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Alteration of P450 distal pocket solvent leads to impaired proton delivery and changes in heme geometry.

Makris TM, von Koenig K, Schlichting I, Sligar SG
Biochemistry 46 14129-40 (2007)
Related entries: 2qbl, 2qbm, 2qbn

Cited: 35 times
EuropePMC logo PMID: 18001135

Abstract

Distal pocket water molecules have been widely implicated in the delivery of protons required in O-O bond heterolysis in the P450 reaction cycle. Targeted dehydration of the cytochrome P450cam (CYP101) distal pocket through mutagenesis of a distal pocket glycine to either valine or threonine results in the alteration of spin state equilibria, and has dramatic consequences on the catalytic rate, coupling efficiency, and kinetic solvent isotope effect parameters, highlighting an important role of the active-site hydration level on P450 catalysis. Cryoradiolysis of the mutant CYP101 oxyferrous complexes further indicates a specific perturbation of proton-transfer events required for the transformation of ferric-peroxo to ferric-hydroperoxo states. Finally, crystallography of the 248Val and 248Thr mutants in both the ferric camphor bound resting state and ferric-cyano adducts shows both the alteration of hydrogen-bonding networks and the alteration of heme geometry parameters. Taken together, these results indicate that the distal pocket microenvironment governs the transformation of reactive heme-oxygen intermediates in P450 cytochromes.

Reviews citing this publication (8)

  1. Heme enzyme structure and function. Poulos TL. Chem Rev 114 3919-3962 (2014)
  2. Hydrocarbon hydroxylation by cytochrome P450 enzymes. Ortiz de Montellano PR. Chem Rev 110 932-948 (2010)
  3. Cellulose degradation by polysaccharide monooxygenases. Beeson WT, Vu VV, Span EA, Phillips CM, Marletta MA. Annu Rev Biochem 84 923-946 (2015)
  4. Conformational plasticity and structure/function relationships in cytochromes P450. Pochapsky TC, Kazanis S, Dang M. Antioxid Redox Signal 13 1273-1296 (2010)
  5. Microsomal monooxygenase as a multienzyme system: the role of P450-P450 interactions. Davydov DR. Expert Opin Drug Metab Toxicol 7 543-558 (2011)
  6. Oxygen activation by cytochrome P450 monooxygenase. Hamdane D, Zhang H, Hollenberg P. Photosynth Res 98 657-666 (2008)
  7. New cytochrome P450 mechanisms: implications for understanding molecular basis for drug toxicity at the level of the cytochrome. Shakunthala N. Expert Opin Drug Metab Toxicol 6 1-15 (2010)
  8. Spectroscopic studies of the cytochrome P450 reaction mechanisms. Mak PJ, Denisov IG. Biochim Biophys Acta Proteins Proteom 1866 178-204 (2018)

Articles citing this publication (27)

  1. The Role of the Secondary Coordination Sphere in a Fungal Polysaccharide Monooxygenase. Span EA, Suess DLM, Deller MC, Britt RD, Marletta MA. ACS Chem Biol 12 1095-1103 (2017)
  2. Resonance Raman characterization of the peroxo and hydroperoxo intermediates in cytochrome P450. Denisov IG, Mak PJ, Makris TM, Sligar SG, Kincaid JR. J Phys Chem A 112 13172-13179 (2008)
  3. The critical iron-oxygen intermediate in human aromatase. Gantt SL, Denisov IG, Grinkova YV, Sligar SG. Biochem Biophys Res Commun 387 169-173 (2009)
  4. Human Cytochrome CYP17A1: The Structural Basis for Compromised Lyase Activity with 17-Hydroxyprogesterone. Mak PJ, Duggal R, Denisov IG, Gregory MC, Sligar SG, Kincaid JR. J Am Chem Soc 140 7324-7331 (2018)
  5. Distant protonated pyridine groups in water-soluble iron porphyrin electrocatalysts promote selective oxygen reduction to water. Matson BD, Carver CT, Von Ruden A, Yang JY, Raugei S, Mayer JM. Chem Commun (Camb) 48 11100-11102 (2012)
  6. Structural Analysis of CYP101C1 from Novosphingobium aromaticivorans DSM12444. Ma M, Bell SG, Yang W, Hao Y, Rees NH, Bartlam M, Zhou W, Wong LL, Rao Z. Chembiochem 12 88-99 (2011)
  7. Toward a systems approach to the human cytochrome P450 ensemble: interactions between CYP2D6 and CYP2E1 and their functional consequences. Davydov DR, Davydova NY, Rodgers JT, Rushmore TH, Jones JP. Biochem J 474 3523-3542 (2017)
  8. A single-site mutation (F429H) converts the enzyme CYP 2B4 into a heme oxygenase: a QM/MM study. Usharani D, Zazza C, Lai W, Chourasia M, Waskell L, Shaik S. J Am Chem Soc 134 4053-4056 (2012)
  9. Synergistic effects of mutations in cytochrome P450cam designed to mimic CYP101D1. Batabyal D, Li H, Poulos TL. Biochemistry 52 5396-5402 (2013)
  10. Investigation of the low frequency dynamics of heme proteins: native and mutant cytochrome P450(cam) and redox partner complexes. Karunakaran V, Denisov I, Sligar SG, Champion PM. J Phys Chem B 115 5665-5677 (2011)
  11. Temperature derivative spectroscopy to monitor the autoxidation decay of cytochromes P450. Luthra A, Denisov IG, Sligar SG. Anal Chem 83 5394-5399 (2011)
  12. Letter Structural characterization of CYP260A1 from Sorangium cellulosum to investigate the 1α-hydroxylation of a mineralocorticoid. Khatri Y, Carius Y, Ringle M, Lancaster CR, Bernhardt R. FEBS Lett 590 4638-4648 (2016)
  13. Unveiling the structure of a novel artificial heme-enzyme with peroxidase-like activity: A theoretical investigation. Perrella F, Raucci U, Chiariello MG, Chino M, Maglio O, Lombardi A, Rega N. Biopolymers 109 e23225 (2018)
  14. Disruption of the proton relay network in the class 2 dihydroorotate dehydrogenase from Escherichia coli. Kow RL, Whicher JR, McDonald CA, Palfey BA, Fagan RL. Biochemistry 48 9801-9809 (2009)
  15. Selectivity-Determining Steps in O2 Reduction Catalyzed by Iron(tetramesitylporphyrin). Brezny AC, Johnson SI, Raugei S, Mayer JM. J Am Chem Soc 142 4108-4113 (2020)
  16. Arene activation by a nonheme iron(III)-hydroperoxo complex: pathways leading to phenol and ketone products. Faponle AS, Banse F, de Visser SP. J Biol Inorg Chem 21 453-462 (2016)
  17. Gating the electron transfer at a monocopper centre through the supramolecular coordination of water molecules within a protein chamber mimic. Le Poul N, Colasson B, Thiabaud G, Dit Fouque DJ, Iacobucci C, Memboeuf A, Douziech B, Řezáč J, Prangé T, de la Lande A, Reinaud O, Le Mest Y. Chem Sci 9 8282-8290 (2018)
  18. Importance of Asparagine 202 in Manipulating Active Site Structure and Substrate Preference for Human CYP17A1. Liu Y, Denisov I, Gregory M, Sligar SG, Kincaid JR. Biochemistry 61 583-594 (2022)
  19. Mechanism of the Clinically Relevant E305G Mutation in Human P450 CYP17A1. Liu Y, Grinkova Y, Gregory MC, Denisov IG, Kincaid JR, Sligar SG. Biochemistry 60 3262-3271 (2021)
  20. Simultaneous measurement of CYP1A2 activity, regioselectivity, and coupling: Implications for environmental sensitivity of enzyme-substrate binding. Traylor MJ, Chai J, Clark DS. Arch Biochem Biophys 505 186-193 (2011)
  21. Characterization of CYP154F1 from Thermobifida fusca YX and Extension of Its Substrate Spectrum by Site-Directed Mutagenesis. Rühlmann A, Groth G, Urlacher VB. Chembiochem 19 478-485 (2018)
  22. Cryoradiolysis and cryospectroscopy for studies of heme-oxygen intermediates in cytochromes p450. Denisov IG, Grinkova YV, Sligar SG. Methods Mol Biol 875 375-391 (2012)
  23. Four second-sphere residues of Thermus thermophilus SG0.5JP17-16 laccase tune the catalysis by hydrogen-bonding networks. Liu H, Zhu Y, Yang X, Lin Y. Appl Microbiol Biotechnol 102 4049-4061 (2018)
  24. Quantum Mechanics/Molecular Mechanics Studies on the Relative Reactivities of Compound I and II in Cytochrome P450 Enzymes. Postils V, Saint-André M, Timmins A, Li XX, Wang Y, Luis JM, Solà M, de Visser SP. Int J Mol Sci 19 E1974 (2018)
  25. Active Site Hydrogen Bonding Induced in Cytochrome P450cam by Effector Putidaredoxin. Mammoser CC, Ramos S, Thielges MC. Biochemistry 60 1699-1707 (2021)
  26. Solvent isotope effects in the catalytic cycle of P450 CYP17A1: Computational modeling of the hydroxylation and lyase reactions. Denisov IG, Sligar SG. J Inorg Biochem 243 112202 (2023)
  27. Letter The "outsized" role of the I-helix kink in human Cytochrome P450s. Zhang J, Liu F, Suo Y, Tong D, Hu J, Lyu HN, Liao J, Wang J, Wang J, Xu C. Clin Transl Med 13 e1378 (2023)


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