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Gene Review

DECR1  -  2,4-dienoyl CoA reductase 1, mitochondrial

Homo sapiens

Synonyms: 2,4-dienoyl-CoA reductase, mitochondrial, DECR, NADPH, SDR18C1, Short chain dehydrogenase/reductase family 18C member 1
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Disease relevance of DECR1


Psychiatry related information on DECR1


High impact information on DECR1


Chemical compound and disease context of DECR1


Biological context of DECR1

  • Thus this structure provides a structural framework for the NADH- or NADPH-dependent flavoenzyme parts of five distinct enzymes involved in photosynthesis, in the assimilation of inorganic nitrogen and sulfur, in fatty-acid oxidation, in the reduction of methemoglobin, and in the metabolism of many pesticides, drugs, and carcinogens [18].
  • Therefore signal transduction pathways that require such soluble factors, including the NADPH-dependent cytochrome P450 pathway, do not mediate the response [19].
  • Sequence homology is greatest in the beta alpha beta-dinucleotide binding fold that is conserved among NADPH- and NADH (reduced form of nicotinamide adenine dinucleotide)-dependent reductases and dehydrogenases [20].
  • This protein is generated through alternative splicing of messenger RNA derived from the gene NOH-1 (NADPH oxidase homolog 1, where NADPH is the reduced form of nicotinamide adenine dinucleotide phosphate) [21].
  • The NADPH-binding site of the respiratory burst oxidase system of neutrophils has been proposed to be either at a cytosolic component or at the beta-subunit of cytochrome b558 [22].

Anatomical context of DECR1


Associations of DECR1 with chemical compounds

  • The chemical mechanism is stepwise where hydride transfer from NADPH occurs followed by protonation of the observable dienolate intermediate, which has an absorbance maximum at 286 nm [26].
  • This enzyme catalyzes the NADPH-dependent reduction of 2,4-dienoyl-coenzyme A (CoA) thiolesters to the resulting trans-3-enoyl-CoA [26].
  • An exception is provided by the phagocyte NADPH oxidase, which generates superoxide (O2.-) through electron transfer from cytosolic NADPH to extracellular oxygen [27].
  • Aldose reductase is the first enzyme in the polyol pathway and catalyses the NADPH-dependent reduction of D-glucose to D-sorbitol [28].
  • 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 [29].

Physical interactions of DECR1

  • The x-ray crystal structure of rat QR1 shows that the 43 amino acid C-terminal tail of QR1 provides the binding site for the hydrophilic portions of NADH and NADPH [30].
  • Recently, however, mammalian catalase was found to have tightly bound NADPH and to require NADPH for the prevention and reversal of inactivation by its toxic substrate (H2O2) [31].
  • Based on these observations, a new model is proposed whereby DHFR exists in two conformations, one bound to DHFR mRNA and the other bound to NADPH [32].
  • Interaction of endothelial and neuronal nitric-oxide synthases with the bradykinin B2 receptor. Binding of an inhibitory peptide to the oxygenase domain blocks uncoupled NADPH oxidation [33].
  • Difference spectra experiments revealed an NADPH-dependent peak at approximately 455 nm [metabolite-inhibitor (MI) complex] following incubation of all three drugs with CYP3A4 [34].

Enzymatic interactions of DECR1

  • Steady-state absorbance spectra of nNOS recorded during uncoupled NADPH oxidation showed that the heme remained oxidized in the presence of the synthetic peptide consisting of amino acids 310-329 of the B2R, whereas the reduced oxyferrous heme complex was accumulated in its absence [33].
  • The k(cat) for the NADPH-dependent reduction of DHT catalyzed by AKR1C2 is 0.033 s(-1) [35].
  • Prostaglandin F synthase (PGFS) was first purified from bovine lung and catalyzes the formation of 9 alpha,11 beta-PGF(2) from PGD(2) and PGF(2)(alpha) from PGH(2) in the presence of NADPH [36].
  • The present study indicates that human liver microsomal CYP3A4 preferentially catalyzes the two NADPH- dependent metabolic routes of trofosfamide, which emphasizes the necessity for awareness of potential interactions with any coadministered drugs that are CYP3A4 substrates [37].
  • Thioredoxin reductase catalyzes the NADPH-dependent reduction of the catalytic disulfide bond of thioredoxin [38].

Co-localisations of DECR1


Regulatory relationships of DECR1


Other interactions of DECR1

  • To clarify the nature of this selective pressure, we studied how G6PD activity and other parameters in a model of the NADPH redox cycle affect metabolic performance [6].
  • Furthermore, NADPH was a potent inhibitor of the W676A NADH-dependent cytochrome c reduction and CYP1A2 activity [45].
  • Apoenzyme alone is quite unstable at 37 degrees C. MSR also is able to reduce aquacobalamin to cob(II)alamin in the presence of NADPH, and this reduction leads to stimulation of the conversion of apoMS and aquacobalamin to MS holoenzyme [46].
  • Since both catalase and the glutathione pathway are dependent on NADPH for function, this finding raises the possibility that both mechanisms destroy H2O2 in human erythrocytes [31].
  • These P450s were reconstituted with P450 reductase and lipid and were incubated with 50 microM [3H]tam and NADPH at 37 degrees C for 60 min [47].

Analytical, diagnostic and therapeutic context of DECR1


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  2. Nitric oxide synthase activity in infantile hypertrophic pyloric stenosis. Vanderwinden, J.M., Mailleux, P., Schiffmann, S.N., Vanderhaeghen, J.J., De Laet, M.H. N. Engl. J. Med. (1992) [Pubmed]
  3. Selective inhibition of acetaminophen oxidation and toxicity by cimetidine and other histamine H2-receptor antagonists in vivo and in vitro in the rat and in man. Mitchell, M.C., Schenker, S., Speeg, K.V. J. Clin. Invest. (1984) [Pubmed]
  4. Association of DNA cross-linking with potentiation of the morpholino derivative of doxorubicin by human liver microsomes. Lau, D.H., Lewis, A.D., Sikic, B.I. J. Natl. Cancer Inst. (1989) [Pubmed]
  5. Relationship between metabolic clearance rate of antipyrine and hepatic microsomal drug-oxidizing enzyme activities in humans without liver disease. Vuitton, D., Miguet, J.P., Camelot, G., Delafin, C., Joanne, C., Bechtel, P., Gillet, M., Carayon, P. Gastroenterology (1981) [Pubmed]
  6. Quantitative evolutionary design of glucose 6-phosphate dehydrogenase expression in human erythrocytes. Salvador, A., Savageau, M.A. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  7. Compartmental loss of NADPH diaphorase in the neuropil of the human striatum in Huntington's disease. Morton, A.J., Nicholson, L.F., Faull, R.L. Neuroscience (1993) [Pubmed]
  8. NADPH diaphorase histochemistry of the human hypothalamus. Sangruchi, T., Kowall, N.W. Neuroscience (1991) [Pubmed]
  9. Hydroxymethylvinyl ketone: a reactive Michael acceptor formed by the oxidation of 3-butene-1,2-diol by cDNA-expressed human cytochrome P450s and mouse, rat, and human liver microsomes. Krause, R.J., Kemper, R.A., Elfarra, A.A. Chem. Res. Toxicol. (2001) [Pubmed]
  10. Alcohol-induced impairment of neuronal nitric oxide synthase (nNOS)-dependent dilation of cerebral arterioles: role of NAD(P)H oxidase. Sun, H., Molacek, E., Zheng, H., Fang, Q., Patel, K.P., Mayhan, W.G. J. Mol. Cell. Cardiol. (2006) [Pubmed]
  11. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Bedard, K., Krause, K.H. Physiol. Rev. (2007) [Pubmed]
  12. Mutations in the genes encoding 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency. Draper, N., Walker, E.A., Bujalska, I.J., Tomlinson, J.W., Chalder, S.M., Arlt, W., Lavery, G.G., Bedendo, O., Ray, D.W., Laing, I., Malunowicz, E., White, P.C., Hewison, M., Mason, P.J., Connell, J.M., Shackleton, C.H., Stewart, P.M. Nat. Genet. (2003) [Pubmed]
  13. Pyridine nucleotide-dependent superoxide production by a cell-free system from human granulocytes. Babior, B.M., Curnutte, J.T., Kipnes, B.S. J. Clin. Invest. (1975) [Pubmed]
  14. Bidirectional regulation of osteoclast function by nitric oxide synthase isoforms. Brandi, M.L., Hukkanen, M., Umeda, T., Moradi-Bidhendi, N., Bianchi, S., Gross, S.S., Polak, J.M., MacIntyre, I. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  15. PTR1: a reductase mediating salvage of oxidized pteridines and methotrexate resistance in the protozoan parasite Leishmania major. Bello, A.R., Nare, B., Freedman, D., Hardy, L., Beverley, S.M. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  16. Genetic susceptibility to benzene-induced toxicity: role of NADPH: quinone oxidoreductase-1. Bauer, A.K., Faiola, B., Abernethy, D.J., Marchan, R., Pluta, L.J., Wong, V.A., Roberts, K., Jaiswal, A.K., Gonzalez, F.J., Butterworth, B.E., Borghoff, S., Parkinson, H., Everitt, J., Recio, L. Cancer Res. (2003) [Pubmed]
  17. Co-induction of fatty acid reductase and luciferase during development of bacterial bioluminescence. Riendeau, D., Meighen, E. J. Biol. Chem. (1980) [Pubmed]
  18. 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]
  19. Arachidonic acid and other fatty acids directly activate potassium channels in smooth muscle cells. Ordway, R.W., Walsh, J.V., Singer, J.J. Science (1989) [Pubmed]
  20. Reductase activity encoded by the HM1 disease resistance gene in maize. Johal, G.S., Briggs, S.P. Science (1992) [Pubmed]
  21. A mammalian H+ channel generated through alternative splicing of the NADPH oxidase homolog NOH-1. Bánfi, B., Maturana, A., Jaconi, S., Arnaudeau, S., Laforge, T., Sinha, B., Ligeti, E., Demaurex, N., Krause, K.H. Science (2000) [Pubmed]
  22. NADPH-binding component of the respiratory burst oxidase system: studies using neutrophil membranes from patients with chronic granulomatous disease lacking the beta-subunit of cytochrome b558. Tsunawaki, S., Mizunari, H., Namiki, H., Kuratsuji, T. J. Exp. Med. (1994) [Pubmed]
  23. NADPH-dependent beta-oxidation of unsaturated fatty acids with double bonds extending from odd-numbered carbon atoms. Smeland, T.E., Nada, M., Cuebas, D., Schulz, H. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  24. Nitric oxide mediates network oscillations of olfactory interneurons in a terrestrial mollusc. Gelperin, A. Nature (1994) [Pubmed]
  25. Priming of neutrophils for enhanced release of oxygen metabolites by bacterial lipopolysaccharide. Evidence for increased activity of the superoxide-producing enzyme. Guthrie, L.A., McPhail, L.C., Henson, P.M., Johnston, R.B. J. Exp. Med. (1984) [Pubmed]
  26. The mechanism of dienoyl-CoA reduction by 2,4-dienoyl-CoA reductase is stepwise: observation of a dienolate intermediate. Fillgrove, K.L., Anderson, V.E. Biochemistry (2001) [Pubmed]
  27. Electron currents generated by the human phagocyte NADPH oxidase. Schrenzel, J., Serrander, L., Bánfi, B., Nüsse, O., Fouyouzi, R., Lew, D.P., Demaurex, N., Krause, K.H. Nature (1998) [Pubmed]
  28. Novel NADPH-binding domain revealed by the crystal structure of aldose reductase. Rondeau, J.M., Tête-Favier, F., Podjarny, A., Reymann, J.M., Barth, P., Biellmann, J.F., Moras, D. Nature (1992) [Pubmed]
  29. 11 beta-Hydroxysteroid dehydrogenase and the syndrome of apparent mineralocorticoid excess. White, P.C., Mune, T., Agarwal, A.K. Endocr. Rev. (1997) [Pubmed]
  30. Unexpected genetic and structural relationships of a long-forgotten flavoenzyme to NAD(P)H:quinone reductase (DT-diaphorase). Zhao, Q., Yang, X.L., Holtzclaw, W.D., Talalay, P. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  31. Catalase and glutathione peroxidase are equally active in detoxification of hydrogen peroxide in human erythrocytes. Gaetani, G.F., Galiano, S., Canepa, L., Ferraris, A.M., Kirkman, H.N. Blood (1989) [Pubmed]
  32. Identification of amino acids required for the functional up-regulation of human dihydrofolate reductase protein in response to antifolate Treatment. Skacel, N., Menon, L.G., Mishra, P.J., Peters, R., Banerjee, D., Bertino, J.R., Abali, E.E. J. Biol. Chem. (2005) [Pubmed]
  33. Interaction of endothelial and neuronal nitric-oxide synthases with the bradykinin B2 receptor. Binding of an inhibitory peptide to the oxygenase domain blocks uncoupled NADPH oxidation. Golser, R., Gorren, A.C., Leber, A., Andrew, P., Habisch, H.J., Werner, E.R., Schmidt, K., Venema, R.C., Mayer, B. J. Biol. Chem. (2000) [Pubmed]
  34. Differences in the inhibition of cytochromes P450 3A4 and 3A5 by metabolite-inhibitor complex-forming drugs. McConn, D.J., Lin, Y.S., Allen, K., Kunze, K.L., Thummel, K.E. Drug Metab. Dispos. (2004) [Pubmed]
  35. Multiple steps determine the overall rate of the reduction of 5alpha-dihydrotestosterone catalyzed by human type 3 3alpha-hydroxysteroid dehydrogenase: implications for the elimination of androgens. Jin, Y., Penning, T.M. Biochemistry (2006) [Pubmed]
  36. Crystal structure of human prostaglandin F synthase (AKR1C3). Komoto, J., Yamada, T., Watanabe, K., Takusagawa, F. Biochemistry (2004) [Pubmed]
  37. Investigation of the major human hepatic cytochrome P450 involved in 4-hydroxylation and N-dechloroethylation of trofosfamide. May-Manke, A., Kroemer, H., Hempel, G., Bohnenstengel, F., Hohenlöchter, B., Blaschke, G., Boos, J. Cancer Chemother. Pharmacol. (1999) [Pubmed]
  38. Characterization of mitochondrial thioredoxin reductase from C. elegans. Lacey, B.M., Hondal, R.J. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  39. Immunohistochemical localization of endothelial nitric oxide synthase in human testis, epididymis, and vas deferens suggests a possible role for nitric oxide in spermatogenesis, sperm maturation, and programmed cell death. Zini, A., O'Bryan, M.K., Magid, M.S., Schlegel, P.N. Biol. Reprod. (1996) [Pubmed]
  40. ZNF143 mediates basal and tissue-specific expression of human transaldolase. Grossman, C.E., Qian, Y., Banki, K., Perl, A. J. Biol. Chem. (2004) [Pubmed]
  41. Mechanism of Ca2+ activation of the NADPH oxidase 5 (NOX5). Bánfi, B., Tirone, F., Durussel, I., Knisz, J., Moskwa, P., Molnár, G.Z., Krause, K.H., Cox, J.A. J. Biol. Chem. (2004) [Pubmed]
  42. Role of CYP3A4 in human hepatic diltiazem N-demethylation: inhibition of CYP3A4 activity by oxidized diltiazem metabolites. Sutton, D., Butler, A.M., Nadin, L., Murray, M. J. Pharmacol. Exp. Ther. (1997) [Pubmed]
  43. Inhibition of coumarin 7-hydroxylase activity in human liver microsomes. Draper, A.J., Madan, A., Parkinson, A. Arch. Biochem. Biophys. (1997) [Pubmed]
  44. In vitro oxidation of oxicam NSAIDS by a human liver cytochrome P450. Zhao, J., Leemann, T., Dayer, P. Life Sci. (1992) [Pubmed]
  45. Engineering of a functional human NADH-dependent cytochrome P450 system. Döhr, O., Paine, M.J., Friedberg, T., Roberts, G.C., Wolf, C.R. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  46. Human methionine synthase reductase is a molecular chaperone for human methionine synthase. Yamada, K., Gravel, R.A., Toraya, T., Matthews, R.G. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  47. CYP2D6 catalyzes tamoxifen 4-hydroxylation in human liver. Dehal, S.S., Kupfer, D. Cancer Res. (1997) [Pubmed]
  48. Modulation of ion channels in rod photoreceptors by nitric oxide. Kurenny, D.E., Moroz, L.L., Turner, R.W., Sharkey, K.A., Barnes, S. Neuron (1994) [Pubmed]
  49. Reductive metabolism of carbon tetrachloride by human cytochromes P-450 reconstituted in phospholipid vesicles: mass spectral identification of trichloromethyl radical bound to dioleoyl phosphatidylcholine. Trudell, J.R., Bösterling, B., Trevor, A.J. Proc. Natl. Acad. Sci. U.S.A. (1982) [Pubmed]
  50. Ferryl intermediates of catalase captured by time-resolved Weissenberg crystallography and UV-VIS spectroscopy. Gouet, P., Jouve, H.M., Williams, P.A., Andersson, I., Andreoletti, P., Nussaume, L., Hajdu, J. Nat. Struct. Biol. (1996) [Pubmed]
  51. Enhanced dihydroflavonol-4-reductase activity and NAD homeostasis leading to cell death tolerance in transgenic rice. Hayashi, M., Takahashi, H., Tamura, K., Huang, J., Yu, L.H., Kawai-Yamada, M., Tezuka, T., Uchimiya, H. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  52. Dissection of NADPH-cytochrome P450 oxidoreductase into distinct functional domains. Smith, G.C., Tew, D.G., Wolf, C.R. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
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