Journal ArticleDOI
Diverse facets of COMT: from a plausible predictive marker to a potential drug target for schizophrenia.
Meenal Gupta,Harpreet Kaur,Ajay Jajodia,Sanjeev Jain,Kapaettu Satyamoorthy,Mitali Mukerji,J. Thirthalli,R. Kukreti +7 more
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TLDR
The rapidly evolving literature exploring the diverse facets of COMT biology, its functional relevance as a predictive marker and a therapeutic target for schizophrenia are summarized.Abstract:
Dopaminergic system in the prefrontal cortex (PFC) is known to regulate the cognitive functions. Catechol-O-methyl transferase (COMT), one of the major modulators of prefrontal dopamine function, has emerged as an important determinant of schizophrenia associated cognitive dysfunction and response to antipsychotics. A common Val->Met polymorphism (rs4680) in the COMT gene, associated with increased prefrontal dopamine catabolism, impairs prefrontal cognition and might increase risk for schizophrenia. Further, the degree of cognitive improvement observed with antipsychotics in schizophrenia patients is influenced by the COMT activity, and Val/Met has been proposed as a potential pharmacogenetic marker. However, studies evaluating the role of COMT have been equivocal. The presence of other functional polymorphisms in the gene, and the observed ethnic variations in the linkage disequilibrium structure at COMT locus, suggest that COMT activity regulation might be complex. Despite these lacunae in our current understanding, the influence of COMT on PFC mediated cognitive tasks is undeniable. COMT thus represents an attractive candidate for novel therapeutic interventions for cognitive dysfunction. The COMT activity inhibiting drugs including tolcapone and entacapone, have shown promising potential as they selectively modulate dopaminergic transmission. This review is an attempt to summarize the rapidly evolving literature exploring the diverse facets of COMT biology, its functional relevance as a predictive marker and a therapeutic target for schizophrenia.read more
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A systematic review comparing sex differences in cognitive function in schizophrenia and in rodent models for schizophrenia, implications for improved therapeutic strategies
Marianne Leger,Joanna C. Neill +1 more
TL;DR: Overall, this review provides evidence of good translation from the animal models into the clinic when sexual dimorphism is assessed, and highlights a male working memory advantage and a female advantage for visual memory and social cognition in rodent models for schizophrenia.
Journal Article
Distribution of genetic polymorphisms of genes encoding drug metabolizing enzymes & drug transporters - a review with Indian perspective.
TL;DR: This review was intended to compile the normative frequency distribution of the variants of genes encoding DMEs and transporter proteins (CYP450s, TPMT, GSTs, COMT, SULT1A1, NAT2 and UGTs) with Indian perspective.
Journal ArticleDOI
Catechol-O-Methyltransferase Val158Met Polymorphism and Clinical Response to Antipsychotic Treatment in Schizophrenia and Schizo-Affective Disorder Patients: a Meta-Analysis
Eric Huang,Clement C. Zai,Amanda Lisoway,Malgorzata Maciukiewicz,Daniel Felsky,Arun K. Tiwari,Jeffrey R. Bishop,Masashi Ikeda,Patricio Molero,Felipe Ortuño,Stefano Porcelli,Jerzy Samochowiec,Paweł Mierzejewski,Shugui Gao,Benedicto Crespo-Facorro,José María Pelayo-Terán,Harpreet Kaur,Ritushree Kukreti,Herbert Y. Meltzer,Jeffrey A. Lieberman,Steven G. Potkin,Daniel J. Müller,James L. Kennedy +22 more
TL;DR: The findings suggest that the COMT Val158Met polymorphism is associated with response to antipsychotics in schizophrenia and schizo-affective disorder patients, and this effect may be more pronounced for atypical antippsychotics.
Journal ArticleDOI
Drug development in schizophrenia: are glutamatergic targets still worth aiming at?
TL;DR: Targeting glutamatergic transmission remains one of the most promising strategies in schizophrenia, particularly early in the course of illness, but therapeutic approaches may require greater specificity for receptor subtype type, illness phase, and individual biology in order to enhance efficacy and overcome problems with reproducibility of clinical results.
Journal ArticleDOI
Mapping the conformational space accessible to catechol-O-methyltransferase.
TL;DR: Crystal structures of mouse, rat and human catechol-O-methyltransferase were determined in apo, semi-holo, holo and Michaelis forms under a variety of conditions, testifying to why this enzyme is a difficult drug target.
References
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Journal ArticleDOI
Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia.
Michael F. Egan,Terry E. Goldberg,Bhaskar Kolachana,Joseph H. Callicott,C.M. Mazzanti,Richard E. Straub,David Goldman,Daniel R. Weinberger +7 more
TL;DR: The data suggest that the COMT Val allele, because it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology, and by this mechanism slightly increases risk for schizophrenia.
Journal ArticleDOI
Functional Analysis of Genetic Variation in Catechol-O-Methyltransferase (COMT): Effects on mRNA, Protein, and Enzyme Activity in Postmortem Human Brain
Jingshan Chen,Barbara K. Lipska,Nader D. Halim,Quang D. Ma,Mitsuyuki Matsumoto,Samer Melhem,Bhaskar Kolachana,Thomas M. Hyde,Mary M. Herman,Jose A. Apud,Michael F. Egan,Joel E. Kleinman,Daniel R. Weinberger +12 more
TL;DR: Val is a predominant factor that determines higher COMT activity in the prefrontal cortex, which presumably leads to lower synaptic dopamine levels and relatively deleterious prefrontal function.
Journal ArticleDOI
Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme.
Timo Lotta,Jukka Vidgren,Carola Tilgmann,I. Ulmanen,Krister Melén,Ilkka Julkunen,Jyrki Taskinen +6 more
TL;DR: Comparison of velocity parameters, substrate selectivity, and regioselectivity of the methylation of both enzyme forms, and a revised mechanism for the reaction cycle are discussed.
Journal ArticleDOI
Does Fast Dissociation From the Dopamine D2 Receptor Explain the Action of Atypical Antipsychotics?: A New Hypothesis
Shitij Kapur,Philip Seeman +1 more
TL;DR: It is predicted that the atypical antipsychotic effect can be produced by appropriate modulation of the D(2) receptor alone; the blockade of other receptors is neither necessary nor sufficient.
Journal Article
Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors.
Pekka T. Männistö,Seppo Kaakkola +1 more
TL;DR: The enzyme responsible for the O- methylation, catechol- O -methyltransferase (COMT) was partly purified and characterized by the same group as EC, which first described the enzyme-catalyzed O-methylation of catechlamines and other catechols in the late 1950s.
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