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.

The 108M polymorph of human catechol O-methyltransferase is prone to deformation at physiological temperatures.

Abstract: The human gene for catechol O-methyltransferase (COMT) contains a common polymorphism that results in substitution of methionine (M) for valine (V) at residue 108 of the soluble form of the protein While the two proteins have similar kinetic properties, 108M COMT loses activity more rapidly than 108V COMT at 37 °C The cosubstrate S-adenosylmethionine (SAM) stabilizes the activity of 108M COMT at 40 °C The 108M allele has been associated with increased risk for breast cancer, obsessive-compulsive disorder, and aggressive and highly antisocial manifestations of schizophrenia In the current work, we have constructed homology models for both human COMT polymorphs and performed molecular dynamics simulations of these models at 25, 37, and 50 °C to explore the structural consequences of the 108V/M polymorphism The simulations indicated that replacing valine with the larger methionine residue led to greater solvent exposure of residue 108 and heightened packing interactions between M108 and helices α2, α4 (

Peripheral and central inhibitors of catechol-O-methyl transferase: effects on liver and brain COMT activity and L-DOPA metabolism

Abstract: Inhibitors of the enzyme catechol-O-methyl transferase (COMT) may be useful adjuncts to L-DOPA in the treatment of Parkinson's disease as they offer the possibility of increasing the availability of the amino acid. It is unknown whether a COMT inhibitor which penetrates the blood-brain barrier is preferable to one restricted to extra-cerebral inhibition. We measured liver and brain COMT activity two hours following administration of two COMT inhibitors: entacapone (ENT), mainly peripherally acting, and dinitrocatechol (DNC), peripheral and central acting. As expected, the full spectrum inhibitor DNC (30 mg/kg) induced a near total inhibition of liver and brain COMT activity. Unexpectedly, however, ENT, at 30 mg/kg, produced the same degree of liverand brain COMT inhibition as DNC; using 10 mg/kg, ENT still inhibited both liver and brain COMT activity by 80%. Only at 2.5 and 5 mg/kg did ENT achieve a differential inhibition of liver (80% inhibition) versus brain (10–30% inhibition) COMT activity. In a second series of experiments, we administered ENT (2.5,10, and 30 mg/kg) and DNC (30 mg/kg) to rats and monitored extracellular striatal dopamine and dopamine metabolite levels with cerebral microdialysis both under basal conditions and following L-DOPA/carbidopa administration. No compound modified basal striatal levels of dopamine. ENT at 30 mg/kg (but not 2.5 or 10 mg), as well as DNC, decreased striatal levels of the methylated dopamine metabolite homovanillic acid (HVA). When L-DOPA/carbidopa was administered, dopamine formation was greatest and HVA formation least in animals pretreated with DNC and 30 mg/kg ENT (but not 2.5 or 10 mg/kg ENT). The finding that ENT at doses relatively specific for peripheral enzyme inhibition did not promote dopamine or inhibit HVA formation is most likely due to the 20% residual liver COMT activity present when the inhibitor was used at less than full doses. Our data indicate that DNC and ENT both inhibit striatal HVA formation and increase dopamine formation from exogenously administered L-DOPA. The dopamine promoting effect of ENT is only present, however, at doses which inhibit central as well as peripheral COMT activity.

Investigating the genetic basis of theory of mind (ToM): the role of catechol-O-methyltransferase (COMT) gene polymorphisms.

Abstract: The ability to deduce other persons' mental states and emotions which has been termed ‘theory of mind (ToM)’ is highly heritable. First molecular genetic studies focused on some dopamine-related genes, while the genetic basis underlying different components of ToM (affective ToM and cognitive ToM) remain unknown. The current study tested 7 candidate polymorphisms (rs4680, rs4633, rs2020917, rs2239393, rs737865, rs174699 and rs59938883) on the catechol-O-methyltransferase (COMT) gene. We investigated how these polymorphisms relate to different components of ToM. 101 adults participated in our study; all were genetically unrelated, non-clinical and healthy Chinese subjects. Different ToM tasks were applied to detect their theory of mind ability. The results showed that the COMT gene rs2020917 and rs737865 SNPs were associated with cognitive ToM performance, while the COMT gene rs5993883 SNP was related to affective ToM, in which a significant gender-genotype interaction was found (p = 0.039). Our results highlighted the contribution of DA-related COMT gene on ToM performance. Moreover, we found out that the different SNP at the same gene relates to the discriminative aspect of ToM. Our research provides some preliminary evidence to the genetic basis of theory of mind which still awaits further studies.

COMT influences on prefrontal and striatal blood oxygenation level-dependent responses during working memory among individuals with schizophrenia, their siblings, and healthy controls

Abstract: Introduction. Recent theories have suggested that corticostriatal interactions may play an important part in mediating working memory demands and may impact clinical symptomology of schizophrenia. These effects are thought to occur through changes in dopamine signalling from the midbrain and via feedback from the frontal cortex. The catechol-O-methyltransferase (COMT) Val158Met polymorphism may prove useful for studying these effects in vivo. Methods. In this study, patients with schizophrenia, their well siblings, and healthy controls were genotyped and scanned using functional magnetic resonance imaging (fMRI) while they performed a working memory task. Results. We found that patients and their siblings, but not controls, who were Val homozygotes displayed greater activity of the DLPFC, striatum, and the cerebellum during the task than respective Met carriers. We also found a relationship between striatal activity and negative symptoms for the Val homozygote group. Conclusions. Our findings support and ...