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Proton transfer in the oxidative half-reaction of pentaerythritol tetranitrate reductase. Structure of the reduced enzyme-progesterone complex and the roles of residues Tyr186, His181, His184.

Khan H, Barna T, Bruce NC, Munro AW, Leys D, Scrutton NS
FEBS J 272 4660-71 (2005)
Cited: 34 times
EuropePMC logo PMID: 16156787

Abstract

The roles of His181, His184 and Tyr186 in PETN reductase have been examined by mutagenesis, spectroscopic and stopped-flow kinetics, and by determination of crystallographic structures for the Y186F PETN reductase and reduced wild-type enzyme-progesterone complex. Residues His181 and His184 are important in the binding of coenzyme, steroids, nitroaromatic ligands and the substrate 2-cyclohexen-1-one. The H181A and H184A enzymes retain activity in reductive and oxidative half-reactions, and thus do not play an essential role in catalysis. Ligand binding and catalysis is not substantially impaired in Y186F PETN reductase, which contrasts with data for the equivalent mutation (Y196F) in Old Yellow Enzyme. The structure of Y186F PETN reductase is identical to wild-type enzyme, with the obvious exception of the mutation. We show in PETN reductase that Tyr186 is not a key proton donor in the reduction of alpha/beta unsaturated carbonyl compounds. The structure of two electron-reduced PETN reductase bound to the inhibitor progesterone mimics the catalytic enzyme-steroid substrate complex and is similar to the structure of the oxidized enzyme-inhibitor complex. The reactive C1-C2 unsaturated bond of the steroid is inappropriately orientated with the flavin N5 atom for hydride transfer. With steroid substrates, the productive conformation is achieved by orientating the steroid through flipping by 180 degrees , consistent with known geometries for hydride transfer in flavoenzymes. Our data highlight mechanistic differences between Old Yellow Enzyme and PETN reductase and indicate that catalysis requires a metastable enzyme-steroid complex and not the most stable complex observed in crystallographic studies.

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  2. Molecular cloning, characterisation and ligand-bound structure of an azoreductase from Pseudomonas aeruginosa. Wang CJ, Hagemeier C, Rahman N, Lowe E, Noble M, Coughtrie M, Sim E, Westwood I. J Mol Biol 373 1213-1228 (2007)
  3. Novel regulatory system nemRA-gloA for electrophile reduction in Escherichia coli K-12. Lee C, Shin J, Park C. Mol Microbiol 88 395-412 (2013)
  4. Structure-Based Insight into the Asymmetric Bioreduction of the C=C Double Bond of alpha,beta-Unsaturated Nitroalkenes by Pentaerythritol Tetranitrate Reductase. Toogood HS, Fryszkowska A, Hare V, Fisher K, Roujeinikova A, Leys D, Gardiner JM, Stephens GM, Scrutton NS. Adv Synth Catal 350 2789-2803 (2008)
  5. Xenobiotic reductase A in the degradation of quinoline by Pseudomonas putida 86: physiological function, structure and mechanism of 8-hydroxycoumarin reduction. Griese JJ, P Jakob R, Schwarzinger S, Dobbek H. J Mol Biol 361 140-152 (2006)
  6. A site-saturated mutagenesis study of pentaerythritol tetranitrate reductase reveals that residues 181 and 184 influence ligand binding, stereochemistry and reactivity. Toogood HS, Fryszkowska A, Hulley M, Sakuma M, Mansell D, Stephens GM, Gardiner JM, Scrutton NS. Chembiochem 12 738-749 (2011)
  7. Focused directed evolution of pentaerythritol tetranitrate reductase by using automated anaerobic kinetic screening of site-saturated libraries. Hulley ME, Toogood HS, Fryszkowska A, Mansell D, Stephens GM, Gardiner JM, Scrutton NS. Chembiochem 11 2433-2447 (2010)
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  14. 1H, 15N and 13C backbone resonance assignments of pentaerythritol tetranitrate reductase from Enterobacter cloacae PB2. Iorgu AI, Baxter NJ, Cliff MJ, Waltho JP, Hay S, Scrutton NS. Biomol NMR Assign 12 79-83 (2018)
  15. Understanding the hydrogen transfer mechanism for the biodegradation of 2,4,6-trinitrotoluene catalyzed by pentaerythritol tetranitrate reductase: molecular dynamics simulations. Yang Z, Chen J, Zhou Y, Huang H, Xu D, Zhang C. Phys Chem Chem Phys 20 12157-12165 (2018)


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