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At least 19 recordsLinked to original sources
PubMed2000

Catechol metabolites of polychlorinated biphenyls inhibit the catechol-O-methyltransferase-mediated metabolism of catechol estrogens.

The catechol metabolites of estradiol, 2- and 4-hydroxyestradiol (2-OHE(2) and 4-OHE(2), respectively) are potent signaling molecules and are hypothesized to be central to estrogen-linked carcinogenesis. Methylation by catechol-O-methyltransferase (COMT) is the principal means of catechol estrogen (CE) deactivation in the liver and other tissues. The present studies were conducted to determine the effects of PCBs and catechol metabolites of PCBs on the COMT-mediated catabolism of 4-OHE(2) and 2-OHE(2) in vitro and in vivo. Liver homogenates of female Sprague-Dawley rats treated with Aroclor 1254 for 21 days (5 mg/kg/day) showed a 30 and 40% reduction of COMT activity toward 2-OHE(2) and 4-OHE(2), respectively. Incubation of [(3)H]-beta-estradiol with these same liver homogenates, followed by HPLC analysis, demonstrated an elevation of CEs and a nearly complete reduction in levels of methylated catechol estrogens. In classical enzyme kinetics studies, COMT was demonstrated to have a high affinity for catechol PCBs, with K(m)'s approximately equivalent to those of CEs. Catechol PCBs were also potent inhibitors of CE O-methylation. These data suggest that PCBs may significantly alter the metabolism of catechol estrogens in vivo and that this effect may be mediated by catechol metabolites of PCBs. It is further speculated that methyltransferase inhibition by PCB catechols may contribute to PCB-mediated endocrine effects and liver carcinogenesis.

Animals↗
PubMed1990

Inhibition of the soluble form of testis adenylate cyclase by catechol estrogens and other catechols.

The soluble form of rat germ cell adenylate cyclase was inhibited by compounds with a catechol moiety. Among the naturally occurring catechols tested, catechol estrogens were the most potent inhibitors. Catechol estrogens at 2-6 microM inhibited enzyme activity by 50% and almost completely at 30-100 microM concentration. The inhibitory activity of catechol estrogens depends on the catechol moiety of the molecule. Catechol per se also inhibited the activity of this enzyme, 50% inhibition being achieved at about 11 microM. The two hydroxyls of the catechol moiety are essential for the inhibitory interaction with the enzyme. Thus, aromatic compounds containing only one hydroxyl group in the benzene ring, such as tyrosine, phenylephrine, estradiol, and 6 alpha-hydroxyestradiol were either completely inactive or had marginal inhibitory activity at concentrations up to 0.3-1 mM. Moreover, methylation of the hydroxyl groups of the catechol moiety of the catechol estrogens as in 2-methoxyestradiol 3-methyl ether rendered the catechol estrogens inactive. The inhibitory potency of these compounds varied greatly depending on the structure associated with the catechol ring. Thus, compounds in which catechol is associated with an aliphatic side chain, such as dopamine, L-dopa, norepinephrine, and isoproterenol, were about 11- to 34-fold less potent than catechol. On the other hand, compounds in which catechol is associated either with a hydroaromatic ring system, as in apomorphine, or with an alicyclic ring system, as in catechol estrogens, were about 2- to 5-fold more potent than catechol. The inhibitory effect of dopamine, apomorphine, and catechol estrogens was not affected by specific D-1 or D-2 antagonist, indicating that they do not act via receptors for dopamine.

Adenylyl Cyclase Inhibitors↗
PubMed1996

17 beta-estradiol metabolism by hamster hepatic microsomes: comparison of catechol estrogen O-methylation with catechol estrogen oxidation and glutathione conjugation.

Catechol estrogens, the cytochromes P450 mediated metabolites of 17 beta-estradiol, undergo further metabolism either via catechol O-methyltransferase (COMT) catalyzed methylation, or by oxidation and subsequent thioether formation with glutathione (GSH). Secondary metabolites of 17 beta-estradiol arising from both these metabolic pathways have been identified in vivo. However, the relative contribution of catechol O-methylation, and catechol oxidation followed by GSH conjugation, to the disposition of the catechol estrogens is unclear. We have therefore quantified both pathways of catechol estrogen disposition, generated in situ from 17 beta-estradiol, in hamster hepatic microsomes. 17 beta-Estradiol was readily converted to 2- and 4-hydroxy-17 beta-estradiol, both of which were effectively methylated in the presence of COMT (300 units/mL). Addition of GSH (50 microM-1 mM) to microsomal incubations resulted in the formation of four catechol estrogen-derived GSH conjugates. Three conjugates of 2-hydroxy-17 beta-estradiol were identified: 2-hydroxy-1,4-bis(glutathione-S-yl)-17 beta-estradiol, 2-hydroxy-1-glutathione-S-yl-17 beta-estradiol, and 2-hydroxy-4-glutathione-S-yl-27 beta-estradiol. In contrast, just one GSH conjugate of 4-hydroxy-17 beta-estradiol was identified: 4-hydroxy-1-glutathione-S-yl-17 beta-estradiol. When a combination of COMT and GSH were simultaneously added to microsomal incubations, both metabolic pathways competed for the same pool of catechol estrogens, and ascorbate dramatically influenced which of these two pathways predominate. In the presence of ascorbate, catechol estrogen methylation predominated over catechol estrogen oxidation and GSH conjugation. In the absence of ascorbic acid, catechol estrogen methylation, and catechol estrogen oxidation inked to GSH conjugation, contributed equally to the disposition of the catechol estrogens. 17 beta-Estradiol 2- and 4-hydroxylase activity was always higher in the absence of ascorbate, irrespective of whether GSH or COMT was used as the trapping agent. Thus, the usual method (COMT plus ascorbate) of determining 17 beta-estradiol 2- and 4-hydroxylase activity underestimates enzyme activity by approximately 50% when compared to the value obtained when GSH is used to trap the o-quinones in the absence of ascorbate. A reassessment of 17 beta-estradiol 2- and 4-hydroxylase activity in different species and tissues is required to permit a more informed evaluation of the role of catechol estrogens in estrogen-induced carcinogenesis.

Animals↗
PubMed1986

Reactions of 3-ethylcatechol and 3-(methylthio)catechol with catechol dioxygenases.

The reactions of 3-ethylcatechol and 3-(methylthio)catechol with catechol 1,2-dioxygenase and catechol 2,3-dioxygenase from Pseudomonas putida were examined. Both 3-substituted catechols are oxidized by catechol 2,3-dioxygenase at approximately 30% of the rate observed for catechol oxidation by this enzyme. Analysis of the products of the reactions showed that ring cleavage occurs in a normal fashion between carbons 2 and 3 of the alternate substrates. 3-Ethylcatechol is oxidized by catechol 1,2-dioxygenase at about 6% of the rate of catechol oxidation; ring cleavage occurs between carbons 1 and 2 to give 2-ethyl-cis,cis-muconic acid. However, 3-(methylthio)catechol is a very poor substrate for catechol 1,2-dioxygenase (0.8% of the rate of catechol), but it is a potent competitive inhibitor (Ki = 0.6 microM). The effects of 3-(methylthio)catechol and 3-ethylcatechol on the visible and EPR spectra of catechol 1,2-dioxygenase are also reported.

Catechol 1,2-Dioxygenase↗
PubMed2003

Conjugation of catechols by recombinant human sulfotransferases, UDP-glucuronosyltransferases, and soluble catechol O-methyltransferase: structure-conjugation relationships and predictive models.

Conjugation of a structurally diverse set of 53 catechol compounds was studied in vitro using six recombinant human sulfotransferases (SULTs), five UDP-glucuronosyltransferases (UGT) and the soluble form of catechol O-methyltransferase (S-COMT) as catalyst. The catechol set comprised endogenous compounds, such as catecholamines and catecholestrogens, drugs, natural plant constituents, and other catechols with diverse substituent properties and substitution patterns. Most of the catechols studied were substrates of S-COMT and four SULT isoforms (1A1, 1A2, 1A3, and 1B1), but the rates of conjugation varied considerably, depending on the substrate structure and the enzyme form. SULT1E1 sulfated fewer catechols. Only low activities were observed for SULT1C2. UGT1A9 glucuronidated catechols representing various structural classes, and almost half of the studied compounds were glucuronidated at a high rate. The other UGT enzymes (1A1, 1A6, 2B7, and 2B15) showed narrower substrate specificity for catechols, but each glucuronidated some catechols at a high rate. Dependence of specificity and rate of conjugation on the molecular structure of the substrate was characterized by structure-activity relationship analysis and quantitative structure-activity relationship modeling. Twelve structural descriptors were used to characterize lipophilicity/polar interaction properties, steric properties, and electronic effects of the substituents modifying the catechol structure. PLS models explaining more than 80% and predicting more than 70% of the variance in conjugation activity were derived for the representative enzyme forms SULT1A3, UGT1A9, and S-COMT. Several structural factors governing the conjugation of catechol hormones, metabolites, and drugs were identified. The results have significant implications for predicting the metabolic fate of catechols.

Catechol O-Methyltransferase↗
PubMed1999

Cytochrome P-450 3A and 2D6 catalyze ortho hydroxylation of 4-hydroxytamoxifen and 3-hydroxytamoxifen (droloxifene) yielding tamoxifen catechol: involvement of catechols in covalent binding to hepatic proteins.

Earlier study suggested that 3,4-dihydroxytamoxifen (tam catechol), a tamoxifen metabolite, is proximate to the reactive intermediate that binds covalently to proteins and possibly to DNA (). The current study demonstrates that rat and human hepatic cytochrome P-450s (CYPs) catalyze tam catechol formation from tamoxifen (tam), 3-hydroxy-tam (Droloxifene), and 4-hydroxy-tam (4-OH-tam). Higher levels of catechol were formed from 4-OH-tam and 3-hydroxy-tam than from tam. Evidence that human hepatic CYP3A4 and 2D6 catalyze the formation of tam catechol from 4-OH-tam and supportive data that the catechol is proximate to the reactive intermediate, was obtained: 1) There was a good correlation (r = 0.82; p </=.0004) between steroidal 6beta-hydroxylase (CYP3A activity) and ortho hydroxylation of 4-OH-tam in human liver microsomes; 2) monospecific antibodies against CYP3A4 strongly inhibited catechol formation from 4-OH-tam and its covalent binding to proteins in human liver microsomes; 3) low levels of ketoconazole inhibited catechol tam accumulation and covalent binding of 4-OH-tam to human liver proteins; 4) among human P-450s expressed in insect cells (supersomes), only CYP3A4 and 2D6 noticeably catalyzed catechol formation, and cytochrome b5 markedly stimulated the CYP3A4 catalysis; and 5) human livers with high CYP3A and low or high CYP2D6 activity exhibited high catechol formation and those with low 3A and 2D6 activities formed only little catechol. These findings demonstrate that CYP3A4 and to a lesser extent 2D6 catalyze tam catechol formation and support the participation of tam catechol in covalent binding to proteins.

Animals↗
PubMed2004

Phytochemicals inhibit catechol-O-methyltransferase activity in cytosolic fractions from healthy human mammary tissues: implications for catechol estrogen-induced DNA damage.

Phytochemicals are natural dietary constituents of fruits and vegetables. Some of these phytochemicals are known to affect estrogen-metabolizing enzymes. In breast tissue, estradiol can be metabolized to the catechol estrogens 2- and 4-hydroxyestradiol (2-OHE(2) and 4-OHE(2)). Catechol estrogens are suspected carcinogens potentially involved in the etiology of breast cancer. Catechol-O-methyltransferase (COMT) converts the catechol estrogens to their inactive methoxy derivatives (2-MeOE(2) and 4-MeOE(2)). In this study we investigated the effects of several phytochemicals on COMT activity in cytosolic fractions of seven healthy human mammary tissues from reduction mammoplasty. Large interindividual variations were observed in the constitutive levels of COMT activity. However, in all cytosol samples the catalytic efficiency of COMT was greater for 2-MeOE(2) formation than for 4-MeOE(2) formation. The known COMT inhibitor Ro 41-0960 and several phytochemicals with a catechol structure (quercetin, catechin, and (-)-epicatechin) concentration-dependently inhibited COMT activity, while phytochemicals without a catechol structure (genistein, chrysin, and flavone) showed no effect up to 30 microM. Distinct interindividual variations were observed in sensitivity toward COMT inhibition among the various tissue samples, as was shown by the range in IC(50) values for Ro 41-0960 (5-42 nM). The toxicological relevance of COMT inhibition and the effect of reduced inactivation of catechol estrogens was studied by determining the amount of catechol estrogen-induced DNA damage in MCF-7 cells using the comet assay. Catechol estrogens alone caused no increase of DNA damage compared with control treated cells. However, both Ro 41-0960 and quercetin caused a decrease of methoxy estradiol formation and an increase of catechol estrogen-induced DNA damage in MCF-7 cells. This suggests that phytochemicals with a catechol structure have the potential to reduce COMT activity in mammary tissues and may consequently reduce the inactivation of potentially mutagenic estradiol metabolites and increase the chance of DNA damage.

Benzophenones↗
PubMed2001

Molecular mechanisms controlling the rate and specificity of catechol O-methylation by human soluble catechol O-methyltransferase.

Molecular mechanisms determining the turn-over rate and specificity of catechol O-methylation were studied by combining enzyme kinetic measurements, computational modeling of substrate properties and fitting ligands in a 3D model of the active site of the enzyme. Enzyme kinetic measurements were carried out for 46 compounds, including most clinically used catechol drugs, by using recombinant human soluble catechol O-methyltransferase (COMT). The most important mechanism decreasing the turnover rate and increasing affinity was the electron withdrawing effect of substituents. Several other mechanisms by which substituents affected reactivity and affinity were identified. Highest turnover rates were determined for unsubstituted catechol and pyrogallol. Pyrogallol derivatives generally seemed to be more specific substrates than catechols. Catecholestrogens were the most specific endogenous substrates, whereas catecholamines were rather poor substrates. Among the catechol drugs used in the L-DOPA treatment of Parkinson's disease, the COMT inhibitors entacapone and tolcapone were not methylated, whereas the DOPA decarboxylase inhibitor benserazide was 15 times more specific substrate than L-DOPA, the target of COMT inhibition. The structure-activity relationships found allow the prediction of reactivity, affinity, and specificity with useful accuracy for catechols with a wide range of structures and properties. The knowledge can be used in the evaluation of metabolic interactions of endogenous catechols, drugs and dietary catechols, and in the designing of drugs with the catechol pharmacophore.

Binding Sites↗
PubMed2001

Acute toxicity of (chloro-)catechols and (chloro-)catechol-copper combinations in Escherichia coli corresponds to their membrane toxicity in vitro.

(Chloro-)catechols are toxic for bacteria and higher organisms, but the mode of action is not yet clearly understood. We have compared the acute toxicity of different chlorinated catechols to Escherichia coli with membrane toxic effects, namely narcosis and uncoupling that we have determined in an in vitro assay. In vitro membrane toxicity was quantified by measuring the accelerated decay of the membrane potential of chromatophores isolated from Rhodobacter sphaeroides. Both acute and membrane toxicity increased with increasing degree of chlorination. Analysis of dose-response curves, pH dependence, and estimated membrane concentrations gave a consistent picture of the mechanisms of membrane toxicity: At pH 7, the higher-chlorinated catechols acted as uncouplers of oxidative and photophosphorylation, and the lower-chlorinated catechols and catechol acted as narcotics. In the case of 3,5-dichlorocatechol and 4-monochlorocatechol at pH 8.8, both mechanisms appeared to contribute to the overall toxicity. Copper exhibited a diverging effect on the toxicity of catechols and of (chloro-)catechols to E. coli. Whereas the presence of copper increased the toxicity of catechol and 4-monochlorocatechol, the toxicity of 3,5-dichlorocatechol, 3,4,5-trichlorocatechol, and tetrachlorocatechol decreased. Again, the results obtained with in vitro assays agreed with the acute toxicity observed in E. coli: The presence of copper accelerated decay of the membrane potential of catechol and 4-monochlorocatechol; however, the effect was reversed by copper in experiments with 3,5-dichlorocatechol, 3,4,5-trichlorocatechol, and tetrachlorocatechol. We have proposed a mechanistic model to explain the diverging effects of copper on the uncoupling activities of the different catechols.

Catechols↗
PubMed2004

Quantitative structure-activity relationship for the cleavage of C3/C4-substituted catechols by a prototypal extradiol catechol dioxygenase with broad substrate specificity.

Catechol 2,3-dioxygenase [EC 1.13.11.2] from Pseudomonas putida mt-2 (Mpc) catalyzes the extradiol cleavage of catechol to produce 2-hydroxymuconate semialdehyde. The K(m) values for the catecholic substrate (K(mA)) and O(2) (K(mO2)), and catalytic constants (k(cat)) were kinetically determined for eight C3/C4-substituted catechols at 25 degrees C and pH 6.5 or 7.5. The first pK(a) values (pK(1)) were determined for eleven catechols (pK(1) = 7.26-9.47), correlated with Hammett substituent constants, and electron-withdrawing substituents significantly stabilized the monoanionic species of free catechols. Mpc preferred catechols with non-ionic substituents at the C3 or C4 position. 3-Phenylcatechol, a biphenyl, was cleaved, while 4-tert-butylcatechol was not. The logarithm of k(cat)/K(mA) (substrate specificity constant) exhibited a good linear correlation with pK(1), with the exception of those for 4-halocatechols. The logarithm of k(cat)/K(mO2) showed a good linear correlation with pK(1), with the exception of that of 3-phenylcatechol. These results demonstrate that catechol binding to the Mpc active site, the following O(2) binding, and the activation of the bound O(2) are all sensitive to electronic effects of the substituents. However, k(cat) did not correlate significantly with pK(1). The present study distinguishes clearly between the electronic and the steric effects of catecholic substrates in the reactivity of Mpc, and provides important insight into the mechanistic basis for a vast range of substrate specificities of extradiol dioxygenases.

Binding Sites↗
PubMed2001

Production of catechol from benzoate by the wild strain Ralstonia species Ba-0323 and characterization of its catechol 1,2-dioxygenase.

Ralstonia sp. Ba-0323, a wild strain isolated from soil, produced catechol from benzoate and accumulated it outside the cells. The bacterium produced a maximal amount of catechol (1.6 mg/ml) from 3 mg/ml of sodium benzoate in a 20-h growing culture. The conversion rate of benzoate to catechol was 70% on a molar basis. The catechol production by the resting cells increased in the presence of glycerol, and the maximal amount of catechol produced from 3 mg/ml of sodium benzoate reached 1.9 mg/ml at the conversion rate of 83% after 8 h of incubation. Catechol 1,2-dioxygenase, which catalyzed the ring cleavage of catechol, was purified to homogeneity from a cell extract of Ralstonia sp. Ba-0323 growing on benzoate and characterized. The specific activity of the purified enzyme was much lower than those of the dioxygenases from other microorganisms reported. The Km for catechol of the purified enzyme was much higher than those of other dioxygenases. In addition, the NH2-terminal amino acid sequence of the enzyme was less similar to the other catechol 1,2-dioxygenases than they are to each other.

Amino Acid Sequence↗
PubMed1998

A semiempirical study on inhibition of catechol O-methyltransferase by substituted catechols.

Catechol and endogenous catechol derivatives are readily methylated by catechol O-methyltransferase (COMT). In contrast, many catechol derivatives possessing electronegative substituents are potent COMT inhibitors. The X-ray structure of the active site of COMT suggests that the methylation involves a lysine as a general base. The lysine can activate one of the catecholic hydroxyl groups for a nucleophilic attack on the active methyl group of the coenzyme S-adenosyl-L-methionine (AdoMet). We studied the effect of dinitrosubstitution of the catecholic ring at the semiempirical PM3 level on the methylation reaction catalysed by COMT. The electronegative nitro groups make the ionized catechol hydroxyls less nucleophilic than the corresponding hydroxyl groups of the non-substituted catechol. As a consequence, dinitrocatechol is not methylated but is instead a potent COMT inhibitor. The implications of this mechanism to the design of COMT inhibitors are discussed.

Binding Sites↗
PubMed1993

Microsomal hydroxylation of 2- and 4-fluoroestradiol to catechol metabolites and their conversion to methyl ethers: catechol estrogens as possible mediators of hormonal carcinogenesis.

In male Syrian hamsters, an animal model for estradiol-induced carcinogenesis, 2-fluoroestradiol was not carcinogenic, whereas 4-fluoroestradiol induced kidney tumors after a prolonged latency period, compared with estradiol (100% tumor incidence), when the compounds were administered to hamsters in hormonally equipotent doses. Catechol estrogen metabolites have previously been postulated to mediate this estrogen-induced kidney carcinogenesis. To examine this proposed mechanism of tumor induction by estrogens, we investigated the conversion of 2- and 4-fluoroestradiol to catechol metabolites by kidney and liver microsomes of hamsters and the further conversion to methyl ethers by catechol-O-methyltransferase, and we compared the values with those obtained with nonfluorinated estrogens as substrates. The rates of conversion of 2-fluoroestradiol to 2-hydroxyestradiol and 2-fluoro-4-hydroxyestradiol by hepatic microsomes were 30-50% lower than corresponding rates with estradiol as substrate. With renal microsomes the rate of 4-hydroxylation was 10 times faster than that of estradiol, whereas 2-hydroxylation was at best marginal. With 4-fluoroestradiol as substrate the rate of 2-hydroxylation by hepatic microsomes was enhanced 5-fold, compared with values for estradiol, but 4-hydroxyestradiol formation was almost eliminated. In contrast, the conversion of this substrate to 4-fluoro-2-hydroxyestradiol by kidney microsomes occurred at a rate 15 times faster than 2-hydroxylation of estradiol, whereas 4-hydroxyestradiol formation proceeded at a rate of 315 pmol/mg of protein/min. Except for the decrease in both 2- and 4-hydroxylation of 2-fluoroestradiol by liver microsomes, fluorine substitution of estrogenic phenols enhanced microsome-mediated aromatic hydroxylation at sites unoccupied by substituents. At pH 7.5, the highest rates of catechol-O-methyltransferase-mediated methylation were observed with the catechol metabolites of 2-fluoroestradiol, 2-fluoro-4-hydroxyestradiol and 2-hydroxyestradiol (3780 and 2960 pmol/mg of protein/min, respectively). Lower rates were found with those of 4-fluoroestradiol, 4-fluoro-2-hydroxyestradiol and 4-hydroxyestradiol (1670 and 470 pmol/mg of protein/min, respectively). These data are consistent with the postulate that catechol metabolites of estrogens are reactive intermediates in estrogen-induced carcinogenesis. For the noncarcinogenic 2-fluoroestradiol, a high metabolic flux was observed through a pathway of renal 2-fluoro-4-hydroxyestradiol formation and further conversion to methyl ethers. This flux likely results in low steady state concentrations of catechol metabolites in kidneys of hamsters treated with this modified estrogen and therefore in its lack of carcinogenic activity. In contrast, the carcinogenic activity of 4-fluoroestradiol is consistent with its rapid conversion in the kidney to 2- and 4-hydroxylated metabolites and a less rapid methylation of these catechols.

Animals↗
PubMed1989

Comparison of assays for catechol estrogen synthase activity: product isolation vs radioenzymatic catechol-O-methyltransferase-coupled procedures.

Reported values for the activity of enzymes mediating catechol estrogen formation by hamster kidney and liver, measured by catechol-O-methyltransferase-coupled radioenzymatic assay, have been uniformly low and there have been marked discrepancies in values reported from different laboratories. Therefore, we examined the validity of the radioenzymatic assay used in these studies. NADPH-dependent estrogen 2- and 4-hydroxylase activity of hamster liver microsomes measured by radioenzymatic assay was comparable to that reported in the literature but at least one order of magnitude lower than that obtained with a direct product isolation assay. Several features of the radioenzymatic assay were identified which, together, contribute to the underestimation of enzyme activity. They include, incomplete protection from oxidative degradation of both the catechol estrogens generated and of the catechol-O-methyltransferase and assay conditions which are suboptimal for O-methylation of the catechol estrogens. We conclude that results obtained using the catechol-O-methyltransferase-based radioenzymatic assay can only be considered valid if a consistent stoichiometric relationship can be demonstrated between the amounts of catechol estrogens and their O-methylated products.

Animals↗
PubMed2001

Models for extradiol cleaving catechol dioxygenases: syntheses, structures, and reactivities of iron(II)-monoanionic catecholate complexes.

Crystallographic and spectroscopic studies of extradiol cleaving catechol dioxygenases indicate that the enzyme-substrate complexes have both an iron(II) center and a monoanionic catecholate. Herein we report a series of iron(II)-monoanionic catecholate complexes, [(L)Fe(II)(catH)](X) (1a, L = 6-Me(3)-TPA (tris(6-methyl-2-pyridylmethyl)amine), catH = CatH (1,2-catecholate monoanion); 1b, L = 6-Me(3)-TPA, catH = DBCH (3,5-di-tert-butyl-1,2-catecholate monoanion); 1c, L = 6-Me(2)-bpmcn (N,N'-dimethyl-N,N'-bis(6-methyl-2-pyridylmethyl)-trans-1,2-diaminocyclohexane), catH = CatH; 1d, L = 6-Me(2)-bpmcn, catH = DBCH), that model such enzyme complexes. The crystal structure of [(6-Me(2)-bpmcn)Fe(II)(DBCH)](+) (1d) shows that the DBCH ligand binds to the iron asymmetrically as previously reported for 1b, with two distinct Fe-O bonds of 1.943(1) and 2.344(1) A. Complexes 1 react with O(2) or NO to afford blue-purple iron(III)-catecholate dianion complexes, [(L)Fe(III)(cat)](+) (2). Interestingly, crystallographically characterized 2d, isolated from either reaction, has the N-methyl groups in a syn configuration, in contrast to the anti configuration of the precursor complex, so epimerization of the bound ligand must occur in the course of isolating 2d. This notion is supported by the fact that the UV-vis and EPR properties of in situ generated 2d(anti) differ from those of isolated 2d(syn). While the conversion of 1 to 2 in the presence of O(2) occurs without an obvious intermediate, that in the presence of NO proceeds via a metastable S = (3)/(2) [(L)Fe(catH)(NO)](+) adduct 3, which can only be observed spectroscopically but not isolated. Intermediates 3a and 3b subsequently disproportionate to afford two distinct complexes, [(6-Me(3)-TPA)Fe(III)(cat)](+) (2a and 2b) and [(6-Me(3)-TPA)Fe(NO)(2)](+) (4) in comparable yield, while 3d converts to 2d in 90% yield. Complexes 2b and anti-2d react further with O(2) over a 24 h period and afford a high yield of cleavage products. Product analysis shows that the products mainly derive from intradiol cleavage but with a small extent of extradiol cleavage (89:3% for 2b and 78:12% for anti-2d). The small amounts of the extradiol cleavage products observed may be due to the dissociation of an alpha-methyl substituted pyridyl arm, generating a complex with a tridentate ligand. Surprisingly, syn-2d does not react with O(2) over the course of 4 days. These results suggest that there are a number of factors that influence the mode and rate of cleavage of catechols coordinated to iron centers.

Catechol 1,2-Dioxygenase↗
PubMed1998

Quantitative structure/activity relationship for the rate of conversion of C4-substituted catechols by catechol-1,2-dioxygenase from Pseudomonas putida (arvilla) C1.

The influence of various C4/C5 substituents in catechol (1,2-dihydroxybenzene) derivatives on the overall rate of conversion by catechol-1,2-dioxygenase from Pseudomonas putida (arvilla) C1 was investigated. Using catechol, 4-methylcatechol, 4-fluorocatechol, 4-chlorocatechol, 4-bromocatechol, 4,5-difluorocatechol and 4-chloro-5-fluorocatechol, it could be demonstrated that substituents at the C4 and/or C5 position decrease the rate of conversion, from 62% (4-methylcatechol) down to 0.7% (4-chloro-5-fluorocatechol) of the activity with non-substituted catechol. The inhibition was reversible upon addition of excess catechol for all substrates tested. This indicates that the lower activities are neither due to irreversible inactivation of the enzyme nor to product inhibition. Based on the reaction mechanism proposed in the literature [Que, L. & Ho, R. Y. N. (1996) Chem. Rev. 96, 2606-2624], the nucleophilic reactivity of the catecholate was expected to be an essential characteristic for its conversion by catechol-1,2-dioxygenase. Therefore, the rates of conversion were compared with calculated energies of the highest occupied molecular orbital (E(HOMO)) of the substrates. A clear quantitative relationship (R>0.97) between the ln kcat and the calculated electronic parameter E(HOMO) was obtained. This indicates that the rate-limiting step of the reaction cycle is dependent on the nucleophilic reactivity of the substrate and not sterically hindered by the relatively large bromine or methyl substituents used in the present study. Possible steps in the reaction mechanism determining the overall rate at 20 degrees C are discussed.

Catechol 1,2-Dioxygenase↗
PubMed1989

Catechol stimulation of ferricyanide Hill reaction by spheroplasts of cyanobacterium, Synechococcus cedrorum: effect of temperature on catechol-stimulated oxygen evolution.

Catechol(o-dihydroxybenzene) at low concentrations (20-100 microM) stimulates FeCN-dependent O2 evolution of spheroplasts isolated from the cyanobacterium Synechococcus both in the presence and absence of DBMIB, an inhibitor of electron flow from PSII to PSI, the stimulation being two-fold with saturating concentration of (60 microM) catechol. Catechol thus appears to mediate the acceptance of electrons at the reducing side of PSII. Similarly it may act on the component of electron donor to PSII and caused the photoreduction of FeCN when O2 evolution capacity of spheroplasts is damaged by heat treatment. Analysis of the temperature effect on FeCN-supported O2 evolution by spheroplasts suggests that catechol shifts the temperature maxima to a lower temperature and thereby hastens the decay of O2 evolution capacity by heat as compared to the normal spheroplasts. Catechol also induces a change in the magnitude of activation energy for ferricyanide Hill activity of spheroplasts and lowers the transition temperature. These results suggest that lipophilic catechol brings about an alteration in membrane fluidity in cyanobacterial spheroplasts. Catechol is involved in a thermotropic destabilization of the membrane of the cyanobacterium. However, Al3+ was found to stabilize the membrane and raise the phase transition temperature. Further increase in temperature caused a gradual decline in the rate of O2 evolution.

Catechols↗