kelley W.N. J.E. J. Scholar). Thus, incorporation into purine be more to in the intracellular PRPP concentration than hypoxanthine or guanine incorporation into of the purine salvage pathway hypoxanthine incorporation into purine hypoxanthine is the major enzyme of purine In the PI3K/Akt cassette regulates de novo and salvage purine nucleotide synthesis by regulating PRPP and ATIC These activities of the PI3K/Akt cassette cellular metabolism and cell growth and We J. R. Woodgett and D. J. Kwiatkowski the Akt1 plasmid with a myristoylation signal sequence and mouse embryo with

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