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Philippe URBAN

Philippe URBAN

Philippe URBAN

CNRS Chargé de Recherche Hors Classe
I2M Team leader

Equipe I2M

Actual position and research subject

Since October 1984, I am a scientist at ISB (Institut des Sciences Biologiques) of the CNRS, and I depend on its Section 20: “Molecular and Structural Biology and Biochemistry”. ISince 2011, I am working at the Toulouse Biotechnology Institute as head of research group i2m (Metabolic and Molecular Engineering).

 

My research interests are cytochromes P450, a superfamily of heme-thiolate monooxygenases that are found in all kingdoms of Nature.  A recent search in the PDB with P450 as a keyword retrieved some 539,610 entries in the UniProtKB TrEMBL database. Since their discovery in the late 1950s, these heme–thiolate proteins have been found in both prokaryotes and eukaryotes with a very few exceptions (less than 10 organisms such as E. coli). Recently, cytochrome P450s have also been spotted in viruses.

My research concerns the enzymology and structural biology of P450s. Identification and functional studies have shown that some P450s are specific to one substrate while others are able to accommodate a vast array of organic molecules. In humans, some P450s are involved in the critical metabolism of drug metabolism and pollutant detoxification. Others are involved in steroid and eicosanoid biosyntheses. In plants, most of the secondary metabolism pathways include one or several cytochrome P450s. Surprisingly, all these numerous P450 enzymes share a very similar 3D fold, and a similar catalytic cycle, though they accepts thousands of substrates very different in size and in nature. This apparent antinomy is appealing to the enzymologist I think I am.

 

Being membrane-bound, eukaryotic P450s are difficult to crystallize. Most of them lack a known experimental 3D structure. The very recent advent of the deep-learning artificial intelligence AlphaFold2 has opened fast access to the 3D structures of all membrane-bound P50s. I am currently working with some poorly documented properties of AlphaFold2_advanced, the latest version of AlphaFold2. The power of this AI tool is appealing to the structural biologist I hope I am.

 

My research concerns also electron transfer properties of flavoenzymes belonging to the family of diflavine reductases that oxidize NADPH and transfers the electrons to FAD then to FMN (bot flavins being on a single polypeptide chain) and from FMN to various protein acceptors, including P450 enzymes. How does the dynamics between the different flavin-containing domains of this flavoenzyme regulate the flow of electron and, hence, its kinetic properties is an interesting question that I try to look at.

Education and Diploma

Others

  • Membre nommé de la Commission Scientifique Spécialisée 1 de l’Inserm pour la mandature 2022-2026.
  • Editeur à Biomolecules.
  • Guest-Editor for a Special issue on: “New Insights in Cytochromes P450” in 2021-2022.
  • Guest-Editor for a Special Issue on: “AlphaFold2 and Structural Biology” in 2022-2023.

List of selected publications

  • P. Urban and D Pompon. Confrontation of AlphaFold2 models with cryo-EM and crystal structures enlightens alternate geometries of the CYP102A1 multidomain protein. bioRxiv (2022) https://doi.org/10.1101/2022.03.21.485149.
  • D. Pompon, B Loouerat, A Bronine, and P. Urban. Yeast expression of animal and plant P450s in optimized redox environments. Methods in Enzymology (1996) 272, 51-64.
  • P. Urban, and F Lederer. Baker’s yeast flavocytochrome b2 A mechanistic study of the dehydrohalogenation reaction. Eur J Biochem (1984) 144, 345-351.
  • P. Urban, G. Truan, and D Pompon. Access channels to the buried active site control substrate specificity in CYP1A P450 enzymes. Biochim Biophys Acta (2015) 1850, 696-707.
  • F Tesson, I Limon-Boulez, P Urban et al. Localization of I2-Imidazoline Binding Sites on Monoamine Oxidases. J Biol Chem (1995) 270, 9856-9861.
  • P Urban, C Mignotte, M Kazmaier, F Delorme, and D Pompon. Cloning, yeast expression, and characterization of the coupling of two distantly related Arabidopsis thaliana NADPH-cytochrome P450 reductases with P450 CYP73A5. J Biol Chem (1997) 272, 19176-19186.
  • G Truan, C Cullin, P Reisdorf, P Urban, and  D Pompon. Enhanced in vivo monooxygenase activities of mammalian P450s in engineered yeast cells producing high levels of NADPH-P450 reductase and human cytochrome b5. Gene (1993) 125, 49-55.
  • P Urban, D Werck-Reichhart et al. Characterization of recombinant plant cinnamate 4‐hydroxylase produced in yeast: Kinetic and spectral properties of the major plant P450 of the phenylpropanoid pathway. Eur J Biochem (1994) 222, 843-850.
  • C Muller, D Pompon, P Urban, and R Morfin. Inter-conversion of 7α-and 7β-hydroxy-dehydroepiandrosterone by the human 11β-hydroxysteroid dehydrogenase type 1. J Steroid Biochem Mol Biol (2006) 99, 215-222.
  • JC Gautier, S Lecoeur, J Cosme, A Perret, P Urban, P Beaune, and D Pompon. Contribution of human cytochrome P450 to benzo[a]pyrene and benzo[a]pyrene-7,8-dihydrodiol metabolism, as predicted from heterologous expression in yeast. Pharmacogenet (1999) 6, 489-499.
  • D Pompon, G Truan, and P Urban. L’ingénierie des cytochromes P450. Biofutur (200) 34-58.
  • P Urban, XO Breakfield, and D Pompon. Expression of membrane-bound flavoenzymes in yeast. Flavins and Flavoproteins (1990) 869-872.
  • F Esteves, P Urban, J Rueff, G Truan, and M Kranendonk. Interaction modes of microsomal cytochrome P450s with its reductase and the role of substrate binding. Int J Mol Sci (2020) 21, e6669.
  • F Esteves, D Campelo, BC Gomes, P Urban et al. The role of the FMN-domain of human cytochrome P450 oxidoreductase in its promiscuous interactions with structurally diverse redox partners. Front Pharmacol (2020) 11, e299.
  • P Urban, G Truan, and D Pompon. High-throughput enzymology and combinatorial mutagenesis for mining cytochrome P450 functions. Exp Opin Drug Metab Toxicol (2008) 4, 733-747.
  • T Lautier, P Urban, J Loeper, L Jezequel, D Pompon, and G Truan. Ordered chimerogenesis applied to CYP2B P450 enzymes. Biochim Biophys Acta (2016) 1860, 1395-1403.
  • S Castaño-Cerezo, M Fournié, P Urban, JL Faulon, and G Truan. Development of a biosensor for detection of benzoic acid derivatives in Saccharomyces cerevisiae. Front Bioeng Biotech (2020) e372.
  • TEM Parente, P Urban, D Pompon, and MF Rebelo. Altered substrate specificity of the Pterygoplichthys sp.(Loricariidae) CYP1A enzyme. Aquat Toxicol (2014) 154, 193-199.
  • KS Shohdy, WA Rashad, MK Fargoun, and P Urban. The morphogen behind primary congenital glaucoma and the dream of targeting. J Morphol Embryol 58, 351-361.
  • D Pompon, JC Gautier, A Perret, G Truan, and P Urban. Simulation of human xenobiotic metabolism in microorganisms: yeast a good compromise between E. coli and human cells. J Hepatol (1997) 26, 81-85.
  • P Urban and F Lederer. Inactivation of flavocytochrome b2 with fluoropyruvate: Reaction at the active‐site histidine. Eur J Biochem (1988) 173, 155-162.

 

 

Google Scholar: Philippe Urban’s all publications

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