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PubMed1993

Effects of three types of catechol O-methylation inhibitors on L-3,4-dihydroxyphenylalanine-induced circling behaviour in rats.

The effects of three new, selective inhibitors of catechol O-methylation were compared regarding their potentiation of L-3,4-dihydroxyphenylalanine (L-dopa)/carbidopa-induced contralateral circling behaviour in male rats. Some studies were also done with amphetamine, which causes ipsilateral turning. A peripherally acting compound, entacapone, a peripherally and centrally acting compound, tolcapone, and an atypical compound, CGP 28014 (3, 10 or 30 mg/kg) increased the effect of L-dopa/carbidopa (2/30 or 5/30 mg/kg) on contralateral circling by 2.0-6.1-fold. Addition of clorgyline (3 mg/kg) did not increase, but rather decreased, the entacapone (3 mg/kg) and L-dopa/carbidopa (2/30 or 5/30 mg/kg)-induced peak circling. Amphetamine (2.5 mg/kg)-induced ipsilateral circling behaviour was not affected by tolcapone (30 mg/kg). We conclude that L-dopa-induced circling behaviour is enhanced and prolonged by all types of catechol O-methyltransferase inhibitors regardless of their brain penetration. The results suggest that catechol O-methylation inhibitors may be beneficial as L-dopa adjuncts in the treatment of patients with Parkinson's disease.

Amidines↗
PubMed1993

Modulation of rat brain endogenous dopamine metabolism by new inhibitors of catechol O-methyltransferase.

The extraneuronal and intraneuronal metabolism of rat brain endogenous dopamine was stimulated by amphetamine (5 mg/kg) and pimozide (2 mg/kg), respectively. Additional metabolic effects of two inhibitors of catechol O-methyltransferase (entacapone and tolcapone (both 30 mg/kg)) and a putative central uptake2 inhibitor (CGP 28014 (30 mg/kg)) were assessed. Amphetamine increased striatal dopamine and 3-methoxytyramine and decreased 3,4-dihydroxyphenylacetic acid (DOPAC) levels. The latter two effects were reversed by tolcapone and CGP 28014, but not by entacapone. Tolcapone, CGP 28014 and even entacapone decreased striatal homovanillic acid (HVA) levels. Pimozide-induced striatal DOPAC levels were further increased by tolcapone and CGP 28014. Both substances also decreased striatal HVA levels. Striatal 3-methoxytyramine levels were significantly lowered only by tolcapone. Our results show that enhanced central dopamine metabolism is modified by the inhibition of catechol O-methyltransferase even in the absence of L-3,4-dihydroxyphenylalanine (L-DOPA). The results also suggest that the mechanism of action of CGP 28014 may be other than true inhibition of catechol O-methyltransferase.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1995

Beneficial effects of co-administration of catechol-O-methyltransferase inhibitors and L-dihydroxyphenylalanine in rat models of depression.

The administration of catechol-O-methyltransferase inhibitors alone changed neither the behavior of the rats in two animal models of depression, the forced swimming test (entacapone and tolcapone) or in the learned helplessness paradigm (tolcapone), nor the locomotor activity. L-Dihydroxyphenylalanine (L-DOPA) and carbidopa treatment as such decreased motility but did not improve the behavior in the antidepressant tests. Co-administration of catechol-O-methyltransferase inhibitors and L-DOPA/carbidopa increased the performance of rats in both tests without increasing locomotor activity. Catechol-O-methyltransferase inhibitors could be beneficial as adjunct drugs of L-DOPA not only in Parkinson's disease but also in the coincident depressive illness.

Analysis of Variance↗
PubMed1983

The absence of a catechol estrogen effect on blood pressure in the male rat.

Since catechol estrogens are potent competitive inhibitors of catechol-O-methyl transferase (COMT), it has been suggested that they may prolong the half-life of catecholamines which in turn can cause hypertension. Thus, experiments were carried out to study the effect of catechol estrogens on blood pressure in the male rat following chronic administration. Results demonstrate that 2-hydroxyesterone (2,3-dihydroxyestra-1,3,5(10)-trien-17-one) and 2-hydroxy-estradiol (estra-1,3,5(10)-triene-2,3,17 beta-triol) even when administered in high doses do not alter blood pressure.

Animals↗
PubMed1987

Tyrosinase-catalyzed oxidation of dopa and related catechol(amine)s: a kinetic electron spin resonance investigation using spin-stabilization and spin label oximetry.

The oxidation of four catechol(amine)s by tyrosinase has been studied by electron spin resonance and optical methods. Rates of oxygen consumption and of dopaquinone and dopachrome formation during the oxidation of dopa have been measured, and compared with rates of dopasemiquinone production measured using spin-stabilization procedures. In the presence of spin-stabilizing metal ions, production of semiquinone is approximately quantitative. Time-dependent ESR spectra obtained from dopa and dopamine show a slow regeneration of semiquinone, suggesting that a semiquinone precursor is slowly reformed. In contrast, time-dependent spectra for 4-methylcatechol and N-acetyldopamine show decay of the primary semiquinone together with buildup of a secondary semiquinone apparently derived from the corresponding 6-hydroxy-catechol(amine). Thus, catecholamines that give rise to a cyclizable quinone show a pattern of behavior that differs from those that produce a non-cyclizable quinone. These results are discussed in terms of their possible significance to melanogenesis and the toxicity of catechol(amine)s, which has been attributed to production of semiquinones and/or other oxygen radicals.

Benzoquinones↗
PubMed1997

Entacapone, a novel catechol-O-methyltransferase inhibitor for Parkinson's disease, does not impair mitochondrial energy production.

Entacapone, a novel mainly peripherally acting catechol-O-methyltransferase inhibitor used in the treatment of Parkinson's disease, was evaluated for its possible uncoupling activity in cell culture, in rat liver mitochondria, and in isolated guinea-pig heart. Entacapone did not stimulate respiration in the L1210 murine T cell lymphoma cell line at the concentrations studied (5-40 microM). Furthermore, entacapone neither increased mitochondrial respiration nor impaired cardiac function at pharmacologically relevant concentrations (< 10 microM). In fact, the threshold concentration for increased mitochondrial oxygen consumption was 20 microM and half-maximal stimulation of respiration was not detected until 58 microM. Surprisingly, tolcapone, another catechol-O-methyltransferase inhibitor, which acts both peripherally and centrally, stimulated respiration in L1210 cells at the lowest concentration studied (5 microM). In addition, 1 microM tolcapone increased mitochondrial respiration, indicating that it caused uncoupling at a much lower concentration than that of 2,4-dinitrophenol, a well-known uncoupler of oxidative phosphorylation. Tolcapone also impaired the mechanical function and oxygen consumption of the isolated guinea-pig heart at 1 microM. These results show that peripherally acting entacapone, unlike the brain-penetrating tolcapone, is a safe catechol-O-methyltransferase inhibitor for the treatment of Parkinson's disease, since it does not interfere with mitochondrial energy metabolism at pharmacologically effective concentrations.

Adenine Nucleotides↗
PubMed1984

Assay for catechol-O-methyltransferase in erythrocytes using a new fluorogenic substrate, 2-(3,4-dihydroxyphenyl)naphtho[1,2-d]thiazole.

A highly sensitive method for the assay of catechol-O-methyltransferase in erythrocytes is described, which employs high-performance liquid chromatography with fluorescence detection. A newly synthesized catechol compound, 2-(3,4-dihydroxyphenyl)naphtho [1,2-d]thiazole is used as a highly fluorogenic substrate for catechol-O-methyltransferase; the m- and p-methylated products formed enzymatically from the substrate under the optimum conditions, after extraction with n-hexane--chloroform, are separated by normal-phase chromatography on LiChrosorb Si 100. The limits of detection for m- and p-methylated products are 3 pmol per assay tube (60 fmol per injection volume of 20 microliter) in each case. The ratio of m- and p-methylated products was 0.54. This method requires as little as 50 microliter of human erythrocytes.

Benzothiazoles↗
PubMed2002

Synthesis, structure and catechol-oxidase activity of copper(II) complexes of 17-hydroxy-16-(N-3-oxo-prop-1-enyl)amino steroids.

Copper is next to iron the most important element in the biological transport, storage and in redox reactions of dioxygen. A bioanalogous activation of dioxygen with copper complexes is used for catalytical epoxidation, allylic hydroxylation and oxidative coupling of aromatic substrates, for example. With stereochemical information in form of chiral ligands, enantioselective reactions may be possible. Another aspect of interest on copper catalyzed reactions with dioxygen is that the exact mechanism and biological function of some enzymes (especially catechol oxidase) is yet not fully clear. For studies mimicking the copper-containing catechol oxidase appropriate chiral steroid ligands with defined stereochemistry and conformation have been synthesized. The four diastereomeric 16,17-aminoalcohols of the 3-methoxy-estra-1,3,5(10)-triene series have been condensed with salicylic aldehyde and different beta-ketoenols to the chiral ligand types 1-5. These compounds with different steric and electronic properties and different arrangements of the neighboring hydroxy and nitrogen functions were reacted with copper(II) acetate to copper complexes. The structure of these complexes will be discussed. The bioanalogous oxidation of 3,5-di-tbutyl-catechol (dtbc) to the corresponding quinone was catalyzed by most of the complexes, indicating their ability to activate dioxygen. The trans configurations c and d showed an activity one magnitude higher than the cis configurations a and b. Comparing compounds with the same diastereomeric configuration, the main influence was that of the peripheral R(1-3) substituents at the beta-ketoenaminic group which are useful for the fine-tuning of the properties of the copper atoms like redox potential and Lewis acidity.

Amines↗
PubMed2005

On the nature of the transition state in catechol O-methyltransferase. A complementary study based on molecular dynamics and potential energy surface explorations.

The way in which enzymes influence the rate of chemical processes is still a question of debate. The protein promotes the catalysis of biochemical processes by lowering the free energy barrier in comparison with the reference uncatalyzed reaction in solution. In this article we are reporting static and dynamic aspects of the enzyme catalysis in a bimolecular reaction, namely a methyl transfer from S-adenosylmethionine to the hydroxylate oxygen of a substituted catechol catalyzed by catechol O-methyltransferase. From QM/MM optimizations, we will first analyze the participation of the environment on the transition vector. The study of molecular dynamics trajectories will allow us to estimate the transmission coefficient from a previously localized transition state as the maximum in the potential of mean force profile. The analysis of the reactive and nonreactive trajectories in the enzyme environment and in solution will also allow studying the geometrical and electronic changes, with special attention to the chemical system movements and the coupling with the environment. The main result, coming from both analyses, is the approximation of the magnesium cation to the nucleophilic and the hydroxyl group of the catecholate as a result of a general movement of the protein, stabilizing in this way the transition state. Consequently, the free energy barrier of the enzyme reaction is dramatically decreased with respect to the reaction in solution.

Catechol O-Methyltransferase↗
PubMed1997

Iron(III)-chelating properties of the novel catechol O-methyltransferase inhibitor entacapone in aqueous solution.

The iron(III) complex formation of entacapone, a novel catechol O-methyltransferase (COMT) inhibitor, has been studied at 25 degrees C in aqueous 0.1 mol/L NaCl solution by using the electromotive force titration method. Entacapone functions as a bidentate ligand chelating through the catecholate oxygen atoms and forms stable iron(III) complexes with the formation constant of a tris complex: log beta-613 ([FeL3(3-)][H]6+/[Fe3+][H2L]3) = -6.9 +/- 0.1. Distribution curves show that entacapone is highly effective for iron(III) in moderately dilute solution (10(-3) mol/L) whereas in very dilute solution (10(-6) mol/L) the iron hydroxo complexes together with FeL3(3-) dominate under physiological pH 7.4. Comparison of iron(III) species distribution in a competitive two-ligand entacapone-catechol system reveals that the complexation of entacepone is favored at high and low dilution.

Catechol O-Methyltransferase Inhibitors↗
PubMedDate not supplied

Metabolism of methoxychlor by hepatic P-450 monooxygenases in rat and human. 1. Characterization of a novel catechol metabolite.

Previous investigations demonstrated that the incubation of the chlorinated hydrocarbon pesticide methoxychlor [1,1,1-trichloro-2,2-bis(4-methoxyphenyl)ethane] with rat liver microsomes generates phenolic estrogenic metabolites. The current study shows that the incubation of liver microsomes from untreated and phenobarbital-treated rats and human donors, in the presence of NADPH, yields three phenolic metabolites. Identification of the metabolites was achieved by TLC, HPLC, GC/MS, and LC/MS and by hydrodynamic voltammetric analysis. These metabolites were identified as the mon- and didemethylated phenolic derivatives (mono-OH-M and bis-OH-M, respectively) and as a novel trihydroxy derivative (tris-OH-M). The tris-OH-M was demonstrated to be a catechol [1,1,1-trichloro-2-(4-hydroxyphenyl)-2-(3,4-dihydroxyphenyl)ethane]. Furthermore, the tris-OH-M becomes radiolabeled by [methyl-3H3]-S- adenosylmethionine (SAM) in a reaction catalyzed by catechol O-methyltransferase (COMT), indicating that tris-OH-M behaves like a catechol. Incubation of the monohydroxy metabolite with liver microsomes from phenobarbital-treated rats (PB microsomes) yields the dihydroxy and the trihydroxy metabolites. Furthermore, the time course of methoxychlor metabolism by PB microsomes demonstrated a rapid appearance and disappearance of the monohydroxy metabolite with the subsequent formation of the dihydroxy and trihydroxy metabolites. On the basis of these findings, it is proposed that the metabolic route of methoxychlor by mono-oxygenases involves sequential demethylations to the dihydroxy derivative and a subsequent ring hydroxylation.

Animals↗
PubMed1965

THE BACTERIAL DEGRADATION OF CATECHOL.

1. Two strains of Pseudomonas were grown with phenol and used to prepare cell extracts that metabolized catechol with the transient formation of 2-hydroxymuconic semialdehyde. 2. One of these preparations catalysed the conversion of 1mol. of catechol into 1mol. each of formate and 4-hydroxy-2-oxovalerate. 3. A method for the determination of 4-hydroxy-2-oxovalerate is described, together with some properties of this compound and its 2,4-dinitrophenylhydrazone. 4. Another partially purified cell extract converted 1mol. of 4-hydroxy-2-oxovalerate, formed enzymically from catechol, into 1mol. each of acetaldehyde and pyruvate. This aldolase had a pH optimum of about 8.8, was stimulated by Mg(2+) ions and appeared to attack only one enantiomer of synthetic 4-hydroxy-2-oxovalerate.

Acetaldehyde↗
PubMed2002

Catechol estrogen metabolites and conjugates in different regions of the prostate of Noble rats treated with 4-hydroxyestradiol: implications for estrogen-induced initiation of prostate cancer.

Prostate carcinomas arise in 100% of Noble rats treated with estradiol and testosterone. We hypothesize that estrogens initiate prostate cancer mainly by formation of 4-catechol estrogens (CE), followed by their oxidation to catechol estrogen-3,4-quinones (CE-3,4-Q), which can react with DNA. To avoid cancer initiation, CE can be detoxified by catechol-O-methyltransferase (COMT), and CE-3,4-Q by conjugation with glutathione (GSH) or by reduction to CE, catalyzed by quinone reductase and/or cytochrome P450 reductase. To investigate the prostatic metabolism of estrogens, Noble rats were treated with the CE 4-hydroxyestradiol (4-OHE2) or estradiol-3,4-quinone (E2-3,4-Q), and CE metabolites and conjugates were analyzed in the four regions of the prostate, which differ in susceptibility to carcinoma formation. Following treatment of rats with 4-OHE2 (6 micromol/100 g body weight in 200 microl of trioctanoin/dimethylsulfoxide (4:1) by intraperitoneal injection) for 90 min, the non-susceptible ventral (VP) and anterior (AP) prostate had higher levels of 4-methoxyCE and GSH conjugates than the susceptible dorsolateral prostate (DLP) and periurethral prostate (PUP). After treatment with the same molar amount of E2-3,4-Q, the VP and AP contained more GSH conjugates, 4-CE and 4-methoxyCE than the susceptible DLP and PUP. These results suggest that prostate areas susceptible to carcinoma induction have less protection by COMT, GSH, and quinone reductase and/or cytochrome P450 reductase, favoring reaction of CE-3,4-Q with DNA, presumably to initiate cancer.

Animals↗
PubMed2006

The role of residue Thr249 in modulating the catalytic efficiency and substrate specificity of catechol-2,3-dioxygenase from Pseudomonas stutzeri OX1.

Bioremediation strategies use microorganisms to remove hazardous substances, such as aromatic molecules, from polluted sites. The applicability of these techniques would greatly benefit from the expansion of the catabolic ability of these bacteria in transforming a variety of aromatic compounds. Catechol-2,3-dioxygenase (C2,3O) from Pseudomonas stutzeri OX1 is a key enzyme in the catabolic pathway for aromatic molecules. Its specificity and regioselectivity control the range of molecules degraded through the catabolic pathway of the microorganism that is able to use aromatic hydrocarbons as growth substrates. We have used in silico substrate docking procedures to investigate the molecular determinants that direct the enzyme substrate specificity. In particular, we looked for a possible molecular explanation of the inability of catechol-2,3-dioxygenase to cleave 3,5-dimethylcatechol and 3,6-dimethylcatechol and of the efficient cleavage of 3,4-dimethylcatechol. The docking study suggested that reduction in the volume of the side chain of residue 249 could allow the binding of 3,5-dimethylcatechol and 3,6-dimethylcatechol. This information was used to prepare and characterize mutants at position 249. The kinetic and regiospecificity parameters of the mutants confirm the docking predictions, and indicate that this position controls the substrate specificity of catechol-2,3-dioxygenase. Moreover, our results suggest that Thr249 also plays a previously unsuspected role in the catalytic mechanism of substrate cleavage. The hypothesis is advanced that a water molecule bound between one of the hydroxyl groups of the substrate and the side chain of Thr249 favors the deprotonation/protonation of this hydroxyl group, thus assisting the final steps of the cleavage reaction.

Binding Sites↗
PubMed1986

Evidence that 6-hydroxydopamine is an inhibitor of catechol-O-methyltransferase in intact tissue.

The effect of in-vitro sympathetic denervation on the O-methylation of 2-hydroxyoestradiol was examined using the rabbit thoracic aorta. Aortic segments were exposed to 6-hydroxydopamine (400 mg litre-1, 10 min), incubated in 2-hydroxyoestradiol (5 microM, 60 min), and the 2-methoxyoestradiol formed was quantified using HPLC with electrochemical detection. Pre-exposure to 6-hydroxydopamine reduced O-methylation by 90% in intact aortic strips. However, O-methylation was also reduced (81%) in rabbit aorta that had been surgically denervated before exposure to 6-hydroxydopamine. Furthermore, the O-methylation of 2-hydroxyoestradiol (20 microM, 15 min) by partially purified soluble catechol-O-methyltransferase was inhibited by 6-hydroxydopamine (400 mg litre-1) by 95% and 51% in the absence and presence of antioxidant, respectively. These results suggest that the inhibition of catechol-O-methyltransferase by 6-hydroxydopamine reported for the purified enzyme, applies to the intact tissue and that the inhibition is dependent on oxidation of the 6-hydroxydopamine. Subsequent experiments using dialysis techniques demonstrated that the inhibition of soluble catechol-O-methyltransferase by 6-hydroxydopamine was irreversible in part, but the degree of irreversibility was influenced by pH and by the extent of in-vitro oxidation of 6-hydroxydopamine.

Animals↗
PubMed2000

Purification and characterization of Streptomyces griseus catechol O-methyltransferase.

A soluble (100,000 x g supernatant) methyltransferase catalyzing the transfer of the methyl group of S-adenosyl-L-methionine to catechols was present in cell extracts of Streptomyces griseus. A simple, general, and rapid catechol-based assay method was devised for enzyme purification and characterization. The enzyme was purified 141-fold by precipitation with ammonium sulfate and successive chromatography over columns of DEAE-cellulose, DEAE-Sepharose, and Sephacryl S-200. The purified cytoplasmic enzyme required 10 mM magnesium for maximal activity and was catalytically optimal at pH 7. 5 and 35 degrees C. The methyltransferase had an apparent molecular mass of 36 kDa for both the native and denatured protein, with a pI of 4.4. Novel N-terminal and internal amino acid sequences were determined as DFVLDNEGNPLENNGGYXYI and RPDFXLEPPYTGPXKARIIRYFY, respectively. For this enzyme, the K(m) for 6,7-dihydroxycoumarin was 500 +/- 21.5 microM, and that for S-adenosyl-L-methionine was 600 +/- 32.5 microM. Catechol, caffeic acid, and 4-nitrocatechol were methyltransferase substrates. Homocysteine was a competitive inhibitor of S-adenosyl-L-methionine, with a K(i) of 224 +/- 20.6 microM. Sinefungin and S-adenosylhomocysteine inhibited methylation, and the enzyme was inactivated by Hg(2+), p-chloromercuribenzoic acid, and N-ethylmaleimide.

Amino Acid Sequence↗
PubMed2004

Construction of chimeric catechol 2,3-dioxygenase exhibiting improved activity against the suicide inhibitor 4-methylcatechol.

Catechol 2,3-dioxygenase (C23O; EC 1.3.11.2), exemplified by XylE and NahH, catalyzes the ring cleavage of catechol and some substituted catechols. C23O is inactivated at an appreciable rate during the ring cleavage of 4-methylcatechol due to the oxidation of the Fe(II) cofactor to Fe(III). In this study, a C23O exhibiting improved activity against 4-methylcatechol was isolated. To isolate this C23O, diverse C23O gene sequences were PCR amplified from DNA which had been isolated from mixed cultures of phenol-degrading bacteria and subcloned in the middle of a known C23O gene sequence (xylE or nahH) to construct a library of chimeric C23O genes. These chimeric C23O genes were then introduced into Pseudomonas putida possessing some of the toluene catabolic genes (xylXYZLGFJQKJI). When a C23O gene (e.g., xylE) is introduced into this strain, the transformants cannot generally grow on p-toluate because 4-methylcatechol, a metabolite of p-toluate, is a substrate as well as a suicide inhibitor of C23O. However, a transformant of this strain capable of growing on p-toluate was isolated, and a chimeric C23O (named NY8) in this transformant was characterized. The rate of enzyme inactivation by 4-methylcatechol was lower in NY8 than in XylE. Furthermore, the rate of the reactivation of inactive C23O in a solution containing Fe(II) and ascorbic acid was higher in NY8 than in XylE. These properties of NY8 might allow the efficient metabolism of 4-methylcatechol and thus allow host cells to grow on p-toluate.

Amino Acid Sequence↗
PubMed1983

Control of catechol meta-cleavage pathway in Alcaligenes eutrophus.

Alcaligenes eutrophus 335 (ATCC 17697) metabolizes phenol and p-cresol via a catechol meta-cleavage pathway. Studies with mutant strains, each defective in an enzyme of the pathway, showed that the six enzymes assayed are induced by the primary substrate. Studies with a putative polarity mutant defective in the expression of aldehyde dehydrogenase suggested that the structural genes encoding this and subsequent enzymes of the pathway exist in the same operon. From studies with mutant strains that constitutively synthesize catechol 2,3-oxygenase and subsequent enzymes and from the coordination of repression of these enzymes by p-toluate, benzoate, and acetate, it is proposed the catechol 2,3-oxygenase structural gene is situated in this operon (2,3-oxygenase operon). Studies with regulatory mutant strains suggest that the 2,3-oxygenase operon is under negative control.

Alcaligenes↗