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. 2013 Dec 2;15(1):2–10. doi: 10.1179/174329210X12650506623122

The phosphate makes a difference: cellular functions of NADP

Line Agledal 1, Marc Niere 1, Mathias Ziegler 1
PMCID: PMC7067316  PMID: 20196923

Abstract

Recent research has unraveled a number of unexpected functions of the pyridine nucleotides. In this review, we will highlight the variety of known physiological roles of NADP. In its reduced form (NADPH), this molecule represents a universal electron donor, not only to drive biosynthetic pathways. Perhaps even more importantly, NADPH is the unique provider of reducing equivalents to maintain or regenerate the cellular detoxifying and antioxidative defense systems. The roles of NADPH in redox sensing and as substrate for NADPH oxidases to generate reactive oxygen species further extend its scope of functions. NADP+, on the other hand, has acquired signaling functions. Its conversion to second messengers in calcium signaling may have critical impact on important cellular processes. The generation of NADP by NAD kinases is a key determinant of the cellular NADP concentration. The regulation of these enzymes may, therefore, be critical to feed the diversity of NADP-dependent processes adequately. The increasing recognition of the multiple roles of NADP has thus led to exciting new insights in this expanding field.

Keywords: NADP, NADPH, REDOX SENSING, REACTIVE OXYGEN SPECIES, ELECTRON DONOR, SECOND MESSENGER, CALCIUM SIGNALING

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References

  • 1.Grose JH, Joss L, Velick SF, Roth JR. Evidence that feedback inhibition of NAD kinase controls responses to oxidative stress. Proc Natl Acad Sci USA 2006; 103: 7601–7606. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Rutter J, Reick M, Wu LC, McKnight SL. Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors. Science 2001; 293: 510–514. [DOI] [PubMed] [Google Scholar]
  • 3.Zheng XF, Dai XY, Zhao YM et al. Restructuring of the dinucleotide-binding fold in an NADP(H) sensor protein. Proc Natl Acad Sci USA 2007; 104: 8809–8814. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Schreiber V, Dantzer F, Ame JC, de Murcia G. Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol 2006; 7: 517–528. [DOI] [PubMed] [Google Scholar]
  • 5.Liou GG, Tanny JC, Kruger RG, Walz T, Moazed D. Assembly of the SIR complex and its regulation by 0-acetyl-ADP-ribose, a product of NAD-dependent histone deacetylation. Cell 2005; 121: 515–527. [DOI] [PubMed] [Google Scholar]
  • 6.Cakir-Kiefer C, Muller-Steffner H, Schuber F. Unifying mechanism for Aplysia ADP-ribosyl cyclase and CD38NAD(+) glycohydrolases. Biochem J 2000; 349: 203–210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Schuber F, Lund FE. Structure and enzymology of ADP-ribosyl cyclases: conserved enzymes that produce multiple calcium mobilizing metabolites. Curr Mol Med 2004; 4: 249–261. [DOI] [PubMed] [Google Scholar]
  • 8.Guse AH, Lee HC. NAADP: a universal Ca2+ trigger. Sci Signal 2008; 1: re10. [DOI] [PubMed] [Google Scholar]
  • 9.Komberg A. Enzymatic synthesis of triphosphopyridine nucleotide. J Biol Chem 1950; 182: 805–813. [Google Scholar]
  • 10.Kawai S, Mori S, Mukai T et al. Inorganic polyphosphate/ATP-NAD kinase of Micrococcus flavus and Mycobacterium tuberculosis H37Rv. Biochem Biophys Res Commun 2000; 276: 57–63. [DOI] [PubMed] [Google Scholar]
  • 11.Shi F, Li YF, Li Y, Wang XY. Molecular properties, functions, and potential applications of NAD kinases. Acta Biochim Biophys Sin ( Shanghai) 2009; 41: 352–361. [DOI] [PubMed] [Google Scholar]
  • 12.Outten CE, Culotta VC. A novel NADH kinase is the mitochondrial source of NADPH in Saccharomyces cerevisiae. EMBO J 2003; 22: 2015–2024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Chai MF, Wei PC, Chen QJ et al. NADK3, a novel cytoplasmic source of NADPH, is required under conditions of oxidative stress and modulates abscisic acid responses in Arabidopsis. Plant J 2006; 47: 665–674. [DOI] [PubMed] [Google Scholar]
  • 14.Waller JC, Dhanoa PK, Schumann U, Mullen RT, Snedden WA. Subcellular and tissue localization of NAD kinases from Arabidopsis: compartmentalization of de novo NADP biosynthesis. Planta 2009; Epub, DOT 10.1007/s00425-009-1047-7. [DOI] [PubMed]
  • 15.Chai MF, Chen QJ, An R, Chen YM, Chen J, Wang XC. NADK2, an Arabidopsis chloroplastic NAD kinase, plays a vital role in both chlorophyll synthesis and chloroplast protection. Plant Mol Biol 2005; 59: 553–564. [DOI] [PubMed] [Google Scholar]
  • 16.Berrin JG, Pierrugues O, Brutesco C et al. Stress induces the expression of AtNADK-1, a gene encoding a NAD(H) kinase in Arabidopsis thaliana. Mol Genet Genomics 2005; 273: 10–19. [DOI] [PubMed] [Google Scholar]
  • 17.Lerner F, Niere M, Ludwig A, Ziegler M. Structural and functional characterization of human NAD kinase. Biochem Biophys Res Commun 2001; 288: 69–74. [DOI] [PubMed] [Google Scholar]
  • 18.Kobayashi K, Ehrlich SD, Albertini A et al. Essential Bacillus subtilis genes. Proc Natl Acad Sci USA 2003; 100: 4678–4683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Labesse G, Douguet D, Assairi L, Gilles AM. Diacylglyceride kinases, sphingosine kinases and NAD kinases: distant relatives of 6-phosphofructokinases. Trends Biochem Sci 2002; 27: 273–275. [DOI] [PubMed] [Google Scholar]
  • 20.Kawai S, Murata K. Structure and function of NAD kinase and NADP phosphatase: key enzymes that regulate the intracellular balance of NAD(H) and NADP(H). Biosci Biotechnol Biochem 2008; 72: 919–930. [DOI] [PubMed] [Google Scholar]
  • 21.Bieganowski P, Seidle HF, Wojcik M, Brenner C. Synthetic lethal and biochemical analyses of NAD and NADH kinases in Saccharomyces cerevisiae establish separation of cellular functions. J Biol Chem 2006; 281: 22439–22445. [DOI] [PubMed] [Google Scholar]
  • 22.Todisco S, Agrimi G, Castegna A, Palmieri F. Identification of the mitochondrial NAD(+) transporter in Saccharomyces cerevisiae. J Biol Chem 2006; 281: 1524–1531. [DOI] [PubMed] [Google Scholar]
  • 23.Epel D, Patton C, Wallace RW, Cheung WY Calmodulin activates NAD kinase of sea urchin eggs: an early event of fertilization. Cell 1981; 23: 543–549. [DOI] [PubMed] [Google Scholar]
  • 24.Heinecke JW, Shapiro BM. Respiratory burst oxidase of fertilization. Proc Natl Acad Sci USA 1989; 86: 1259–1263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Dieter P, Marme D. A Ca2*, calmodulin-dependent NAD kinase from corn is located in the outer mitochondrial membrane. J Biol Chem 1984; 259: 184–189. [PubMed] [Google Scholar]
  • 26.Pollak N, Niere M, Ziegler M. NAD kinase levels control the NADPH concentration in human cells. J Biol Chem 2007; 282: 33562–33571. [DOI] [PubMed] [Google Scholar]
  • 27.Myasoedova KN. New findings in studies of cytochromes P450. Biochemistry ( Mosc) 2008; 73: 965–969. [DOI] [PubMed] [Google Scholar]
  • 28.Purnapatre K, Khattar SK, SaM KS. Cytochrome P450s in the development of target-based anticancer drugs. Cancer Lett 2008; 259: 1–15. [DOI] [PubMed] [Google Scholar]
  • 29.Iyanagi T. Structure and function of NADPH-cytochrome P450 reductase and nitric oxide synthase reductase domain. Biochem Biophys Res Commun 2005; 338: 520–528. [DOI] [PubMed] [Google Scholar]
  • 30.Kikuchi G, Yoshida T, Noguchi M. Heme oxygenase and heme degradation. Biochem Biophys Res Commun 2005; 338: 558–567. [DOI] [PubMed] [Google Scholar]
  • 31.Hayes JD, Flanagan JU, Jowsey IR. Glutathione transferases. Annu Rev Pharmacol Toxicol 2005; 45: 51–88. [DOI] [PubMed] [Google Scholar]
  • 32.Jones DP. Radical-free biology of oxidative stress. Am J Physiol 2008; 295: C849–C868. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Geiszt M. NADPH oxidases: new kids on the block. Cardiovasc Res 2006; 71: 289–299. [DOI] [PubMed] [Google Scholar]
  • 34.Quinn MT, Gauss KA. Structure and regulation of the neutrophil respiratory burst oxidase: comparison with nonphagocyte oxidases. J Leukoc Biol 2004; 76: 760–781. [DOI] [PubMed] [Google Scholar]
  • 35.Li JM, Shah AM. ROS generation by nonphagocytic NADPH oxidase: potential relevance in diabetic nephropathy. J Am Soc Nephrol 2003; 14: S221–S226. [DOI] [PubMed] [Google Scholar]
  • 36.Cappellini MD, Fiorelli G. Gluclose-6-phosphate dehydrogenase deficiency. Lancet 2008; 371: 64–74. [DOI] [PubMed] [Google Scholar]
  • 37.Ursini MV, Parrella A, Rosa G, Salzano S, Martini G. Enhanced expression of glucose-6-phosphate dehydrogenase in human cells sustaining oxidative stress. Biochem J1997; 323: 801-806. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Tian WN, Braunstein LD, Apse K et al. Importance of glucose-6-phosphate dehydrogenase activity in cell death. Am J Physiol 1999; 276: C1121–C1131. [DOI] [PubMed] [Google Scholar]
  • 39.Salvemini F, Franze A, Iervolino A, Filosa S, Salzano S, Ursini MV. Enhanced glutathione levels and oxidoresistance mediated by increased glucose-6-phosphate dehydrogenase expression. J Biol Chem 1999; 274: 2750–2757. [DOI] [PubMed] [Google Scholar]
  • 40.Longo L, Vanegas OC, Patel M . et al. Maternally transmitted severe glucose 6-phosphate dehydrogenase deficiency is an embryonic lethal. EMBO J2002; 21: 4229-4239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Pandolfi PP, Sonati F, Rivi R, Mason P, Grosveld F, Luzzatto L. Targeted disruption of the housekeeping gene encoding glucose-6-phosphate-dehydrogenase (G6PD) - G6PD is dispensable for pentose synthesis but essential for defense against oxidative stress. EMBO J1995; 14: 5209-5215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Filosa S, Fico A, Paglialunga F . et al. Failure to increase glucose consumption through the pentose-phosphate pathway results in the death of glucose-6-phosphate dehydrogenase gene-deleted mouse embryonic stem cells subjected to oxidative stress. Biochem J 2003; 370: 935–943. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Veech RL, Eggleston LV, Krebs HA. Redox state of free nicotinamide-adenine dinucleotide phosphate in cytoplasm of rat liver. Biochem J1969; 115: 609-619. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Jo SH, Son MK, Koh HJ . et al. Control of mitochondrial redox balance and cellular defense against oxidative damage by mitochondrial NADP(+)-dependent isocitrate dehydrogenase. J Biol Chem 2001; 276: 16168–16176. [DOI] [PubMed] [Google Scholar]
  • 45.Lee SM, Koh HJ, Park DC, Song BJ, Huh TL, Park JW. Cytosolic NADP(+)-dependent isocitrate dehydrogenase status modulates oxidative damage to cells. Free Radic Biol Med 2002; 32: 1185–1196. [DOI] [PubMed] [Google Scholar]
  • 46.Kim HJ, Kang BS, Park JW. Cellular defense against heat shock-induced oxidative damage by mitochondrial NADP(+)-dependent isocitrate dehydrogenase. Free Radic Res 2005; 39: 441–448. [DOI] [PubMed] [Google Scholar]
  • 47.Sanz N, DiezFemandez C, Valverde AM, Lorenzo M, Benito M, Cascales M. Malic enzyme and glucose 6-phosphate dehydrogenase gene expression increases in rat liver cirrhogenesis. Br J Cancer 1997; 75: 487–492. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Macdonald MJ. Feasibility of a mitochondrial pyruvate malate shuttle pancreatic-islets - Further implication of cytosolic NADPH in insulin-secretion. J Biol Chem 1995; 270: 20051–20058. [PubMed] [Google Scholar]
  • 49.McKenna MC, Stevenson JH, Huang XL, Tildon JT, Zielke CL, Hopkins TB. Mitochondrial malic enzyme activity is much higher in mitochondria from cortical synaptic terminals compared with mitochondria from primary cultures of cortical neurons or cerebellar granule cells. Neurochem Int 2000; 36: 451–459. [DOI] [PubMed] [Google Scholar]
  • 50.Vasiliou V, Nebert DW. Analysis and update of the human aldehyde dehydrogenase (ALDH) gene family. Hum Genomics 2005; 2: 138–143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Sauer U, Canonaco F, Hen i S, Perrenoud A, Fischer E. The soluble and membrane-bound transhydrogenases UdhA and PntAB have divergent functions in NADPH metabolism of Escherichia colt. J Biol Chem 2004; 279: 6613–6619. [DOI] [PubMed] [Google Scholar]
  • 52.Arkblad EL, Tuck S, Pestov NB et al. A Caenorhabditis elegans mutant lacking functional nicotinamide nucleotide transhydrogenase displays increased sensitivity to oxidative stress. Free Radic Biol Med 2005; 38: 1518–1525. [DOI] [PubMed] [Google Scholar]
  • 53.Toye AA, Lippiat JD, Proks P et al. A genetic and physiological study of impaired glucose homeostasis control in C57BL/6J mice. Diabetologia 2005; 48: 675–686. [DOI] [PubMed] [Google Scholar]
  • 54.Freeman H, Shimomura K, Cox RD, Ashcroft FM. Nicotinamide nucleotide transhydrogenase: a link between insulin secretion, glucose metabolism and oxidative stress. Biochem Soc Trans 2006; 34: 806–810. [DOI] [PubMed] [Google Scholar]
  • 55.Chen RD. Plant NADP-dependent isocitrate dehydrogenases are predominantly localized in the cytosol. Planta 1998; 207: 280–285. [DOI] [PubMed] [Google Scholar]
  • 56.Minard KI, McAlister-Henn L. Sources of NADPH in yeast vary with carbon source. J Biol Chem 2005; 280: 39890–39896. [DOI] [PubMed] [Google Scholar]
  • 57.Shi YJ, Shi Y. Metabolic enzymes and coenzymes in transcription metabolism - a direct link between and transcription? Trends Genet 2004; 20: 445–452. [DOI] [PubMed] [Google Scholar]
  • 58.Sen CK. Redox signaling and the emerging therapeutic potential of thiol antioxidants. Biochem Pharmacol 1998; 55: 1747–1758. [DOI] [PubMed] [Google Scholar]
  • 59.Borjesson SI, Elinder F. Structure, function, and modification of the voltage sensor in voltage-gated ion channels. Cell Biochem Biophys 2008; 52: 149–174. [DOI] [PubMed] [Google Scholar]
  • 60.Weng J, Cao Y, Moss N, Zhou M. Modulation of voltage-dependent Shaker family potassium channels by an aldo-keto reductase. J Biol Chem 2006; 281: 15194–15200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Dai XY, Li YY, Meng Get al. NADPH is an allosteric regulator of HSCARG. J Mol Biol 2009; 387: 1277–1285. [DOI] [PubMed] [Google Scholar]
  • 62.Zhao YM, Zhang JF, Li HY et al. An NADPH sensor protein (HSCARG) down-regulates nitric oxide synthesis by association with argininosuccinate synthetase and is essential for epithelial cell viability. J Biol Chem 2008; 283: 11004–11013. [DOI] [PubMed] [Google Scholar]
  • 63.Lian M, Zheng XF. HSCARG regulates NF-kappa B activation by promoting the ubiquitination of RelA or COMMD1. J Biol Chem 2009; 284: 17998–18006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Gallais S, de Crescenzo MA, Laval-Martin DL. Evidence of active NADP(+) phosphatase in dormant seeds of Avena sativa L. J Exp Bot 2000; 51: 1389–1394. [PubMed] [Google Scholar]
  • 65.Richter C. NADP* phosphatase: a novel mitochondrial enzyme. Biochem Biophys Res Commun 1987; 146: 253–257. [DOI] [PubMed] [Google Scholar]
  • 66.Berridge G, Cramer R, Galione A, Patel S. Metabolism of the novel Ca2*-mobilizing messenger nicotinic acid-adenine dinucleotide phosphate via a 2'-specific Ca2*-dependent phosphatase. Biochem J 2002; 365: 295–301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Vu CQ, Lu PJ, Chen CS, Jacobson MK. T-Phospho-cyclic ADP-ribose, a calcium-mobilizing agent derived from NADP. J Biol Chem 1996; 271: 4747–4754. [PubMed] [Google Scholar]
  • 68.Vu CQ, Coyle DL, Jacobson MK. Natural occurrence of 2'-phospho-cyclic ADP ribose in mammalian tissues. Biochem Biophys Res Commun 1997; 236: 723–726. [DOI] [PubMed] [Google Scholar]

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