Metabolism, Pharmacochemistry and Neurochemistry
A. Cabaye, Ph.D.
N. Cristiano, Ph.D.
H. Xiong, Ph.D.
The team MPN team is a multidisciplinary team composed of chemists and biochemists . Our current research projects are the following :
1. TRP metabolism (PIs: M-A Sari and J Dairou)
This is a joint project that will benefit from the expertise of the participants in the fields of P450 and the metabolism of endogenous and exogenous compounds, the P450-AhR relations ship and the regulation of CNS receptors such as mGluRs; It concerns the nature and biological activities of the metabolites formed from the compounds of the Kynurenine Pathway. This new research project of the new group indicated above will be developed in the 2019-2024 period. Very preliminary experiments have been started quite recently. This new project will benefit from the expertise of the participants in the fields of cytochromes P450 and the metabolism of endogenous and exogenous compounds, the P450-AhR relationships, and the regulation of various central nervous system (CNS) receptors such as the mGluR receptors. It concerns the “Nature and Biological Activities of the Metabolites Possibly Formed from the Compounds of the Kynurenine Pathway”. An increasing number of data have been published during these last few years to show that several metabolites issued from the catabolism of tryptophan (the “kynurenine” pathway) exhibit remarkable activities towards various receptors involved in the CNS and the immune system. This is true for kynurenine, xanthurenic acid, kynurenic acid, and cinnabarinic acid. Thus, this last compound was recently found as a good ligand of AhR and of several subtype4 mGluRs. However, the possible metabolism of these kynurenine derivatives by the P450-dependent monooxygenases has not been evaluated so far.
2. DJ-1-Park7 (PI J Dairou)
Recently, we showed that DJ-1/Park7, whose deficiency results in early onset parkinsonism, repairs guanines, both in the nucleotide pool and DNA, from their covalent contamination by glyoxals (R-CO-CHO), which are harmful by-products derived from glucose metabolism. The covalent addition of glyoxals to guanine is referred to as guanine glycation, and constitutes the major glycation assault to DNA. Unless repaired by DJ-1/Park7, the covalent reaction between glyoxals and guanine is responsible for mutations, DNA strand breaks and tumorigenesis. Moreover, like enzymes involved in guanine oxidation repair, DJ-1 may constitute a target for novel anti-cancer agents.
The study of the Parkinsonism-associated DJ-1/PARK7 will be continued and more precisely DJ-1 catalytic regulation by pesticides. Epidemiological studies also demonstrate a causal link between pesticides exposure and Parkinson’s disease. The aim of the project is the study of the effects of pesticides on DJ-1 activity in order to determine if DJ-1 is implicated in the link between pesticides and Parkinson’s disease. A second research axis concerns the identification of specific DJ-1/Park7 inhibitors that might function as novel anti-cancer agents (our discovery that DJ-1 is DNA and protein repair enzyme suggests that DJ-1 inhibitors could be anticancer agents). Increase of DJ-1 has been described in several types of cancers; however the mechanistic basis is still unclear. We suggest that increased DJ-1 expression may result from the increased aerobic glycolysis of cancer cells, necessary to meet the metabolic requirements of cell proliferation. In this context, we believed that DJ-1 could be a new target for anticancer drug development.
3. Medicinal Chemistry for the Modulation of Synaptic Transmission (PI F Acher)
The group is focused on small molecules that target receptors and transporters of synaptic transmission and their mechanisms. Using synthetic organic chemistry and molecular modeling, we develop pharmacological and therapeutic tools and investigate receptor activation and neurotransmitter transport. The team is involved in various projects from the initial design (molecules, 3D models…) all along to the in vivo studies.
For further detail on F Acher’s research Group
4. Orphan CYP (PIs: JL Boucher and D Mansuy)
Cytochrome P450 2U1 (CYP2U1) has been identified from the human genome and is highly conserved in the living kingdom. In humans, it has been found to be predominantly expressed in the thymus and brain. It is considered as an orphan enzyme as few data are available on its physiological function(s) and active site topology (our review article of 2017). Its only substrates reported so far were unsaturated fatty acids such as arachidonic acid (AA), and, more recently, N-arachidonoyl-serotonin (AS). Several mutations of CYP2U1 have been observed in a neurological disease, Hereditary Spastic Paraplegia (HSP) (Am. J. Hum., Genet, 2012, 91, 1051). Our objectives were to develop CYP2U1 over-expression systems to perform structural and functional studies of CYP2U1(discovery of inhibitors and specific substrates).
- Richarme G, Abdallah J, Mathas N, Gautier V, Dairou J. Further characterization of the Maillard deglycase DJ-1 and its prokaryotic homologs, deglycase 1/Hsp31, deglycase 2/YhbO, and deglycase 3/YajL. Biochem Biophys Res Commun. 2018 Jun 22. pii: S0006-291X(18)31376-7. doi: 10.1016/j.bbrc.2018.06.064.
- Richarme G, Liu C, Mihoub M, Abdallah J, Leger T, Joly N, Liebart JC, Jurkunas UV, Nadal M, Bouloc P, Dairou J, Lamouri A. Guanine glycation repair by DJ-1/Park7 and its bacterial homologs. Science. 2017 Jun 8. pii: eaag1095. doi: 10.1126/science.aag1095
- Dhers L, Pietrancosta N, Ducassou LM, Ramassamy B, Dairou J, Jaouen M, André F, Mansuy D, Boucher JL. Spectral and 3D model studies of the interaction of orphan human cytochrome P450 2U1 with substrates and ligands. Biochim Biophys Acta. 2017, 1861(1 Pt A): 3144-3153.
- Selvam C, Lemasson IA, Brabet I, Oueslati N, Karaman B, Cabaye A, Tora AS, Commare B, Courtiol T, Cesarini S, McCort-Tranchepain I, Rigault D, Mony L, Bessiron T, McLean H, Leroux FR, Colobert F, Daniel H, Goupil-Lamy A, Bertrand HO, Goudet C, Pin JP, Acher FC. Increased Potency and Selectivity for Group III Metabotropic Glutamate Receptor Agonists Binding at Dual sites. J Med Chem. 2018, 61(5): 1969-1989
Metabolism, Pharmacochemistry and Neurochemistry
K. Nouri Jradi