Home Research | Biotransformation, bioactivation and biocatalysis

The Biotransformation, Bioactivation & Biocatalysis research group

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People involved:
Staff: Jan N.M. Commandeur, Nico P.E. Vermeulen
Postdocs: Jelle Reinen
PhD Students: Sanja Dragovic, Michiel den Braver, Shalenie Sewradj, Marlies Verkade-Vreeker, Stefan Dekker, Yongjie Zhang, Daan Verstappen, Katarzyna Lazarska

 

Research activities:
The aim of the research of the Biotransformation, Bioactivation & Biocatalysis group is to elucidate the molecular mechanisms underlying as yet poorly understood adverse drug reactions (ADR). Is is well-established that drug metabolism and factors interfering with drug metabolism (drug-drug interaction, genetic polymorphism) play an important role in most ADR. In a number of cases, drug toxicity is the result from the formation of highly reactive drug metabolites, which may react to biomacromolecules and thereby interfere with their biological functions. Also, drug metabolites might have potent pharmacologically activity, which may contribute to the drug action, but which may also cause undesired pharmacological side-effects.

The research of the Biotransformation, Bioactivation & Biocatalysis group is focused on the elucidation of the enzymes involved in bioactivation of drugs, identification and characterization of (re)active drug metabolites, identification of cellular targets of reactive metabolites, and elucidation of protective mechanisms against reactive drug metabolites. The main emphasis of the research is on the enzyme systems cytochrome P450, which is involved in the large majority of bioactivation reactions, and glutathione S-transferases, which play an important role in protection against reactive drug metabolites. Both classes of biotransformation enzymes consist of multiple forms ('isoenzymes') with widely different catalytic properties. The activity of some of these isoenzymes are genetically determined. It is investigated whether these genetically determined enzymes are involved in the bioactivation or inactivation of drugs causing rare idiosyncratic drug reactions. This might explain why some individuals are much more susceptible to ADR than others.

Furthermore, the group of Biotransformation, Bioactivation & Biocatalysis develops novel biocatalysts, by genetic modification of the highly active bacterial P450 BM3, for the large-scale production of (re)active drug metabolites

Key publications:
Rea V, Dragovic S, Boerma JS, de Kanter FJ, Vermeulen NP, Commandeur JN.
Role of Residue 87 in the Activity and Regioselectivity of Clozapine Metabolism by Drug-Metabolizing CYP102A1 M11H: Application for Structural Characterization of Clozapine GSH Conjugates.
Drug Metab Dispos. 2011 Dec;39(12):2411-20.

Reinen J, van Leeuwen JS, Li Y, Sun L, Grootenhuis PD, Decker CJ, Saunders J, Vermeulen NP, Commandeur JN.
Efficient screening of cytochrome P450 BM3 mutants for their metabolic activity and diversity toward a wide set of drug-like molecules in chemical space.
Drug Metab Dispos. 2011 Sep;39(9):1568-76

Boerma JS, Vermeulen NP, Commandeur JN.
Application of CYP102A1M11H as a tool for the generation of protein adducts of reactive drug metabolites.
Chem Res Toxicol. 2011 Aug 15;24(8):1263-74.

Reinen J, Kalma LL, Begheijn S, Heus F, Commandeur JN, Vermeulen NP.
Application of cytochrome P450 BM3 mutants as biocatalysts for the profiling of estrogen receptor binding metabolites of the mycotoxin zearalenone.
Xenobiotica. 2011 Jan;41(1):59-70.

Dragovic S, Boerma JS, van Bergen L, Vermeulen NP, Commandeur JN.
Role of human glutathione S-transferases in the inactivation of reactive metabolites of clozapine.
Chem Res Toxicol. 2010 Sep 20;23(9):1467-76.

Vottero E, Rea V, Lastdrager J, Honing M, Vermeulen NP, Commandeur JN.
Role of residue 87 in substrate selectivity and regioselectivity of drug-metabolizing cytochrome P450 CYP102A1 M11.
J Biol Inorg Chem. 2011 Aug;16(6):899-912.

Damsten MC, van Vugt-Lussenburg BM, Zeldenthuis T, de Vlieger JS, Commandeur JN, Vermeulen NP.
Application of drug metabolising mutants of cytochrome P450 BM3 (CYP102A1) as biocatalysts for the generation of reactive metabolites.
Chem Biol Interact. 2008 Jan 10;171(1):96