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Chemical Compound Review

AC1L9M8R     [(2S,3R,4R,5S)-5- [[[[(2S,3R,4S,5R)-5-(5...

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Disease relevance of NADP


High impact information on NADP

  • The presence of a human-specific enzyme identified by this method correlated with the presence of a particular human chromosome permitting assignments of the human cytoplasmic forms of NADP-linked IDH, human PGI, and human HGPRT genes to chromosomes 2, 19, and X, respectively [6].
  • Directed mutagenesis and molecular modelling have been used to identify a set of amino-acid side chains in glutathione reductase that confer specificity for the coenzyme NADP+ [7].
  • The liver or type I isozyme is expressed at high levels in the liver, has a relatively low affinity for steroids (micromolar Km), catalyzes both dehydrogenation and the reverse reductase reaction, and utilizes NADP+ or NADPH as cofactors [8].
  • A 1.65 angstrom refined structure of a recombinant human placenta aldose reductase reveals that the enzyme contains a parallel beta 8/alpha 8-barrel motif and establishes a new motif for NADP-binding oxidoreductases [9].
  • Binding of the competitive inhibitor 2'-phospho-AMP (AMP, adenosine monophosphate) places the NADP binding site at the carboxyl-terminal edge of the sheet in a manner similar to the nucleotide binding of the dehydrogenase family [10].

Chemical compound and disease context of NADP


Biological context of NADP


Anatomical context of NADP

  • These characteristics are consistent with the interpretation that the function of the enzyme in human erythrocytes may be to generate oxidizing potential in the form of NADP+ [21].
  • The Y' fraction of hepatic cytosol was exclusively responsible for this activity and 3H was transferred selectively to NADP+ [22].
  • In mitochondria, TH utilizes protonmotive force to promote direct hydride ion transfer from NADH to NADP, which are bound at the distinct extramembranous domains I and III, respectively [23].
  • A full-length cDNA coding for a mutant dihydrofolate reductase (DHFR; 5,6,7,8-tetrahydrofolate: NADP+ oxidoreductase, EC, cloned from a mouse fibroblast cell line grown in high concentrations of methotrexate (MTX), was microinjected into mouse embryos to produce transgenic mice [24].
  • Immunohistochemical studies on the cellular localization of NADP-linked 15-hydroxyprostaglandin D2 dehydrogenase were performed with the same cerebellum and revealed the presence of this enzyme also in the Purkinje cells [19].

Associations of NADP with other chemical compounds

  • By a comparison of the 14CO2 produced from D-[1-14C]glucose and from D-[6-14C]glucose in the presence and absence of an electron acceptor (methylene blue), it was demonstrated that regeneration of NADP+ from NADPH was a rate-limiting step for the pentose phosphate pathway in the tumors [25].
  • Extraction in the presence of sodium hydroxide and cysteine allows estimates of NADPH and total NADP in human red cells without the erroneously high values of NADP+ obtained with earlier methods [26].
  • We suggest that NADP-dependent isocitrate dehydrogenase isoenzymes function in an NADP redox shuttle across the peroxisomal membrane to keep intraperoxisomal NADP reduced [27].
  • We have determined the crystal structure of mouse sepiapterin reductase by multiple isomorphous replacement at a resolution of 1.25 A in its ternary complex with oxaloacetate and NADP [28].
  • Three crystal structures of the catalytic portion of human HMGR in complexes with HMG-CoA, with HMG and CoA, and with HMG, CoA and NADP(+), provide a detailed view of the enzyme active site [29].

Gene context of NADP

  • We have solved the structure of human BVR-B in complex with NADP+ at 1.15 A resolution [30].
  • Since the intracellular concentrations of G6P and NADP+ are below their KmS for G6PD, these data suggest that high concentrations of pyrimidine 5'-nucleotides depress pentose phosphate shunt activity in pyrimidin 5'-nucleotidase deficiency [31].
  • Thiol titration of the two forms of aldose reductase with Ellman's reagent indicated that two thiol groups were lost when the enzyme was dialyzed in the absence of dithiothreitol or NADP [32].
  • Mutational analysis of photosystem I polypeptides in Synechocystis sp. PCC 6803. Subunit requirements for reduction of NADP+ mediated by ferredoxin and flavodoxin [33].
  • In isolated wild-type membranes, the rate of flavodoxin reduction and flavodoxin-mediated NADP+ reduction were 800 and 480 mumol/mg of chlorophyll/h, respectively [33].

Analytical, diagnostic and therapeutic context of NADP


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  2. Competitive protein binding assay for methotrexate. Myers, C.E., Lippman, M.E., Elliot, H.M., Chabner, B.A. Proc. Natl. Acad. Sci. U.S.A. (1975) [Pubmed]
  3. Redesigning secondary structure to invert coenzyme specificity in isopropylmalate dehydrogenase. Chen, R., Greer, A., Dean, A.M. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  4. Identification of the binding domain for NADP+ of human glucose-6-phosphate dehydrogenase by sequence analysis of mutants. Hirono, A., Kuhl, W., Gelbart, T., Forman, L., Fairbanks, V.F., Beutler, E. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  5. Myocardial adenylate cyclase activity in acute murine Chagas' disease. Morris, S.A., Tanowitz, H., Factor, S.M., Bilezikian, J.P., Wittner, M. Circ. Res. (1988) [Pubmed]
  6. Immunochemical detection of human enzymes in hybrid cells. Shimizu, N., Shimizu, Y., Kucherlapati, R.S., Ruddle, F.H. Cell (1976) [Pubmed]
  7. Redesign of the coenzyme specificity of a dehydrogenase by protein engineering. Scrutton, N.S., Berry, A., Perham, R.N. Nature (1990) [Pubmed]
  8. 11 beta-Hydroxysteroid dehydrogenase and the syndrome of apparent mineralocorticoid excess. White, P.C., Mune, T., Agarwal, A.K. Endocr. Rev. (1997) [Pubmed]
  9. An unlikely sugar substrate site in the 1.65 A structure of the human aldose reductase holoenzyme implicated in diabetic complications. Wilson, D.K., Bohren, K.M., Gabbay, K.H., Quiocho, F.A. Science (1992) [Pubmed]
  10. Atomic structure of ferredoxin-NADP+ reductase: prototype for a structurally novel flavoenzyme family. Karplus, P.A., Daniels, M.J., Herriott, J.R. Science (1991) [Pubmed]
  11. Alpha-pyridine nucleotides as substrates for a plasmid-specified dihydrofolate reductase. Smith, S.L., Burchall, J.J. Proc. Natl. Acad. Sci. U.S.A. (1983) [Pubmed]
  12. Structure of a bacterial enzyme regulated by phosphorylation, isocitrate dehydrogenase. Hurley, J.H., Thorsness, P.E., Ramalingam, V., Helmers, N.H., Koshland, D.E., Stroud, R.M. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  13. Molecular basis and enzymatic properties of glucose 6-phosphate dehydrogenase volendam, leading to chronic nonspherocytic anemia, granulocyte dysfunction, and increased susceptibility to infections. Roos, D., van Zwieten, R., Wijnen, J.T., Gómez-Gallego, F., de Boer, M., Stevens, D., Pronk-Admiraal, C.J., de Rijk, T., van Noorden, C.J., Weening, R.S., Vulliamy, T.J., Ploem, J.E., Mason, P.J., Bautista, J.M., Khan, P.M., Beutler, E. Blood (1999) [Pubmed]
  14. Modification of glucose-6-phosphate dehydrogenase from Leuconostoc mesenteroides with the 2',3'-dialdehyde derivative of NADP+ (oNADP+). White, B.J., Levy, H.R. J. Biol. Chem. (1987) [Pubmed]
  15. Thermal destabilization of non-phosphorylating glyceraldehyde-3-phosphate dehydrogenase from Streptococcus mutans upon phosphate binding in the active site. Rahuel-Clermont, S., Arutyunov, D., Marchal, S., Orlov, V., Muronetz, V., Branlant, G. J. Biol. Chem. (2005) [Pubmed]
  16. In vitro activity of nicotinamide adenine dinucleotide- and nicotinamide adenine dinucleotide phosphate-linked 15-hydroxyprostaglandin dehydrogenases in placentas from normotensive and preeclamptic/eclamptic pregnancies. Jarabak, J., Watkins, J.D., Lindheimer, M. J. Clin. Invest. (1987) [Pubmed]
  17. Arabidopsis thaliana defense-related protein ELI3 is an aromatic alcohol:NADP(+) oxidoreductase. Somssich, I.E., Wernert, P., Kiedrowski, S., Hahlbrock, K. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  18. Regulation of ferredoxin-catalyzed photosynthetic phosphorylations. Arnon, D.I., Chain, R.K. Proc. Natl. Acad. Sci. U.S.A. (1975) [Pubmed]
  19. Localization of prostaglandin D2 binding protein and NADP-linked 15-hydroxyprostaglandin D2 dehydrogenase in the Purkinje cells of miniature pig cerebellum. Watanabe, Y., Yamashita, A., Tokumoto, H., Hayaishi, O. Proc. Natl. Acad. Sci. U.S.A. (1983) [Pubmed]
  20. Isolation and expression of rat liver sepiapterin reductase cDNA. Citron, B.A., Milstien, S., Gutierrez, J.C., Levine, R.A., Yanak, B.L., Kaufman, S. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  21. Pyrroline-5-carboxylate reductase in human erythrocytes. Yeh, G.C., Harris, S.C., Phang, J.M. J. Clin. Invest. (1981) [Pubmed]
  22. Cyclical oxidation-reduction of the C3 position on bile acids catalyzed by rat hepatic 3 alpha-hydroxysteroid dehydrogenase. I. Studies with the purified enzyme, isolated rat hepatocytes, and inhibition by indomethacin. Takikawa, H., Stolz, A., Kaplowitz, N. J. Clin. Invest. (1987) [Pubmed]
  23. Crystal structure of transhydrogenase domain III at 1.2 A resolution. Prasad, G.S., Sridhar, V., Yamaguchi, M., Hatefi, Y., Stout, C.D. Nat. Struct. Biol. (1999) [Pubmed]
  24. Systemic resistance to methotrexate in transgenic mice carrying a mutant dihydrofolate reductase gene. Isola, L.M., Gordon, J.W. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  25. Lipid metabolism and enzyme activities in hormone-dependent and hormone-independent mammary adenocarcinoma in GR mice. Abraham, S., Briand, P., Hansen, F.N. J. Natl. Cancer Inst. (1986) [Pubmed]
  26. Red cell NADP+ and NADPH in glucose-6-phosphate dehydrogenase deficiency. Kirkman, H.N., Gaetani, G.D., Clemons, E.H., Mareni, C. J. Clin. Invest. (1975) [Pubmed]
  27. Peroxisomal beta-oxidation of polyunsaturated fatty acids in Saccharomyces cerevisiae: isocitrate dehydrogenase provides NADPH for reduction of double bonds at even positions. van Roermund, C.W., Hettema, E.H., Kal, A.J., van den Berg, M., Tabak, H.F., Wanders, R.J. EMBO J. (1998) [Pubmed]
  28. The 1.25 A crystal structure of sepiapterin reductase reveals its binding mode to pterins and brain neurotransmitters. Auerbach, G., Herrmann, A., Gütlich, M., Fischer, M., Jacob, U., Bacher, A., Huber, R. EMBO J. (1997) [Pubmed]
  29. Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis. Istvan, E.S., Palnitkar, M., Buchanan, S.K., Deisenhofer, J. EMBO J. (2000) [Pubmed]
  30. Structure of human biliverdin IXbeta reductase, an early fetal bilirubin IXbeta producing enzyme. Pereira, P.J., Macedo-Ribeiro, S., Párraga, A., Pérez-Luque, R., Cunningham, O., Darcy, K., Mantle, T.J., Coll, M. Nat. Struct. Biol. (2001) [Pubmed]
  31. Hemolytic anemia in hereditary pyrimidine 5'-nucleotidase deficiency: nucleotide inhibition of G6PD and the pentose phosphate shunt. Tomoda, A., Noble, N.A., Lachant, N.A., Tanaka, K.R. Blood (1982) [Pubmed]
  32. Aldose reductase from human skeletal and heart muscle. Interconvertible forms related by thiol-disulfide exchange. Vander Jagt, D.L., Robinson, B., Taylor, K.K., Hunsaker, L.A. J. Biol. Chem. (1990) [Pubmed]
  33. Mutational analysis of photosystem I polypeptides in Synechocystis sp. PCC 6803. Subunit requirements for reduction of NADP+ mediated by ferredoxin and flavodoxin. Xu, Q., Jung, Y.S., Chitnis, V.P., Guikema, J.A., Golbeck, J.H., Chitnis, P.R. J. Biol. Chem. (1994) [Pubmed]
  34. A productive NADP+ binding mode of ferredoxin-NADP + reductase revealed by protein engineering and crystallographic studies. Deng, Z., Aliverti, A., Zanetti, G., Arakaki, A.K., Ottado, J., Orellano, E.G., Calcaterra, N.B., Ceccarelli, E.A., Carrillo, N., Karplus, P.A. Nat. Struct. Biol. (1999) [Pubmed]
  35. Three-dimensional structure of a mammalian thioredoxin reductase: implications for mechanism and evolution of a selenocysteine-dependent enzyme. Sandalova, T., Zhong, L., Lindqvist, Y., Holmgren, A., Schneider, G. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  36. Biochemical mechanisms of glucose-6-phosphate dehydrogenase deficiency. Morelli, A., Benatti, U., Gaetani, G.F., De Flora, A. Proc. Natl. Acad. Sci. U.S.A. (1978) [Pubmed]
  37. Regulation of aldehyde dehydrogenase activity in five rat hepatoma cell lines. Lin, K.H., Winters, A.L., Lindahl, R. Cancer Res. (1984) [Pubmed]
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