1w8d Citations

Structure and reactivity of human mitochondrial 2,4-dienoyl-CoA reductase: enzyme-ligand interactions in a distinctive short-chain reductase active site.

J. Biol. Chem. 280 3068-77 (2005)
Related entries: 1w6u, 1w73

Cited: 29 times
EuropePMC logo PMID: 15531764


Fatty acid catabolism by beta-oxidation mainly occurs in mitochondria and to a lesser degree in peroxisomes. Poly-unsaturated fatty acids are problematic for beta-oxidation, because the enzymes directly involved are unable to process all the different double bond conformations and combinations that occur naturally. In mammals, three accessory proteins circumvent this problem by catalyzing specific isomerization and reduction reactions. Central to this process is the NADPH-dependent 2,4-dienoyl-CoA reductase. We present high resolution crystal structures of human mitochondrial 2,4-dienoyl-CoA reductase in binary complex with cofactor, and the ternary complex with NADP(+) and substrate trans-2,trans-4-dienoyl-CoA at 2.1 and 1.75 A resolution, respectively. The enzyme, a homotetramer, is a short-chain dehydrogenase/reductase with a distinctive catalytic center. Close structural similarity between the binary and ternary complexes suggests an absence of large conformational changes during binding and processing of substrate. The site of catalysis is relatively open and placed beside a flexible loop thereby allowing the enzyme to accommodate and process a wide range of fatty acids. Seven single mutants were constructed, by site-directed mutagenesis, to investigate the function of selected residues in the active site thought likely to either contribute to the architecture of the active site or to catalysis. The mutant proteins were overexpressed, purified to homogeneity, and then characterized. The structural and kinetic data are consistent and support a mechanism that derives one reducing equivalent from the cofactor, and one from solvent. Key to the acquisition of a solvent-derived proton is the orientation of substrate and stabilization of a dienolate intermediate by Tyr-199, Asn-148, and the oxidized nicotinamide.

Reviews citing this publication (3)

  1. Order, Disorder, and Everything in Between. DeForte S, Uversky VN. Molecules 21 (2016)
  2. Medium- and short-chain dehydrogenase/reductase gene and protein families : the SDR superfamily: functional and structural diversity within a family of metabolic and regulatory enzymes. Kavanagh KL, Jörnvall H, Persson B, Oppermann U. Cell. Mol. Life Sci. 65 3895-3906 (2008)
  3. Structural biology of the thioester-dependent degradation and synthesis of fatty acids. Bhaumik P, Koski MK, Glumoff T, Hiltunen JK, Wierenga RK. Curr. Opin. Struct. Biol. 15 621-628 (2005)

Articles citing this publication (26)

  1. Convergent evolution of enzyme active sites is not a rare phenomenon. Gherardini PF, Wass MN, Helmer-Citterich M, Sternberg MJ. J. Mol. Biol. 372 817-845 (2007)
  2. The human short-chain dehydrogenase/reductase (SDR) superfamily: a bioinformatics summary. Bray JE, Marsden BD, Oppermann U. Chem. Biol. Interact. 178 99-109 (2009)
  3. Epithelial cell specificity and apotope recognition by serum autoantibodies in primary biliary cirrhosis. Rong G, Zhong R, Lleo A, Leung PS, Bowlus CL, Yang GX, Yang CY, Coppel RL, Ansari AA, Cuebas DA, Worman HJ, Invernizzi P, Gores GJ, Norman G, He XS, Gershwin ME. Hepatology 54 196-203 (2011)
  4. The crystal structure of progesterone 5beta-reductase from Digitalis lanata defines a novel class of short chain dehydrogenases/reductases. Thorn A, Egerer-Sieber C, Jäger CM, Herl V, Müller-Uri F, Kreis W, Muller YA. J Biol Chem 283 17260-17269 (2008)
  5. Nonprocessive [2 + 2]e- off-loading reductase domains from mycobacterial nonribosomal peptide synthetases. Chhabra A, Haque AS, Pal RK, Goyal A, Rai R, Joshi S, Panjikar S, Pasha S, Sankaranarayanan R, Gokhale RS. Proc. Natl. Acad. Sci. U.S.A. 109 5681-5686 (2012)
  6. Interactions among mitochondrial proteins altered in glioblastoma. Deighton RF, Le Bihan T, Martin SF, Gerth AMJ, McCulloch M, Edgar JM, Kerr LE, Whittle IR, McCulloch J. J. Neurooncol. 118 247-256 (2014)
  7. Elevated expression of DecR1 impairs ErbB2/Neu-induced mammary tumor development. Ursini-Siegel J, Rajput AB, Lu H, Sanguin-Gendreau V, Zuo D, Papavasiliou V, Lavoie C, Turpin J, Cianflone K, Huntsman DG, Muller WJ. Mol. Cell. Biol. 27 6361-6371 (2007)
  8. Mitochondrial 2,4-dienoyl-CoA reductase deficiency in mice results in severe hypoglycemia with stress intolerance and unimpaired ketogenesis. Miinalainen IJ, Schmitz W, Huotari A, Autio KJ, Soininen R, Ver Loren van Themaat E, Baes M, Herzig KH, Conzelmann E, Hiltunen JK. PLoS Genet. 5 e1000543 (2009)
  9. Structural modelling and comparative analysis of homologous, analogous and specific proteins from Trypanosoma cruzi versus Homo sapiens: putative drug targets for chagas' disease treatment. Capriles PV, Guimarães AC, Otto TD, Miranda AB, Dardenne LE, Degrave WM. BMC Genomics 11 610 (2010)
  10. Structure and catalytic mechanism of human steroid 5beta-reductase (AKR1D1). Di Costanzo L, Drury JE, Christianson DW, Penning TM. Mol. Cell. Endocrinol. 301 191-198 (2009)
  11. Crystal structure of yeast peroxisomal multifunctional enzyme: structural basis for substrate specificity of (3R)-hydroxyacyl-CoA dehydrogenase units. Ylianttila MS, Pursiainen NV, Haapalainen AM, Juffer AH, Poirier Y, Hiltunen JK, Glumoff T. J. Mol. Biol. 358 1286-1295 (2006)
  12. The functional divergence of short-chain dehydrogenases involved in tropinone reduction. Brock A, Brandt W, Dräger B. Plant J. 54 388-401 (2008)
  13. Letter Metabolic fate of docosahexaenoic acid (DHA; 22:6n-3) in human cells: direct retroconversion of DHA to eicosapentaenoic acid (20:5n-3) dominates over elongation to tetracosahexaenoic acid (24:6n-3). Park HG, Lawrence P, Engel MG, Kothapalli K, Brenna JT. FEBS Lett. 590 3188-3194 (2016)
  14. A proteomic insight into the effects of the immunomodulatory hydroxynaphthoquinone lapachol on activated macrophages. Oliveira RA, Correia-Oliveira J, Tang LJ, Garcia RC. Int. Immunopharmacol. 14 54-65 (2012)
  15. Aldo-keto reductases in which the conserved catalytic histidine is substituted. Di Costanzo L, Penning TM, Christianson DW. Chem. Biol. Interact. 178 127-133 (2009)
  16. Quantitative proteomics analysis reveals glutamine deprivation activates fatty acid β-oxidation pathway in HepG2 cells. Long B, Muhamad R, Yan G, Yu J, Fan Q, Wang Z, Li X, Purnomoadi A, Achmadi J, Yan X. Amino Acids 48 1297-1307 (2016)
  17. Formation of an enolate intermediate is required for the reaction catalyzed by 3-hydroxyacyl-CoA dehydrogenase. Liu X, Deng G, Chu X, Li N, Wu L, Li D. Bioorg. Med. Chem. Lett. 17 3187-3190 (2007)
  18. Improving heterologous production of phenylpropanoids in Saccharomyces cerevisiae by tackling an unwanted side reaction of Tsc13, an endogenous double-bond reductase. Lehka BJ, Eichenberger M, Bjørn-Yoshimoto WE, Vanegas KG, Buijs N, Jensen NB, Dyekjær JD, Jenssen H, Simon E, Naesby M. FEMS Yeast Res. 17 (2017)
  19. In silico structural characterization of protein targets for drug development against Trypanosoma cruzi. Lima CR, Carels N, Guimaraes AC, Tufféry P, Derreumaux P. J Mol Model 22 244 (2016)
  20. Studies of human 2,4-dienoyl CoA reductase shed new light on peroxisomal β-oxidation of unsaturated fatty acids. Hua T, Wu D, Ding W, Wang J, Shaw N, Liu ZJ. J. Biol. Chem. 287 28956-28965 (2012)
  21. Sphenostylisins A-K: bioactive modified isoflavonoid constituents of the root bark of Sphenostylis marginata ssp. erecta. Li J, Pan L, Deng Y, Muñoz-Acuña U, Yuan C, Lai H, Chai H, Chagwedera TE, Farnsworth NR, Carcache de Blanco EJ, Li C, Soejarto DD, Kinghorn AD. J. Org. Chem. 78 10166-10177 (2013)
  22. Structure and reaction mechanism of a novel enone reductase. Hou F, Miyakawa T, Kitamura N, Takeuchi M, Park SB, Kishino S, Ogawa J, Tanokura M. FEBS J. 282 1526-1537 (2015)
  23. Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis. Nassar ZD, Mah CY, Dehairs J, Burvenich IJ, Irani S, Centenera MM, Helm M, Shrestha RK, Moldovan M, Don AS, Holst J, Scott AM, Horvath LG, Lynn DJ, Selth LA, Hoy AJ, Swinnen JV, Butler LM. Elife 9 (2020)
  24. Consensus model of a cyanobacterial light-dependent protochlorophyllide oxidoreductase in its pigment-free apo-form and photoactive ternary complex. Schneidewind J, Krause F, Bocola M, Stadler AM, Davari MD, Schwaneberg U, Jaeger KE, Krauss U. Commun Biol 2 351 (2019)
  25. Leishmania Encodes a Bacterium-like 2,4-Dienoyl-Coenzyme A Reductase That Is Required for Fatty Acid β-Oxidation and Intracellular Parasite Survival. Semini G, Paape D, Blume M, Sernee MF, Peres-Alonso D, Calvignac-Spencer S, Döllinger J, Jehle S, Saunders E, McConville MJ, Aebischer T. mBio 11 (2020)
  26. Sex-specific regulation of cardiac microRNAs targeting mitochondrial proteins in pressure overload. Sanchez-Ruderisch H, Queirós AM, Fliegner D, Eschen C, Kararigas G, Regitz-Zagrosek V. Biol Sex Differ 10 8 (2019)