Topic
Catechol-O-methyl transferase
About: Catechol-O-methyl transferase is a research topic. Over the lifetime, 1646 publications have been published within this topic receiving 87360 citations.
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TL;DR: Allele and genotype frequencies were similar in the affected and control subjects, indicating that variation of COMT activity is not an aetiological factor in IPD, but it remains possible that allelic variation in COMT influences severity, type of pathology or treatment response to levodopa or COMT inhibitors.
89 citations
Journal Article•
TL;DR: It is suggested that the reduced frequency of the met allele in the non-affected relatives of FM patients acts as a 'protective' allele in this group and prevents the development of clinical FM.
Abstract: Objectives. Fibromyalgia syndrome (FM) is an idiopathic chronic pain syndrome characterised by widespread nonarticular musculoskeletal pain, generalised tender points, in the absence of inflammatory or structural musculoskeletal abnormalities, accompanied by a constellation of symptoms that include fatigue and disturbances of sleep and mood. Catechol-O-methyltransferase (COMT) is the major catecholamine-clearing pathway and involved in the mediation of pain perception in humans, and the hypothesized role of pain perception in FM. The association between Val/Met polymorphism at the COMT gene was evaluated in FM disorder. Methods. 209 FM female patients were compared with 152 of their non-affected relatives. DNA was obtained from all family members and extracted. We used the logistic based variant of the transmission disequilibrium test to assess association (and linkage) without confounding effect of population stratification. Results. We observed an association between FM and the COMT val 158 met polymorphism in a dose response effect of the COMT genotype and the number of pressure points reported. We also observed that non-affected relatives of FM patients had a reduced percentage of the COMT met allele. Conclusions. Our results are consistent with carriers of the COMT met/met genotype showing increased sensitivity to pain as one mechanism for the role of this gene in conferring risk for FM. We suggest that the reduced frequency of the met allele in the non-affected relatives acts as a 'protective' allele in this group and prevents the development of clinical FM.
89 citations
TL;DR: Analysis of the topological characteristics of the default network showed homozygous val individuals had significantly fewer node degrees in the prefrontal regions, which may partially elucidate previous reports that the COMT val variant is associated with inefficient prefrontal information processing and poor cognitive performance.
Abstract: Previous studies have supported the concept that the default network is an intrinsic brain system that participates in internal modes of cognition. Neural activity and connectivity within the default network, which are correlated with cognitive ability even at rest, may be plausible intermediate phenotypes that will enable us to understand the genetic mechanisms of individuals' cognitive function or the risk for genetic brain diseases. Using resting functional magnetic resonance imaging and imaging genetic paradigms, we investigated whether individual default network connectivity was modulated by COMT val(158)met in 57 healthy young subjects. Compared with COMT heterozygous individuals, homozygous val individuals showed significantly decreased prefrontal-related connectivities, which primarily occurred between prefrontal regions and the posterior cingulate/restrosplenial cortices. Further analyses of the topological characteristics of the default network showed homozygous val individuals had significantly fewer node degrees in the prefrontal regions. This finding may partially elucidate previous reports that the COMT val variant is associated with inefficient prefrontal information processing and poor cognitive performance. Our findings suggest that default network connectivity that involves the prefrontal cortex is modulated by COMT val(158)met through differential effects on prefrontal dopamine levels.
89 citations
Bial1
TL;DR: This is the first report of a three-dimensional structure determination of COMT complexed with a potent, reversible, and tight-binding inhibitor that is expected to have therapeutic applications.
Abstract: Catechol- O -methyltransferase (COMT; E.C. 2.1.1.6) is a ubiquitous enzyme in nature that plays an important role in the metabolism of catechol neurotransmitters and xenobiotics. In particular, inactivation of drugs such asl-3,4-dihydroxyphenylalanine (l-DOPA) via O -methylation is of relevant pharmacological importance, because l-DOPA is currently the most effective drug used in the treatment of Parkinson's disease. This justified the interest in developing COMT inhibitors as potential adjuncts to l-DOPA therapy. The kinetics of inhibition by BIA 3-335 (1-[3,4-dihydroxy-5-nitrophenyl]-3-( N -3′-trifluormethylphenyl)-piperazine-1-propanone dihydrochloride) were characterized using recombinant rat soluble COMT. BIA 3-335 was found to act as a potent, reversible, tight-binding inhibitor of COMT with a K i of 6.0 ± 1.6 nM and displaying a competitive inhibition toward the substrate binding site and uncompetitive inhibition toward the S -adenosyl-l-methionine (SAM) binding site. The 2.0-A resolution crystal structure of COMT in complex with its cosubstrate SAM and a novel inhibitor BIA 3-335 shows the atomic interactions between the important residues at the active site and the inhibitor. This is the first report of a three-dimensional structure determination of COMT complexed with a potent, reversible, and tight-binding inhibitor that is expected to have therapeutic applications.
88 citations
TL;DR: A significant effect of gender on brain activations in the left amygdala and right temporal pole is found, where females demonstrated increased activations over males, particularly in females.
Abstract: The functional catechol- O -methyltransferase (COMT Val108/158Met) polymorphism has been shown to have an impact on tasks of executive function, memory and attention and recently, tasks with an affective component. As oestrogen reduces COMT activity, we focused on the interaction between gender and COMT genotype on brain activations during an affective processing task. We used functional MRI (fMRI) to record brain activations from 74 healthy subjects who engaged in a facial affect recognition task; subjects viewed and identified fearful compared to neutral faces. There was no main effect of the COMT polymorphism, gender or genotype×gender interaction on task performance. We found a significant effect of gender on brain activations in the left amygdala and right temporal pole, where females demonstrated increased activations over males. Within these regions, Val/Val carriers showed greater signal magnitude compared to Met/Met carriers, particularly in females. The COMT Val108/158Met polymorphism impacts on gender-related patterns of activation in limbic and paralimbic regions but the functional significance of any oestrogen-related COMT inhibition appears modest.
87 citations