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2009 | 56 | 3 | 447-454
Article title

Inhibition of 4-hydroxyphenylpyruvate dioxygenase by 2-[2-nitro-4-(trifluoromethyl)benzoyl]-1,3-cyclohexanedione

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Triketone herbicides are inhibitors of 4-hydroxyphenylpyruvate dioxygenase (HPPD), a key enzyme of the tyrosine transformation pathway, common for plants and animals. One of these herbicides, 2-[2-nitro-4-(trifluoromethyl)benzoyl]-1,3-cyclohexanedione (NTBC), is so selective and efficient that it can be applied as a medicine in a hereditary metabolic disease - tyrosinemia type I. In this paper the available information concerning the molecular mechanism of HPPD inhibition by NTBC, originating from experimental investigations as well as theoretical modeling, has been collected. It is supplemented by results of additional theoretical DFT and/or MP2 calculations of the energetic effects of individual elementary molecular transformations. All these data are discussed and a consistent picture of HPPD inhibition by NTBC is proposed.
Physical description
  • Faculty of Chemistry, Warsaw University of Technology, Warszawa, Poland
  • Faculty of Chemistry, Warsaw University of Technology, Warszawa, Poland
  • Bassan A, Borowski T, Siegbahn PEM (2004) Quantum chemical studies of dioxygen activation by mononuclear non-heme iron enzymes with the 2-His-1-carboxylate facial triad. Dalton Trans 3153-3162.
  • Bassan A, Blomberg MRA, Borowski T, Siegbahn PEM (2006) Theoretical studies of enzyme mechanisms involving high-valent iron intermediates. J Inorg Biochem 100: 727-743.
  • Beg S, Waggoner K, Ahmad Y, Watt M, Lewis M (2008) Predicting face-to-face arene-arene binding energies. Chem Phys Lett 455: 98-102.
  • Borowski T, Bassan A, Siegbahn PEM (2004) 4-Hydroxyphenylpyruvate dioxygenase: A hybrid density functional study of the catalytic reaction mechanism. Biochemistry 43: 12331-12342.
  • Boys SF, Bernardi F (1970) The calculations of small molecular interaction by the difference of separate total energies-some procedures with reduced error. Mol Phys 19: 553-566.
  • Brownlee JM, Johnson-Winters K, Harrison DHT, Moran GR (2004) Structure of the ferrous form of (4-hydroxyphenyl)pyruvate dioxygenase from Streptomyces avermitilis in complex with the therapeutic herbicide NTBC. Biochemistry 43: 6370-6377.
  • Conrad JA, Moran GR (2008) The interaction of hydroxymandelate synthase with the 4-hydroxyphenylpyruvate dioxygenase inhibitor: NTBC. Inorganica Chim Acta 361: 1197-1201.
  • Ellis MK, Whitfield AC, Gowans LA, Auton TR, Provan WM, Lock EA, Smith LL (1995) Inhibition of 4-hydroxyphenylpyruvate dioxygenase by 2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione and 2-(2-chloro-4-methanesulfonylbenzoyl)-cyclohexane-1,3-dione. Toxicol Appl Pharmacol 133: 12-19.
  • Ellis MK, Whitfield AC, Gowans LA, Auton TR, Provan WM, Lock EA, Lee DL, Smith LL (1996) Characterization of the interaction of 2-[2-nitro-4-(trifluoromethyl) benzoyl]-4,4,6,6-tetramethyl-cyclohexane-1,3,5-trione with rat hepatic 4-hydroxyphenylpyruvate dioxygenase. Chem Res Toxicol 9: 24-27.
  • Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Montgomery Jr. JA, Vreven T, Kudin KN, Burant JC, Millam JM, Iyengar SS, Tomasi J, Barone V, Mennucci B, Cossi M, Scalmani G, Rega N, Petersson GA, Nakatsuji H, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Klene M, Li X, Knox JE, Hratchian HP, Cross JB, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Ayala PY, Morokuma K, Voth GA, Salvador P, Dannenberg JJ, Zakrzewski VG, Dapprich S, Daniels AD, Strain MC, Farkas O, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Ortiz JV, Cui Q, Baboul AG, Clifford S, Cioslowski J, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng CY, Nanayakkara A, Challacombe M, Gill PMW, Johnson B, Chen W, Wong MW, Gonzalez C, Pople JA (2003) Gaussian 03 Revision B.05. Gaussian Inc.: Pittsburgh PA.
  • Fritze IM, Linden L, Freigang J, Auerbach G, Huber R, Steinbacher S (2004) The crystal structures of Zea mays and Arabidopsis 4-hydroxyphenylpyruvate dioxygenase. Plant Physiol 134: 1388-1400.
  • Grompe M (2001) The pathophysiology and treatment of hereditary tyrosinemia type 1. Semin Liver Dis 21: 563-571.
  • Hall MG, Wilks MF, Provan WM, Eksborg S, Lumholtz B (2001) Pharmacokinetics and pharmacodynamics of NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-13-cyclohexanedione) and mesotrione inhibitors of 4-hydroxyphenyl pyruvate dioxygenase (HPPD) following a single dose to healthy male volunteers. Brit J Clin Pharm 52: 169-177.
  • Hausinger RP (2004) Fe(II)/alpha-ketoglutarate-dependent hydroxylases and related enzymes. Crit Rev Biochem Mol Biol 39: 21-68.
  • Kavana M, Moran GR (2003) Interaction of (4-hydroxy­phenyl)pyruvate dioxygenase with the specific inhibitor 2-[2-nitro-4-(trifluoromethyl)benzoyl]-1,3-cyclohexanedione. Biochemistry 42: 10238-10245.
  • Krebs C, Fujimori DG, Walsh CT, Bollinger JM (2007) Non-heme Fe(IV)-oxo intermediates. Acc Chem Res 40: 484-492.
  • Lee DL, Prisbylla MP, Cromartie TH, Dagarin DP, Howard SW, Provan WM, Ellis MK, Fraser T, Mutter LC (1997) The discovery and structural requirements of inhibitors of p-hydroxyphenylpyruvate dioxygenase. Weed Sci 45: 601-609.
  • Lee DL, Knudsen CG, Michaely WJ, Chin HL, Nguyen NH, Carter CG, Cromartie TH, Lake BH, Shribbs JM, Fraser T (1998) The structure-activity relationships of the triketone class of HPPD herbicides. Pestic Sci 54: 377-384.
  • Lock EA, Ellis MK, Gaskin P, Robinson M, Auton TR, Provan WM, Smith LL, Prisbylla MP, Mutter LC, Lee DL (1998) From toxicological problem to therapeutic use: The discovery of the mode of action of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) its toxicology and development as a drug. J Inherit Metab Dis 21: 498-506.
  • Mitchell G, Bartlett DW, Fraser TEM, Hawkes TR, Holt DC, Townson JK, Wichert RA (2001) Mesotrione: a new selective herbicide for use in maize. Pest Manag Sci 57: 120-128.
  • Neidig ML, Kavana M, Moran GR, Solomon EI (2004) CD and MCD studies of the non-heme ferrous active site in (4-hydroxyphenyl)pyruvate dioxygenase: Correlation between oxygen activation in the extradiol and alpha-KG-dependent dioxygenases. J Am Chem Soc 126: 4486-4487.
  • Neidig ML, Decker A, Kavana M, Moran GR, Solomon EI (2005) Spectroscopic and computational studies of NTBC bound to the non-heme iron enzyme (4-hydroxyphenyl)pyruvate dioxygenase: Active site contributions to drug inhibition. Biochem Biophys Res Commun 338: 206-214.
  • Neidig ML, Brown CD, Kavana M, Choroba OW, Spencer JB, Moran GR, Solomon EI (2006a) Spectroscopic and electronic structure studies of the role of active site interactions in the decarboxylation reaction of alpha-keto acid-dependent dioxygenases. J Inorg Biochem 100: 2108-2116.
  • Neidig ML, Decker A, Choroba OW, Huang F, Kavana M, Moran GR, Spencer JB, Solomon EI (2006b) Spectroscopic and electronic structure studies of aromatic electrophilic attack and hydrogen-atom abstraction by non-heme iron enzymes. Proc Natl Acad Sci USA 103: 12966-12973.
  • Pohorecka M, Wawer Z, Filipez M, Sykut-Cegielska J, Pronicka E (2008) Pharmacokinetics of NTBC (nitisinone) following a single dose to 5 children with tyrosinemia type 1. J Inher Metab Dis 31: (Suppl 1) 020P.
  • Prescott AG, Lloyd MD (2000) The iron(II) and 2-oxoacid-dependent dioxygenases and their role in metabolism. Nat Prod Rep 17: 367-383.
  • Russo PA, Mitchell GA, Tanguay RM (2001) Tyrosinemia: A review. Pediatr Dev Pathol 4: 212-221.
  • Serre L, Sailland A, Sy D, Boudec P, Rolland A, Pebay-Peyroula E, Cohen-Addad C (1999) Crystal structure of Pseudomonas fluorescens 4-hydroxyphenylpyruvate dioxygenase: an enzyme involved in the tyrosine degradation pathway. Structure 7: 977-988.
  • Siegbahn PEM, Borowski T (2006) Modeling enzymatic reactions involving transition metals. Acc Chem Res 39: 729-738.
  • Szczeciński P, Gryff-Keller A, Molchanov S (2006) 1H NMR 13C NMR and computational DFT study of the structure of 2-acylcyclohexane-1,3-diones and their alkali metal salts in solution. J Org Chem 71: 4636-4641.
  • Szczeciński P, Lamparska D, Gryff-Keller A, Gradowska W (2008) Identification of 2-[2-nitro-4-(trifluoromethyl) benzoyl]-1,3-cyclohexanedione metabolites in urine of patients suffering from tyrosinemia type I with the use of 1H and 19F NMR spectroscopy. Acta Biochim Pol 55: 749-752.
  • Tanguay RM, Jorquera R, Poudrier J, St'Louis M (1996) Tyrosine and its catabolites: From disease to cancer. Acta Biochim Polon 43: 209-216.
  • Tauer TP, Sherrill CD (2005) Beyond the benzene dimer: An investigation of the additivity of π-π interactions. J Phys Chem A 109: 10475-10478.
  • Yang C, Pflugrath JW, Camper DL, Foster ML, Pernich DJ, Walsh TA (2004) Structural basis for herbicidal inhibitor selectivity revealed by comparison of crystal structures of plant and mammalian 4-hydroxyphenylpyruvate dioxygenases. Biochemistry 43: 10414-10423.
  • Ye XY, Li ZH, Wang WN, Fan KN, Xu W, Hua ZY (2004) The parallel π-π stacking: a model study with MP2 and DFT methods. Chem Phys Lett 397: 56-61.
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