O-Methylation of Epinephrine and Other Catechols
            <i>in vitro</i>
            and
            <i>in vivo</i>

Axelrod, Julius

doi:10.1126/science.126.3270.400

Cited by 574 publications

(352 citation statements)

References 9 publications

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“…In the presence of AdoMet and magnesium, COMT inactivates biologically active catechols through O-methylation [33]. COMT has a range of catechol substrates, including dopamine, norepinephrine, 3-(3,4-dihydroxyphenyl)-L-alanine (L-DOPA), and catecholic steroids [33][34][35][36].…”

Section: Fp Assay Validation Using the Comt Enzyme And Inhibitor Withmentioning

confidence: 99%

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A universal competitive fluorescence polarization activity assay for S-adenosylmethionine utilizing methyltransferases

Graves

Zhang

Scott

2008

Analytical Biochemistry

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A high-throughput, competitive fluorescence polarization immunoassay has been developed for the detection of methyltransferase activity. The assay was designed to detect Sadenosylhomocysteine (AdoHcy), a product of all S-adenosylmethionine (AdoMet)-utilizing methyltransferase reactions. We employed commercially available anti-AdoHcy antibody and fluorescein-AdoHcy conjugate tracer to measure AdoHcy generated as a result of methyltransferase activity. AdoHcy competes with tracer in the antibody/tracer complex. The release of tracer results in a decrease in fluorescence polarization. Under optimized conditions, AdoHcy and AdoMet titrations demonstrated that the antibody had more than a 150-fold preference for binding AdoHcy relative to AdoMet. Mock methyltransferase reactions using both AdoHcy and AdoMet indicated that the assay tolerated 1 to 3 μM AdoMet. The limit of detection was approximately 5 nM (0.15 pmol) AdoHcy in the presence of 3 μM AdoMet. To validate the assay's ability to quantitate methyltransferase activity, the methyltransferase catechol-Omethyltransferase (COMT) and a known selective inhibitor of COMT activity were used in proofof-principle experiments. A time-and enzyme concentration-dependent decrease in fluorescence polarization was observed in the COMT assay that was developed. The IC 50 value obtained using a selective COMT inhibitor was consistent with previously published data. Thus, this sensitive and homogeneous assay is amenable for screening compounds for inhibitors of methyltransferase activity. KeywordsFluorescence polarization; Methyltransferase; S-Adenosylhomocysteine; S-Adenosylmethionine; Catechol-O-methyltransferase Methyltransferases are a diverse class of enzymes that catalyze the transfer of a single methyl group from a methyl donor molecule to a methyl acceptor. The vast majority use Sadenosylmethionine (AdoMet) 1 as the methyl donor [1,2]. AdoMet is the second most HHMI Author Manuscript HHMI Author Manuscript HHMI Author Manuscriptwidely used substrate molecule in the cell after ATP. Methylation is an essential and highly choreographed regulatory metabolic process. Small organic molecules and peptides and most types of cellular macromolecules, including DNA, RNA, protein, and lipids, can serve as substrates for methylation (for detailed reviews, see Refs. [2][3][4][5][6][7]).A rapidly growing area of methyltransferase research focuses on methylation of histone tails by histone methyltransferases (HMTs) (for reviews, see Refs. [8,9]). Histone methylation is an epigenetic modification that has a role in formation of heterochromatin, X chromosome inactivation, and modification of gene expression patterns. Histone methylation occurs on arginine and lysine residues and is catalyzed by methyltransferases belonging to three distinct families of proteins: the protein arginine N-methyltransferase 1 (PRMT1) family, the SET-domain-containing protein family, and the non-SET-domain proteins DOT1/DOT1L. This histone methylation alters chromatin structure and, thus, regulates...

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Section: Fp Assay Validation Using the Comt Enzyme And Inhibitor Withmentioning

confidence: 99%

“…COMT has a range of catechol substrates, including dopamine, norepinephrine, 3-(3,4-dihydroxyphenyl)-L-alanine (L-DOPA), and catecholic steroids [33][34][35][36]. There are also several catechol-like and non-catechollike inhibitors of COMT activity [37][38][39].…”

Section: Fp Assay Validation Using the Comt Enzyme And Inhibitor Withmentioning

confidence: 99%

A universal competitive fluorescence polarization activity assay for S-adenosylmethionine utilizing methyltransferases

Graves

Zhang

Scott

2008

Analytical Biochemistry

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“…1 The catechol-O-methyltransferase (COMT; MIM 116790) gene, which is located in the 22q11 microdeletion, has been considered as a candidate gene for schizophrenia because of its function of degrading catecholamines including dopamine. 2 The Val158Met functional polymorphism among the COMT polymorphisms leads to a fourfold reduction in enzyme activity, 3,4 and this variation of enzyme activity presumably affects the risk of schizophrenia. The associations between cognition in 22q11 deletion syndrome and COMT polymorphisms have been scrutinized in several studies, but the results have not been consistent and are as yet controversial.…”

Section: Introductionmentioning

confidence: 99%

Association analysis of COMT polymorphisms with schizophrenia and smooth pursuit eye movement abnormality

et al. 2009

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Schizophrenia is a multifactorial disorder characterized by the contribution of multiple susceptibility genes that may act in conjunction with epigenetic processes and environmental factors. The catechol-O-methyltransferase (COMT) gene, which is located in the 22q11 microdeletion, has been considered as a candidate gene for schizophrenia because of its ability to degrade catecholamines, including dopamine. In a genetic analysis, neurophysiological endophenotype in schizophrenia, such as smooth pursuit eye movement (SPEM) disturbance, is considered to be a good trait marker, because it may be under more direct genetic control. This study was performed to examine the genetic association of COMT polymorphisms with the risk of schizophrenia and SPEM abnormality in a Korean population. Six single-nucleotide polymorphisms of COMT were genotyped by TaqMan assay. Their genetic effects on the risk of schizophrenia were analyzed in 354 patients and 396 controls using v 2 analyses. Among the schizophrenic patients, 166 subjects were selected for association analyses of COMT polymorphisms with SPEM abnormality. From the six COMT polymorphisms, rs6267 showed an association with the reduced risk of schizophrenia after correction (P corr ¼ 0.02). In analysis of SPEM abnormality, no significant associations were detected with COMT polymorphisms. The results of the present study provide the evidence that in a Korean population, COMT on the 22q11 locus is likely involved in the development of schizophrenia, but not in the SPEM function abnormality.

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“…Nevertheless the COMT gene has been very consistently associated with panic disorder. COMT is an enzyme inactivating catecholamines, including adrenaline, noradrenaline and dopamine (Axelrod and Tomchick, 1958). The COMT gene is located on chromosome 22q11.2.…”

Section: Introductionmentioning

confidence: 99%

Association of the Val158Met Catechol O-Methyltransferase Genetic Polymorphism with Panic Disorder

Rothe

Koszycki

Bradwejn

et al. 2006

Neuropsychopharmacol

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Genetic as well as clinical data suggest that catechol O-methyltransferase (COMT) is involved in multiple complex psychiatric conditions. Recent studies have described an association between the Val158Met COMT polymorphism and panic disorder. Other recent investigations provide evidence that there are other loci within or nearby the COMT gene that may contribute to the susceptibility to panic disorder. To further evaluate the influence of the Val158Met COMT polymorphism in panic disorder we genotyped this marker in the coding region of the COMT gene and two additional variants (rs737865 and rs165599) in the 5 0 and the 3 0 region, respectively, in two independent Canadian samples: 121 nuclear families, and 89 cases with matched controls. In the nuclear families, significant transmission disequilibrium for the valine allele was observed between the alleles of the Val158Met COMT polymorphism and panic disorder (po0.01). A significant excess of the valine allele was found in analysis of the case-control sample (po0.01). This effect was mainly derived from the subgroup of females. This finding, including the female effect, replicates earlier results in studies of the Val158Met polymorphism in panic disorder. No significant results were found for the other two markers. These results support the hypothesis that the valine allele of the Val158Met COMT polymorphism or a nearby locus is involved in the etiopathogenesis of panic disorder.

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O-Methylation of Epinephrine and Other Catechols in vitro and in vivo

Cited by 574 publications

References 9 publications

A universal competitive fluorescence polarization activity assay for S-adenosylmethionine utilizing methyltransferases

A universal competitive fluorescence polarization activity assay for S-adenosylmethionine utilizing methyltransferases

Association analysis of COMT polymorphisms with schizophrenia and smooth pursuit eye movement abnormality

Association of the Val158Met Catechol O-Methyltransferase Genetic Polymorphism with Panic Disorder

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