Catechol-O-methyltransferase (COMT; EC 2.1.1.6 ) catalyzes the transfer of a methyl group from S-adenosylmethionine to
catecholamines, including the neurotransmitters dopamine, epinephrine, and norepinephrine. This O-methylation results in one
of the major degradative pathways of the catecholamine transmitters. In addition to its role in the metabolism of endogenous
substances, COMT is important in the metabolism of catechol drugs used in the treatment of hypertension, asthma, and
Parkinson disease.
NCBI Summary:
Catechol-O-methyltransferase catalyzes the transfer of a methyl group from S-adenosylmethionine to catecholamines, including the neurotransmitters dopamine, epinephrine, and norepinephrine. This O-methylation results in one of the major degradative pathways of the catecholamine transmitters. In addition to its role in the metabolism of endogenous substances, COMT is important in the metabolism of catechol drugs used in the treatment of hypertension, asthma, and Parkinson disease. COMT is found in two forms in tissues, a soluble form (S-COMT) and a membrane-bound form (MB-COMT). The differences between S-COMT and MB-COMT reside within the N-termini. Several transcript variants are formed through the use of alternative translation initiation sites and promoters. [provided by RefSeq, Sep 2008]
General function
Enzyme, Transferase
Comment
Catechol-O-methyltransferase (COMT) single nucleotide polymorphisms and haplotypes are not major risk factors for polycystic ovary syndrome. Hill LD et al. Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects 5-8% of reproductive age women. The primary features of PCOS are hyperandrogenemia, chronic anovulation and infertility. It has been suggested that defects in ovarian steroid metabolism contribute to the follicular growth arrest and abnormal production of ovarian steroid hormones that are characteristic of PCOS. 2-Methoxyestradiol (2-ME) is formed by the action of catechol-O-methyltransferase (COMT) on 2-hydroxyestradiol. COMT expression is increased in the follicles and ovarian stroma of women with PCOS. Moreover, 2-ME decreases granulosa cell proliferation and steroidogenesis, raising the possibility that ovarian dysfunction associated with PCOS is due, in part, to increased synthesis of 2-ME resulting from increased COMT activity. Four single-nucleotide polymorphisms (SNPs) (rs6269, rs4633, rs4818, rs4680) in the COMT gene characterize haplotypes, which are associated with large variations in COMT enzymatic activity. The aim of this study was to determine whether individual COMT SNPs and the COMT haplotypes are associated with PCOS using a family-based test of association and linkage. Additionally, we examined the relationships between COMT SNPs and haplotypes with quantitative variables usually assessed in the evaluation of women with PCOS. There were no significant correlations between genotype and total testosterone, non-SHBG bound testosterone and BMI. However, we found that the prolactin level in women with PCOS varied significantly with COMT haplotype, and suggest that this association reflects a genetic factor influencing the stress response. Our findings suggest that common variants and haplotypes of the COMT gene are not major contributors to risk for PCOS, but that COMT genotype may influence prolactin levels.
Cellular localization
Cytoplasmic
Comment
Lower levels of urinary 2-hydroxyestrogens in polycystic ovary syndrome. Salih S et al. (2007) Women with polycystic ovary syndrome (PCOS) have anovulation due to arrested follicular maturation. The substrate (2-hydroxyestrogen) and product (2-methoxyestrogen) of catechol-O-methyl transferase (COMT) have been shown to modulate proliferation and angiogenesis of granulosa cells. The objective of the study was to evaluate COMT ovarian expression as well as the production of estrogen metabolites (2-hydroxyestrogen and 2-methoxyestrogen) in subjects with PCOS. Immunohistochemistry was used to assess COMT expression in ovarian tissues. Urinary levels of 10 different estrogens and estrogen metabolites were measured using enzyme-labeled immunoassays and/or liquid chromatography with tandem mass spectrometry. The study was conducted at a tertiary university referral center. Ovarian tissues were obtained from six control subjects and six subjects with PCOS. Fasting first-void urinary samples were collected from 49 subjects with PCOS and 36 healthy control subjects. COMT protein expression in ovarian tissues was measured. Urinary levels of 2-hydroxyestrogen and 2-methoxyestrogen levels in PCOS patients were also measured. Whereas immunohistochemistry showed that COMT was expressed in ovaries from control and PCOS subjects, its expression was significantly higher in ovaries from subjects with PCOS, in both the follicular structures and ovarian stroma. The urinary 2-hydroxyestrogen level was significantly lower in subjects with PCOS, compared with normal controls (P = 0.009). Additionally, urinary 2-hydroxyestrogen levels negatively correlated with serum insulin levels in subjects with PCOS (r = -0.333, P =0 .031). Urinary 2-hydroxyestrogen is decreased in subjects with PCOS, which could be due in part to increased ovarian expression of COMT. Further studies are needed to ascertain the role of estrogen metabolism in PCOS before this information can be used in clinical settings.//////////////////
Ovarian function
Steroid metabolism, Oogenesis
Comment
Senthilkumaran B, et al 2001 reported periovulatory changes in catfish ovarian oestradiol-17 beta,
oestrogen-2-hydroxylase and catechol-O-methyltransferase during
GnRH analogue-induced ovulation and in vitro induction of
oocyte maturation by catecholoestrogens
In the catfish Heteropneustes fossilis and Clarias batrachus, ovarian
oestrogen-2-hydroxylase (OE-2-H) activity increased significantly at 8 h after
the injection of an ovulatory dose (0.15 mug/g body weight) of a mammalian
GnRH analogue (D-Ala(6)-Pro(9)-LHRH ethylamide) and was restored to the 0 h
(control) level after egg-stripping at 16 h. On the other hand, ovarian
oestradiol-17 beta (OE2) level and catechol-O-methyltransferase (COMT)
activity decreased significantly at 8 h. While the OE2 level was restored to
the 0 h level, COMT activity increased significantly at 16 h. Changes in
ovarian OE2 level and enzymes indicate higher synthesis of 2-hydroxylated
catecholoestrogens and their degradation during the periovulatory period.
Under in vitro conditions, the synthetic catecholoestrogens (CEs, 2- and
4-hydroxylated oestradiol-17 beta and oestrone (OE1)) induced germinal vesicle
break down (GVBD) in a dose- (0.01-10 mug/ml) and duration-(1-36 h) dependent
manner, the mean values of the responses being in the order 2-OH OE2>4-OH OE2>
2-OH OE1>4-OH OE1. The CE-induced
8-h stimulation of GVBD was mildly blocked by propranolol, the beta
-adrenergic inhibitor, suggesting the response was partly mediated through a
beta -adrenergic receptor mechanism. Incubations with phentolamine, an alpha
-adrenergic inhibitor, did not interfere with the CE-induced GVBD response.
The results demonstrate CE-related enzymatic changes in teleost (catfish)
ovaries and maturation-inducing substance activity of CEs.
Regulation of catechol O-methyltransferase expression in granulosa cells: a potential role for follicular arrest in polycystic ovary syndrome. Salih SM et al. OBJECTIVE: To investigate the regulation of catechol O-methyltransferase (COMT) expression in granulosa cells and assess potential effects of 2-methoxyestradiol (2-ME(2)) and COMT inhibitors on granulosa cell steroidogenesis and proliferation. DESIGN AND SETTING: Controlled experimental study in an academic research laboratory. INTERVENTION(S): JC410 porcine and HGL5 human granulosa cell lines were used for in vitro experiments. Effects of 2-ME(2) and COMT inhibitor treatment on DNA proliferation and steroidogenesis were assessed by using Hoechst dye and p450SCC-luciferase reporter assays. Effects of dihydrotestosterone (DHT), insulin, and all-trans retinoic acid (ATRA) on COMT messenger RNA expression were investigated by using COMTP1 promoter-luciferase reporter and Northern blot. MAIN OUTCOME MEASURE(S): Granulosa cell steroidogenesis and proliferation following COMP inhibitor and 2-ME(2) treatment. Regulation of COMT expression with DHT, insulin, and ATRA. RESULT(S): 2-Methoxyestradiol had a dual effect on granulosa cell proliferation and p450SCC- luciferase activity; low doses were stimulatory and high doses were inhibitory. Catechol O-methyltransferase inhibitor was associated with up to a 65% increase in JC410 cell number and a maximal 5.6-fold increase in p450SCC-luciferase activity at 20 mumol/L. Dihydrotestosterone, insulin, and ATRA all induced a dose-dependent increase in COMTP1-luciferase transactivation, as well as up-regulated COMT messenger RNA expression in granulosa cells. CONCLUSION(S): Catechol O-methyltransferase expression in granulosa cells was up-regulated by insulin, DHT, and ATRA. Catechol O-methyltransferase product, 2-ME(2), decreased, whereas COMT inhibitor increased granulosa cell proliferation and steroidogenesis. These data suggest that COMT overexpression with subsequent increased level of 2-ME(2) may lead to ovulatory dysfunction.
Expression regulated by
Comment
Ovarian localization
Granulosa, Luteal cells, ovarian tumor
Comment
To define the molecular changes associated with ovarian cancer, DNA microarray analysis has been adapted to detect differentially expressed genes in human normal ovary tissue, borderline, and invasive epithelial ovarian tumors. The differential expression of genes in the tumor tissues and normal tissues was confirmed by Northern and/or semi-quantitative RT-PCR analysis. Analysis of the differential gene-expression profiles of the normal and neoplastic ovary allowed us to detect previously unidentified genes in ovarian tissues. Lee BC, et al observed up-regulation of the following genes in ovarian cancer: catechol-O-methyltransferase (COMT), the autocrine motility factor neuroleukin (NLK), the transcription regulator high mobility group I proteins (HMGI), the tyrosine kinase receptor ErbB-3, S100-alpha protein and Acyl-CoA-binding protein (ACBP). The transcription factor, chicken ovalbumin up-stream promoter transcription factor II (COUP-TFII), was the only gene down-regulated in ovarian cancer. Comparable gene-expression profiles were previously reported in breast cancer, suggesting that similar molecular events also exist in ovarian cancer. Our microarray analysis showed that most differentially expressed genes in ovarian cancer are linked to glucose/insulin metabolism, providing a possible molecular link between the glucose/insulin signaling pathway and the neoplasms of ovarian cancer.
Follicle stages
Corpus luteum
Comment
2-Methoxyestradiol in the human corpus luteum throughout the luteal phase and its influence on lutein cell steroidogenesis andangiogenic activity. Kohen P 2013 et al.
OBJECTIVE
To quantitate 2-methoxyestradiol (2-ME) in human corpus luteum (CL) of different ages and to determine the expression of cytochrome-P450-1A1 (CYP1A1) and catechol-O-methyl transferase (COMT) in CL and the action of 2-ME on P, vascular endothelial growth factor (VEGF) secretion, and luteal angiogenesis.
DESIGN
Experimental study.
SETTING
University division of reproductive endocrinology.
PATIENT(S)
Twenty-four women of reproductive age.
INTERVENTION(S)
CL was collected from 15 women during the minilaparotomy for tubal sterilization. Granulosa lutein cells were harvested 36 hours after hCG administration in patients undergoing IVF.
MAIN OUTCOMES MEASURE(S)
Levels of 2-ME were determined by high-performance liquid chromatography in CL. CYP1A1 and COMT were assessed by immunohistochemistry and Western blot. P and VEGF were measured by radioimmunoassay and ELISA. The angiogenic potential was analyzed using EA.hy926 cells.
RESULT(S)
Plasma levels of E2 decreased in the late luteal phase in association with an increase in luteal tissue of 2-ME concentrations. Concomitantly, there was a significant reduction of angiogenic activity in late CL. There was no significant variation in CYP1A1 and COMT expression in all CL. In physiological doses, 2-ME inhibited basal VEGF by granulosa lutein cells and diminished the angiogenic activity in conditioned media but did not prevent P and VEGF production stimulated by hCG.
CONCLUSION(S)
These data suggest the participation of 2-ME in physiological luteolysis by reducing angiogenesis. However, 2-ME did not prevent invitro hCG stimulation of P biosynthesis, providing a mechanism for CL rescue in the cycle of conception.
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Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
1 mutations
Species: human
Mutation name: None
type: naturally occurring fertility: fertile Comment: Catechol-O-methyltransferase (COMT) single nucleotide polymorphisms and haplotypes are not major risk factors for polycystic ovary syndrome. Hill LD et al. Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects 5-8% of reproductive age women. The primary features of PCOS are hyperandrogenemia, chronic anovulation and infertility. It has been suggested that defects in ovarian steroid metabolism contribute to the follicular growth arrest and abnormal production of ovarian steroid hormones that are characteristic of PCOS. 2-Methoxyestradiol (2-ME) is formed by the action of catechol-O-methyltransferase (COMT) on 2-hydroxyestradiol. COMT expression is increased in the follicles and ovarian stroma of women with PCOS. Moreover, 2-ME decreases granulosa cell proliferation and steroidogenesis, raising the possibility that ovarian dysfunction associated with PCOS is due, in part, to increased synthesis of 2-ME resulting from increased COMT activity. Four single-nucleotide polymorphisms (SNPs) (rs6269, rs4633, rs4818, rs4680) in the COMT gene characterize haplotypes, which are associated with large variations in COMT enzymatic activity. The aim of this study was to determine whether individual COMT SNPs and the COMT haplotypes are associated with PCOS using a family-based test of association and linkage. Additionally, we examined the relationships between COMT SNPs and haplotypes with quantitative variables usually assessed in the evaluation of women with PCOS. There were no significant correlations between genotype and total testosterone, non-SHBG bound testosterone and BMI. However, we found that the prolactin level in women with PCOS varied significantly with COMT haplotype, and suggest that this association reflects a genetic factor influencing the stress response. Our findings suggest that common variants and haplotypes of the COMT gene are not major contributors to risk for PCOS, but that COMT genotype may influence prolactin levels.