• Title, Summary, Keyword: COMT

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Comparative Homology Modeling and Ligand Docking Study of Human Catechol-O-Methyltransferase for Antiparkinson Drug Design

  • Lee, Jee-Young;Kim, Yang-Mee
    • Bulletin of the Korean Chemical Society
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    • v.26 no.11
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    • pp.1695-1700
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    • 2005
  • Catechol-O-methyltransferase (COMT, EC 2.1.1.6) is an S-adenosylmethionine (SAM, AdoMet) dependent methyltransferase, and is related to the functions of the neurotransmitters in various mental processes, such as Parkinson’s disease. COMT inhibitors represent a new class of antiparkinson drugs, when they are coadministered with levodopa. Based on x-ray structure of rat COMT (rCOMT), the three dimensional structure of human COMT (hCOMT) was constructed by comparative homology modeling using MODELLER. The catalytic site of these two proteins showed subtle differences, but these differences are important to determine the characterization of COMT inhibitor. Ligand docking study is carried out for complex of hCOMT and COMT inhibitors using AutoDock. Among fifteen inhibitors chosen from world patent, nine models were energetically favorable. The average value of heavy atomic RMSD was 1.5 $\AA$. Analysis of ligand-protein binding model implies that Arg201 on hCOMT plays important roles in the interactions with COMT inhibitors. This study may give insight to develop new ways of antiparkinson drug.

An Association Study of COMT Gene Polymorphism with Korean Alcoholism (한국인 알코올리즘과 Catechol-O-methyltransferase(COMT) 유전자 다형성의 연합)

  • Kim, Min-Jung;Yang, Byung-Hwan;Lee, Jung-Sik;Chai, Young-Gyu;Park, Taek-Kyu
    • Korean Journal of Biological Psychiatry
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    • v.8 no.1
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    • pp.111-115
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    • 2001
  • An association study with Korean alcoholic patients(n=50) and normal controls(n=53) was performed to find the relationship between catechol-O-methyltransferase(COMT) gene polymorphism and alcoholism using polymerase chain reaction-restriction fragment length polymorphism. When we compared the allele and genotype frequencies of Nla III COMT gene polymorphism in alcoholism and normal controls, there was no significant difference between two groups. Our results do not support an association between the Nla III polymorphism of COMT gene and alcoholism.

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Effects of Bupleuri Radix on Rat Hepatic COMT by Common Bile Duct Ligation and Taurocholate Load after Common Bile Duct Ligation (시호가 총담관결찰 및 Taurocholate 부하 흰쥐 간의 COMT 활성에 미치는 영향)

  • 김승모;윤주현;박재현
    • The Journal of Korean Medicine
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    • v.21 no.3
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    • pp.68-76
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    • 2000
  • Object : This study was earned out to examine the effect of Bupleuri Radix on experimental cholestasis, and make clear a part of this mechanism. Methods : Two models of common bile duct ligation group and taurocholate load group after common bile duct ligation were induced, and Bupleuri Radix extract was taken orally for 14 days. In the 1, 2, 4, 7 and l4days after treatment, cytosolic, mitochondrial and microsomal catechol-O-methyltransferase(COMT) activities in liver were measured. Results : The activities of cytosolic, mitochondrial and microsomal COMT increased in the Blupleuri Radix treated group after common bile duct ligation and after taurocholate load and common bile duct ligation. The activities of cytosolic and mitochondrial COMT increased particularly in Blupleuri Radix treated group after taurocholate load and common bile duct ligation. Conclusions : According to the result, it is considered that Blupleuri Radix not only improves cholestatis in liver, but also decreases a genetic synthesis of taurocholic acid.

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Effects of Intravenous Administration of Taurocholate on Hepatic Catechol-O-Methyltransferase Activity in Common Bile Duct Ligated Rats

  • Do Jun-Young;Kwak Chun-Sik
    • Biomedical Science Letters
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    • v.11 no.4
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    • pp.473-479
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    • 2005
  • Possible mechanism of decreased catechol-O-methyltransferase (COMT) activity in cholestatic rat liver was studied. Hepatic and serum COMT activities were determined from the experimental rats with common bile duct ligation (CBDL). The Michaelis-Menten constants in this hepatic enzyme were also measured. The activities of cytosolic, mitochondrial and mircosomal COMT as well as their Vmax values were found to be decreased significantly in CBDL plus taurocholic acid (TCA) injected group than in the control group, such as CBDL alone groups. However, their Km values in the experimental groups did not vary. Serum COMT activity increased slightly in the CBDL plus TCA injected group than in the control group. The above results suggest that TCA represses biosynthesis of the COMT in the liver. The elevated activity of the serum COMT is believed to be caused by the increment of membrane permeability of hepatocytes upon TCA mediated liver cell necrosis.

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Association of the COMT Gene Polymorphism with the Risk of Endometriosis in Korean Women (한국여성에서 자궁내막증의 발생위험도와 Catechol-O-Methyltransferase 유전자 다형성과의 관련성에 관한 연구)

  • Lee, Sa-Ra;Lee, So-Hyun;Lee, Woon-Jeong;Hur, Sung-Eun;Lee, Ji-Young;Moon, Hye-Sung;Chung, Hye-Won
    • Clinical and Experimental Reproductive Medicine
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    • v.31 no.1
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    • pp.51-57
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    • 2004
  • Objective: To investigate whether polymorphism of gene encoding COMT is associated with the risk of endometriosis in Korean women. Methods: We investigated 136 patients with histopathologically confirmed endometriosis rAFS stage III/IV and 251 control group women who were surgically proven to have no endometriosis. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) of PCR products were done to determine each participant's COMT genotype. Results: The distribution according to NIaIII genetic polymorphisms of COMT were as follows. $COMT^{HH}$, $COMT^{HL}$, and $COMT^{LL}$ genotypes were 56.6% (77 women), 34.6% (47 women) and 8.8% (12 women) in the study group and 50.6% (127 women), 39.4% (99 women) and 10.0% (25 women) in the control group. There was no significant difference between the study group and the control group. Conclusion: The results suggest that COMT genetic polymorphism may not be associated with the development of endometriosis in Korean women.

Determination of Peripheral Catechol O-methyltransferase (COMT) Activity in vivo using $[2-^{14}C]-3',4'-Dihydroxyacetophenone$

  • Kim, Eun-Joo;Ahn, Jong-Woong;Lee, Hye-Suk;Christ, Wolfram
    • Archives of Pharmacal Research
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    • v.14 no.4
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    • pp.290-294
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    • 1991
  • For the determination of peripheral COMT activity, we synthesized $[2-^{14}C]-3',4'-dihydroxyacetophenone([^{14}C]-DHAP)$, a model substrate closely related to catecholamines, which cannot be attacked by monoamine oxidase. After i.v.-injection of $[^{14}C]-DHAP$ in living animals, only 3',4'-dihydroxy-acetophenone (3',4'-DHAP) and 3'-methoxy-4'-hydroxyacetophenone (3'-MHAP) were detected in blood by thin layer radio chromatography. It could be speculated that 3',4'-DHAP was primarily O-methylated by COMT, followed by subsequent conjugations. The concentration of 3',4'-DHAP, a substrate for COMT, in blood at 5 min after injection of $[^{14}C]-DHAP$, were similar in all animals. The rate of 3'-MHAP formation can be therefore used as an indicator for peripheral COMT activity. The velocity of methylation in 15 min after i.v.-administration of $[^{14}C]-DHAP$ was $0.28\;{\mu}g/ml{\cdot}min$. From these results, 3',4'-DHAP was shown to be used as an appropriate substrate to determine the COMT activity in vivo.

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Association between COMT and 5-HTTLPR Polymorphisms in Korean Patients with Panic Disorder : A Replication Study (한국 공황장애 환자에서 COMT 및 5-HTTLPR 다형성의 연관 분석 : 재현 연구)

  • Kim, Se-Woong;Choi, Tai Kiu;Lee, Sang-Hyuk
    • Korean Journal of Biological Psychiatry
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    • v.23 no.4
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    • pp.166-172
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    • 2016
  • Objectives We investigated whether the catechol-O-methyltransferase (COMT) and serotonin related gene polymorphisms may be associated with agoraphobia in patients with panic disorder in Korea. Methods The COMT gene (rs4680), 5-hydroxytryptamine (serotonin) transporter linked polymorphic region (5-HTTLPR) gene (rs25531), serotonin receptor 1A (HTR1A) gene (rs6295) genotypes were analyzed in 406 patients with panic disorder and age-sex matched 206 healthy controls. Patients with panic disorder were dichotomized by the presence of agoraphobia. The following instruments were applied : the Beck Depression Inventory, the Beck Anxiety Inventory, the Panic Disorder Severity Scale. Results There was a significant difference in the distribution of 5-HTTLPR genotype between panic patients with agoraphobia and without agoraphobia (p = 0.024). That is, the panic patients with agoraphobia had a significant excess of the less active 5-HTTLPR allele (S allele). (p = 0.039) Also, we replicated previous western reports which indicated a significant difference in the distribution of COMT genotype between the patients with panic disorder and the healthy controls (p = 0.040). However, no significant associations of agora-phobia or panic disorder with HTR1A gene polymorphisms were found. Conclusions This result supports that the COMT polymorphisms may be associated with panic disorder and suggests that the 5-HTTLPR polymorphisms may play a role in the pathogenesis of agoraphobia in the Korean patients with panic disorder.

Catechol-O-Methyltransferase Activity in Cholestatic Rat's Liver Induced by Bile Duct Ligation

  • Mun, Kyo-Cheol
    • BMB Reports
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    • v.29 no.2
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    • pp.142-145
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    • 1996
  • To investigate the cause of increased plasma catecholamine levels in liver disease, catechol-O-methyltransferase (COMT), which provides a major route of catabolism for circulating catecholamines, was studied under the cholestasis induced by mechanical biliary obstruction in rats. Monoamine oxidase (MAO) activity and the $K_m$ and $V_{max}$ values for both enzymes were also measured. Cytosolic, microsomal, and mitochondrial COMT activities in the cholestatic liver were significantly decreased throughout the experiment. Microsomal, and mitochondrial MAO activity in the cholestatic liver were also significantly decreased. Vmax values of COMT and MAO were lower. Serum COMT and MAO activities were detected after CBD ligation. These results indicate that plasma catecholamine levels are increased in liver disease due to decreased hepatic degradation of catecholamines by decreased activities of COMT and MAO. The decreased activity of these enzymes is caused by decreased biosynthesis and by flowage into the blood from the damaged hepatocyte.

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An Association Study of COMT Gene Polymorphism with Korean Schizophrenics (정신분열병과 Catechol-O-methyltransferase(COMT) 유전자 다형성의 연합)

  • Song, En-Sook;Yang, Byung-Hwan;Park, Kang-Kyu;Lee, Yu-Sang;An, Eun-Soog;Oh, Dong-Yul;Kim, Jong-Won;Choi, Ihn-Geun;Kim, Gil-Sook;Chai, Young-Gyu
    • Korean Journal of Biological Psychiatry
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    • v.5 no.2
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    • pp.210-214
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    • 1998
  • An association study with Korean schizophrenic patients(N=84) and normal controls(N=87) was performed to find the relationship between catechol-O-methyltransferase(COMT) gene polymorphism and schizophrenia using polymerase chain reaction-restriction fragment length polymorphism. When we compared the allele and genotype frequencies of Bgl I COMT gene polymorphism in schizophrenics and normal controls, there was no significant difference between two groups. Our results do not support an association between the Bgl I polymorphism of COMT gene and schizophrenia.

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Effects of Intravenous Administration of Taurocholic Acid on Hepatic Catechol-O-Methyltransferase Activity in Rats with Choledocho-Caval Shunt

  • Do, Jun-Young;Mun, Kyo-Cheol;Kim, You-Hee;Kwak, Chun-Sik
    • Biomedical Science Letters
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    • v.13 no.2
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    • pp.135-140
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    • 2007
  • The possible mechanism of decreased catechol-O-methyltransferase (COMT) activity in cholestatic rat liver was studied. Hepatic and serum COMT activities were determined from the experimental rats with choledocho-caval shunt (CCS). The Michaelis-Menten constants in this hepatic enzyme was also measured. The activities of cytosolic, mitochondrial and mircosomal COMT as well as their $V_{max}$ values were found to be decreased significantly in CCS plus taurocholic acid (TCA) injected group than in the control group, such as CCS alone groups. However, their $K_m$ values in the experimental groups did not vary. Seru4m COMT activity increased slightly in the CCS plus TCA injerted group than in the control group. The above results suggest that TCA represses biosynthesis of the COMT in the liver, The elevated activity of the serum COMT is believed to be caused by the increment of membrane permeability of hepatocytes upon TCA mediated liver cell necrosis.

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