RGD Reference Report - Molecular modeling and metabolic studies of the interaction of catechol-O-methyltransferase and a new nitrocatechol inhibitor. - Rat Genome Database

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Molecular modeling and metabolic studies of the interaction of catechol-O-methyltransferase and a new nitrocatechol inhibitor.

Authors: Palma, PN  Bonifacio, MJ  Loureiro, AI  Wright, LC  Learmonth, DA  Soares-da-Silva, P 
Citation: Palma PN, etal., Drug Metab Dispos 2003 Mar;31(3):250-8.
RGD ID: 1359089
Pubmed: PMID:12584150   (View Abstract at PubMed)

Catechol-O-methyltransferase (COMT, EC plays a central role in the metabolic inactivation of neurotransmitters and neuroactive xenobiotics possessing a catechol motif. 1-(3,4-Dihydroxy-5-nitrophenyl)-2-phenyl-ethanone (BIA 3-202) is a novel nitrocatechol-type inhibitor of COMT, the potential clinical benefit of which is currently being evaluated in the treatment of Parkinson's disease. In the present work we characterize the molecular interactions of BIA 3-202 within the active site of COMT and discuss their implication on the regioselectivity of metabolic O-methylation. Unrestrained flexible-docking simulations suggest that the solution structure of this complex is better described as an ensemble of alternative binding modes, in contrast to the well defined bound configuration revealed by the X-ray structures of related nitrocatechol inhibitors, co-crystallized with COMT. The docking results wherein presented are well supported by experimental evidence, where the pattern of in vitro enzymatic O-methylation and O-demethylation reactions are analyzed. We propose a plausible explanation for the paradoxical in vivo regioselectivity of O-methylation of BIA 3-202, as well as of its related COMT inhibitor tolcapone. Both compounds undergo in vivo O-methylation by COMT at either meta or para catechol hydroxyl groups. However, results herein presented suggest that, in a subsequent step, the p-O-methyl derivatives are selectively demethylated by a microsomal enzyme system. The overall balance is the accumulation of the m-O-methylated metabolites over the para-regioisomers. The implications for the general recognition of nitrocatechol-type inhibitors by COMT and the regioselectivity of their metabolic O-methylation are discussed.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
ComtRatS-adenosylhomocysteine metabolic process  TAS  RGD 
ComtRatS-adenosylmethionine metabolic process  TAS  RGD 

Molecular Function

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
ComtRatcatechol O-methyltransferase activity  IDA  RGD 

Molecular Pathway Annotations    Click to see Annotation Detail View

RGD Manual Annotations

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
COMTHumanhomocysteine metabolic pathway   ISS  RGD 
ComtRathomocysteine metabolic pathway   TAS  RGD 
COMTHumanmethionine cycle/metabolic pathway   ISS  RGD 
ComtRatmethionine cycle/metabolic pathway   TAS  RGD 
Objects Annotated

Genes (Rattus norvegicus)
Comt  (catechol-O-methyltransferase)

Genes (Homo sapiens)
COMT  (catechol-O-methyltransferase)

Additional Information