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PubMed1993

New aerobic benzoate oxidation pathway via benzoyl-coenzyme A and 3-hydroxybenzoyl-coenzyme A in a denitrifying Pseudomonas sp.

A denitrifying Pseudomonas sp. is able to oxidize aromatic compounds compounds completely to CO2, both aerobically and anaerobically. It is shown that benzoate is aerobically oxidized by a new degradation pathway via benzoyl-coenzyme A (CoA) and 3-hydroxybenzoyl-CoA. The organism grew aerobically with benzoate, 3-hydroxybenzoate, and gentisate; catechol, 2-hydroxybenzoate, and protocatechuate were not used, and 4-hydroxybenzoate was a poor substrate. Mutants were obtained which were not able to utilize benzoate as the sole carbon source aerobically but still used 3-hydroxybenzoate or gentisate. Simultaneous adaptation experiments with whole cells seemingly suggested a sequential induction of enzymes of a benzoate oxidation pathway via 3-hydroxybenzoate and gentisate. Cells grown aerobically with benzoate contained a benzoate-CoA ligase (AMP forming) (0.1 mumol min-1 mg-1) which converted benzoate but not 3-hydroxybenzoate into its CoA thioester. The enzyme of 130 kDa composed of two identical subunits of 56 kDa was purified and characterized. Cells grown aerobically with 3-hydroxybenzoate contained a similarly active CoA ligase for 3-hydroxybenzoate, 3-hydroxybenzoate-CoA ligase (AMP forming). Extracts from cells grown aerobically with benzoate catalyzed a benzoyl-CoA- and flavin adenine dinucleotide-dependent oxidation of NADPH with a specific activity of at least 25 nmol NADPH oxidized min-1 mg of protein-1; NADH and benzoate were not used. This new enzyme, benzoyl-CoA 3-monooxygenase, was specifically induced during aerobic growth with benzoate and converted [U-14C]benzoyl-CoA stoichiometrically to [14C]3-hydroxybenzoyl-CoA.

Acyl Coenzyme A↗
PubMed1978

Skin tumor-initiating activities of the twelve isomeric phenols of benzo(a)pyrene.

The skin tumor-initiating activities of the 12 isomeric phenols of benzo(a)pyrene (BP) were determined in mice by use of a two-stage system of tumorigenesis. 11-Hydroxybenzo(a)pyrene was moderately active, whereas 2-hydroxybenzo(a)pyrene and BP were strong tumor initiators when applied topically to CD-1 mice and followed by twice-weekly applications of the promoter 12-O-tetradecanoylphorbol-13-acetate. 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, and 12-hydroxybenzo(a)pyrene had less than 5% of the tumor-initiating activity of BP when the data were expressed as papillomas per mouse. After 30 weeks of promotion, the number of papillomas per mouse was 8.4, 8.5, and 2.8, respectively, for the animals treated with BP, 2-hydroxybenzo(a)pyrene, and 11-hydroxybenzo(a)pyrene. A 5-week latency period before the appearance of the first tumor was observed after the application of either 2-hydroxybenzo(a)pyrene or BP, whereas a slightly longer latency period of 7 weeks was observed following application of 11-hydroxybenzo(a)pyrene. The time required for 50% of the animals to develop tumors was 13 weeks for animals treated with BP and 15 weeks for animals treated with 2- or 11-hydroxybenzo(a)pyrene.

Animals↗
PubMed2003

Transcriptional cross-regulation of the catechol and protocatechuate branches of the beta-ketoadipate pathway contributes to carbon source-dependent expression of the Acinetobacter sp. strain ADP1 pobA gene.

Transcriptional control of carbon source preferences by Acinetobacter sp. strain ADP1 was assessed with a pobA::lacZ fusion during growth on alternative substrates. The pobA-encoded enzyme catalyzes the first step in the degradation of 4-hydroxybenzoate, a compound consumed rapidly as a sole carbon source. If additional aromatic carbon sources are available, 4-hydroxybenzoate consumption is inhibited by unknown mechanisms. As reported here, during growth on aromatic substrates, pobA was not expressed despite the presence of 4-hydroxybenzoate, an inducer that normally causes the PobR regulator to activate pobA transcription. Growth on organic acids such as succinate, fumarate, and acetate allowed higher levels of pobA expression. In each case, pobA expression increased at the end of the exponential growth phase. Complex transcriptional regulation controlled 4-hydroxybenzoate catabolism in multisubstrate environments. Additional studies focused on the wild-type preference for benzoate consumption prior to 4-hydroxybenzoate consumption. These compounds are degraded via the catechol and protocatechuate branches of the beta-ketoadipate pathway, respectively. Here, mutants were characterized that degraded benzoate and 4-hydroxybenzoate concurrently. These mutants lacked the BenM and CatM transcriptional regulators that normally activate genes for benzoate catabolism. A model is presented in which BenM and CatM prevent pobA expression indirectly during growth on benzoate. These regulators may affect pobA expression by lowering the PcaK-mediated uptake of 4-hydroxybenzoate. Consistent with this model, BenM and CatM bound in vitro to an operator-promoter fragment controlling the expression of several pca genes, including pcaK. These studies provide the first direct evidence of transcriptional cross-regulation between the distinct but analogous branches of the beta-ketoadipate pathway.

Acinetobacter↗
PubMed2000

Lack of oestrogenic effects of food preservatives (parabens) in uterotrophic assays.

The oestrogenic activity of the parabens, methyl-, ethyl- and propyl p-hydroxybenzoate, widely used as antimicrobials in food, and butyl p-hydroxybenzoate, which is used in cosmetic products, and their shared main metabolite p-hydroxybenzoic acid was investigated in a mouse uterotrophic assay. Immature B6D2F1 mice were treated with oral or subcutaneous doses of the test compounds for three consecutive days. p-Hydroxybenzoic acid and butyl p-hydroxybenzoate were also tested by the subcutaneous route in a rat uterotrophic assay. A significant increase in the uterus weight at day 4 was considered an oestrogenic effect. In the mouse assay, none of the compounds tested produced any oestrogenic response at dose levels up to 100mg/kg body weight per day, for ethyl p-hydroxybenzoate even at a dose level of 1000mg/kg body weight per day. In immature Wistar rats, subcutaneous administration of butyl p-hydroxybenzoate produced a weak oestrogenic response at 600mg/kg body weight per day.

Administration, Oral↗
PubMed2004

Synergistic effect of antioxidant phenolic acids on human phenolsulfotransferase activity.

Sulfate conjugation by phenolsulfotransferases (PSTs) is an important process in the detoxification of xenobiotics and endogenous compounds. There are two forms of PSTs for the sulfation of small phenols (PST-P) and monoamines (PST-M). Phenolic acids are known to increase the activities of PST-P and PST-M. The purpose of this study is to investigate the synergistic effect of the combinations of phenolic acids on human PSTs activities. The combinations of p-hydroxybenzoic acid, gentisic acid, ferulic acid, gallic acid, and coumaric acid in a random order for their effects on PSTs activities were evaluated at concentrations of 2.5, 5.0, and 7.5 microM. The PST-M activity was significantly increased when gentisic acid was combined with each of the other phenolic acids. When p-hydroxybenzoic acid was combined with each of the other phenolic acids, a synergistic effect with respect to the promotion of PST-P activity was obtained. A potential synergistic effect for the PST-P activity was also found in the following combination: p-hydroxybenzoic acid + gallic acid + gentisic acid, p-hydroxybenzoic acid + gallic acid + m-coumaric acid, p-hydroxybenzoic acid + o-coumaric acid + p-coumaric acid, p-hydroxybenzoic acid + o-coumaric acid + m-coumaric acid, gallic acid + gentisic acid + p-coumaric acid, and gallic acid + o-coumaric acid + m-coumaric acid. Therefore, the activities of both forms of PSTs can be promoted by all of these combinations of phenolic acids. These results provide a better understanding regarding the effect of phenolic acids on human PSTs activities, as well as more information on the intake of antioxidant phenolic acids for human health.

Antioxidants↗
PubMed2005

Functional identification of novel genes involved in the glutathione-independent gentisate pathway in Corynebacterium glutamicum.

Corynebacterium glutamicum used gentisate and 3-hydroxybenzoate as its sole carbon and energy source for growth. By genome-wide data mining, a gene cluster designated ncg12918-ncg12923 was proposed to encode putative proteins involved in gentisate/3-hydroxybenzoate pathway. Genes encoding gentisate 1,2-dioxygenase (ncg12920) and fumarylpyruvate hydrolase (ncg12919) were identified by cloning and expression of each gene in Escherichia coli. The gene of ncg12918 encoding a hypothetical protein (Ncg12918) was proved to be essential for gentisate-3-hydroxybenzoate assimilation. Mutant strain RES167Deltancg12918 lost the ability to grow on gentisate or 3-hydroxybenzoate, but this ability could be restored in C. glutamicum upon the complementation with pXMJ19-ncg12918. Cloning and expression of this ncg12918 gene in E. coli showed that Ncg12918 is a glutathione-independent maleylpyruvate isomerase. Upstream of ncg12920, the genes ncg12921-ncg12923 were located, which were essential for gentisate and/or 3-hydroxybenzoate catabolism. The Ncg12921 was able to up-regulate gentisate 1,2-dioxygenase, maleylpyruvate isomerase, and fumarylpyruvate hydrolase activities. The genes ncg12922 and ncg12923 were deduced to encode a gentisate transporter protein and a 3-hydroxybenzoate hydroxylase, respectively, and were essential for gentisate or 3-hydroxybenzoate assimilation. Based on the results obtained in this study, a GSH-independent gentisate pathway was proposed, and genes involved in this pathway were identified.

Bacterial Proteins↗
PubMed2004

Interaction of mushroom tyrosinase with aromatic amines, o-diamines and o-aminophenols.

3-Amino-L-tyrosine was found to be a substrate of mushroom tyrosinase, contrary to what had previously been reported in the literature. A series of amino derivatives of benzoic acid were tested as substrates and inhibitors of the enzyme. 3-Amino-4-hydroxybenzoic acid, 4-amino-3-hydroxybenzoic acid and 3,4-diaminobenzoic acid were oxidized by this enzyme, as previously reported for Neurospora crassa tyrosinase, but 4-aminobenzoic acid and 3-aminobenzoic acid were not. Interestingly, 3-amino-4-hydroxybenzoic acid was oxidized five times faster than 4-amino-3-hydroxybenzoic acid, confirming the importance of proton transfer from the hydroxyl group at C-4 position. All compounds inhibited the monophenolase activity but their effect on the diphenolase activity was small or negligible. 3-Amino-4-hydroxybenzoic acid was a stronger inhibitor than 4-amino-3-hydroxybenzoic acid, indicating their different binding affinity to the oxy form of the enzyme. Both, however, were weaker inhibitors than 3-amino-L-tyrosine, 4-methoxy-o-phenylenediamine and 3,4-diaminobenzoic acid, which was the strongest inhibitor from among the compounds tested. These results show that the relative positioning of the amino group and the hydroxy group in o-aminophenols with respect to the side chain is important both for binding to the dicopper center and for catalysis.

Agaricales↗
PubMed1980

Evidence for isofunctional enzymes used in m-cresol and 2,5-xylenol degradation via the gentisate pathway in Pseudomonas alcaligenes.

Study of the reaction sequence by which Pseudomonas alcaligenes (P25X1) and derived mutants degrade m-cresol, 2,5-xylenol, and their catabolites has provided indirect evidence for the existence of two or more isofunctional enzymes at three different steps. Maleylpyruvate hydrolase activity appears to reside in two different proteins with different specificity ranges, one of which (MPH1) is expressed constitutively; the other (MPH11) is strictly inducible. Two gentisate 1,2-dioxygenase activities were found, one of which is constitutively expressed and possesses a broader specificity range than the other, which is inducible. From oxidation studies with intact cells, there appear to be two activities responsible for the 6-hydroxylation of 3-hydroxybenzoate, and again a broadly specific activity is present regardless of growth conditions; the other is inducible by 3-hydroxybenzoate. Three other enzyme activities are also detected in uninduced cells, viz., xylenol methylhydroxylase, benzylalcohol dehydrogenase, and benzaldehyde dehydrogenase. All apparently possess broad specificity. Fumarylpyruvate hydrolase was also detected but only in cells grown with m-cresol, 3-hydroxybenzoate, or gentisate. Mutants, derived either spontaneously or after treatment with mitomycin C, are described, certain of which have lost the ability to grow with m-cresol and 2,5-xylenol and some of which have also lost the ability to form the constitutive xylenol methylhydroxylase, benzylalcohol dehydrogenase, benzaldehyde dehydrogenase, 3-hydroxybenzoate 6-hydroxylase, and gentisate 1,2-dioxygenase. Such mutants, however, retain ability to synthesize inducibly a second 3-hydroxybenzoate 6-hydroxylase and gentisate 1,2-dioxygenase, as well as maleylpyruvate hydrolase (MPH11) and fumarylpyruvate hydrolase; MPH1 was still synthesized. These findings suggest the presence of a plasmid for 2,5-xylenol degradation which codes for synthesis of early degradative enzymes. Other enzymes, such as the second 3-hydroxybenzoate 6-hydroxylase, gentisate 1,2-dioxygenase, maleylpyruvate hydrolase (MPH1 and MPH11), and fumarylpyruvate hydrolase, appear to be chromosomally encoded and, with the exception of MPH1, strictly inducible.

Alcohol Oxidoreductases↗
PubMed2004

Phenylphosphate carboxylase: a new C-C lyase involved in anaerobic phenol metabolism in Thauera aromatica.

The anaerobic metabolism of phenol in the beta-proteobacterium Thauera aromatica proceeds via carboxylation to 4-hydroxybenzoate and is initiated by the ATP-dependent conversion of phenol to phenylphosphate. The subsequent para carboxylation of phenylphosphate to 4-hydroxybenzoate is catalyzed by phenylphosphate carboxylase, which was purified and studied. This enzyme consists of four proteins with molecular masses of 54, 53, 18, and 10 kDa, whose genes are located adjacent to each other in the phenol gene cluster which codes for phenol-induced proteins. Three of the subunits (54, 53, and 10 kDa) were sufficient to catalyze the exchange of 14CO2 and the carboxyl group of 4-hydroxybenzoate but not phenylphosphate carboxylation. Phenylphosphate carboxylation was restored when the 18-kDa subunit was added. The following reaction model is proposed. The 14CO2 exchange reaction catalyzed by the three subunits of the core enzyme requires the fully reversible release of CO2 from 4-hydroxybenzoate with formation of a tightly enzyme-bound phenolate intermediate. Carboxylation of phenylphosphate requires in addition the 18-kDa subunit, which is thought to form the same enzyme-bound energized phenolate intermediate from phenylphosphate with virtually irreversible release of phosphate. The 54- and 53-kDa subunits show similarity to UbiD of Escherichia coli, which catalyzes the decarboxylation of a 4-hydroxybenzoate derivative in ubiquinone (ubi) biosynthesis. They also show similarity to components of various decarboxylases acting on aromatic carboxylic acids, such as 4-hydroxybenzoate or vanillate, whereas the 10-kDa subunit is unique. The 18-kDa subunit belongs to a hydratase/phosphatase protein family. Phenylphosphate carboxylase is a member of a new family of carboxylases/decarboxylases that act on phenolic compounds, use CO2 as a substrate, do not contain biotin or thiamine diphosphate, require K+ and a divalent metal cation (Mg2+or Mn2+) for activity, and are strongly inhibited by oxygen.

Anaerobiosis↗
PubMed1995

Hydroxylation of aromatic compounds as indices of hydroxyl radical production: a cautionary note revisited.

While setting up an intracerebral microdialysis system to estimate the extent of oxidative stress induced by the neurotoxin, N-methylphenylpyridinium ion (MPP+), we encountered a problem in the use of hydroxybenzoic acids as traps of hydroxyl radicals. Using either 2-hydroxybenzoate (salicylate) or 4-hydroxybenzoate as trapping agents, we observed a nonspecific, that is, nontissue derived, production of hydroxyl radicals as measured by the hydroxylation products, 2,3- and 2,5-dihydroxybenzoate from 2-hydroxybenzoate and 3,4-dihydroxybenzoate from 4-hydroxybenzoate. This production of dihydroxybenzoates was 10 times that expected due to the administration of MPP+, thus making it impossible to interpret our results. Careful investigation of the various components of the microdialysis system indicated that contact of the microdialysate with metal surfaces resulted in dihydroxybenzoic acid formation. These results should serve as a reminder to perform stringent tests of the experimental system prior to experiments with biological tissues to evaluate the contribution of hydroxyl radical production from nonbiological sources. Therefore, along with the possibility of enzymatic production of dihydroxybenzoates, artefactual production by components of the experimental apparatus must be considered before assuming that one is measuring hydroxyl radical production by a biological system.

1-Methyl-4-phenylpyridinium↗
PubMed1981

Resonance Raman studies on protocatechuate 3,4-dioxygenase-inhibitor complexes.

Resonance Raman spectra of a number of protocatechuate 3,4-dioxygenase-inhibitor complexes were studied by use of the available lines of an argon and a krypton laser. Three types of inhibitors were investigated-hydroxybenzoates, dicarboxylates, and 4-nitrocatechol. The hydroxybenzoate study shows that the hydroxy group in 3-hydroxybenzoate does not coordinate to the active site iron, in agreement with earlier suggestions, and confirms the coordination of the hydroxy group in the isomeric 4-hydroxybenzoate. The dicarboxylate study demonstrates that both glutarate and terephthalate perturb the active-site environment, shifting the charge-transfer interaction to lower energy. The pH dependence of terephthalate binding as well as the spectral similarities of the dicarboxylate complexes to the ESO2 intermediate provides further evidence for the suggestion that this intermediate is a tightly bound enzyme-product complex. The 4-nitrocatechol study indicates that, unlike the substrate catechols, 4-nitrocatechol does not bind to the iron; a binding configuration wherein the acidic phenolate group interacts with the carboxylate binding site has been suggested by others. Finally the spectra of the 4-hydroxybenzoate and terephthalate complexes demonstrate the presence of two tyrosines coordinated to the active-site iron as suggested by others; these tyrosines have different vCO's and excitation profiles.

Catechols↗
PubMed1978

Metabolism of cyclohexane carboxylic acid by Alcaligenes strain W1.

Thirty-three microorganisms capable of growth with cyclohexane carboxylate as the sole source of carbon were isolated from mud, water, and soil samples from the Aberystwyth area. Preliminary screening and whole-cell oxidation studies suggested that, with one exception, all of the strains metabolized the growth substrate by beta-oxidation of the coenzyme A ester. This single distinctive strain, able to oxidize rapidly trans-4-hydroxycyclohexane carboxylate, 4-ketocyclohexane carboxylate, p-hydroxybenzoate, and protocatechuate when grown with cyclohexane carboxylate, was classified as a strain of Alcaligenes and given the number W1. Enzymes capable of converting cyclohexane carboxylate to p-hydroxybenzoate were induced by growth with the alicyclic acid and included the first unambiguous specimen of a cyclohexane carboxylate hydroxylase. Because it is a very fragile protein, attempts to stabilize the cyclohexane carboxylate hydroxylase so that a purification procedure could be developed have consistently failed. In limited studies with crude cell extracts, we found that hydroxylation occurred at the 4 position, probably yielding the trans isomer of 4-hydroxycyclohexane carboxylate. Simultaneous measurement of oxygen consumption and reduced nicotinamide adenine dinucleotide oxidation, coupled with an assessment of reactant stoichiometry, showed the enzyme to be a mixed-function oxygenase. Mass spectral analysis enabled the conversion of cyclohexane carboxylate to p-hydroxybenzoate by cell extracts to be established unequivocally, and all of our data were consistent with the pathway: cyclohexane carboxylate --> trans-4-hydroxycyclohexane carboxylate --> 4-ketocyclohexane carboxylate --> p-hydroxybenzoate. The further metabolism of p-hydroxybenzoate proceeded by meta fission and by the oxidative branch of the 2-hydroxy-4-carboxymuconic semialde-hyde-cleaving pathway.

Alcaligenes↗
PubMed1993

Catabolism of benzene compounds by ascomycetous and basidiomycetous yeasts and yeastlike fungi. A literature review and an experimental approach.

A literature review is given on growth of yeasts on benzene compounds and on the catabolic pathways involved. Additionally, a yeast collection was screened for assimilation of phenol and 3-hydroxybenzoic acid. Fifteen ascomycetous and thirteen basidiomycetous yeast species were selected and were tested for growth on 84 benzene compounds. It appeared that 63 of these compounds supported growth of one or more yeast species. The black yeast Exophiala jeanselmei assimilated 54 of these compounds. The catechol branch of the 3-oxoadipate pathway and its hydroxyhydroquinone variant were involved in phenol and resorcinol catabolism of ascomycetes as well as of basidiomycetes. However, these two groups of yeasts showed characteristic differences in hydroxybenzoate catabolism. In the yeastlike fungus E. jeanselmei and in basidiomycetes of the genera Cryptococcus, Leucosporidium and Rhodotorula, the protocatechuate branch of the 3-oxoadipate pathway was induced by growth on 3- and 4-hydroxybenzoic acids. In three Trichosporon species and in all ascomycetous yeasts tested, 4-hydroxybenzoic acid was catabolyzed via protocatechuate and hydroxyhydroquinone. These yeasts were unable to cleave protocatechuate. 3-Hydroxybenzoic and 3-hydroxycinnamic acids were catabolized in ascomycetous yeasts via the gentisate pathway, but in basidiomycetes via protocatechuate. Incomplete oxidation of phenol, some chlorophenols, cresols and xylenols was observed in cultures of Candida parapsilosis growing on hydroquinone. Most compounds transformed by the growing culture were also converted by the phenol monooxygenase present in cell-free extracts of this yeast. They did not support growth. The relationship between the ability of ascomycetous yeasts to assimilate n-alkanes, amines and benzene compounds, and the presence of Coenzyme Q9 is discussed.

Ascomycota↗
PubMed1989

Identification of regulatory sites in the biosynthesis of ubiquinone in the perfused rat heart.

The biosynthesis of ubiquinone was studied in an isolated perfused beating heart preparation from adult male rats to determine rate-limiting steps in the biosynthetic pathway. The isolated heart could incorporate p-hydroxy[U-14C]benzoate into ubiquinones (ubiquinone-9 and -10) and two other lipids which were identified as 3-nonaprenyl 4-hydroxybenzoate and 3-decaprenyl 4-hydroxybenzoate. No other lipids could be detected. Addition of unlabeled mevalonolactone to the perfusate stimulated the rate of incorporation of p-hydroxy[U-14C]benzoate into 3-nonaprenyl 4-hydroxybenzoate and 3-decaprenyl 4-hydroxybenzoate. The level of radioactivity in these intermediates was much greater than that in ubiquinone-9 and -10. These results show that in the intact heart there is a large excess capacity to form postmevalonate isoprenoid precursors of ubiquinone and suggest a possible regulatory step at the premevalonate level. Moreover, the accumulation of prenylated derivatives of 4-hydroxybenzoic acid indicates further rate limitation at one or more of the subsequent steps in conversion of these intermediates to ubiquinone.

Animals↗
PubMed1984

Structural requirements for preventing the aspirin- and the arachidonate-induced inactivation of platelet cyclo-oxygenase: additional evidence for distinct enzymatic sites.

2-Hydroxybenzoic acid (salicylic acid) prevents the inhibition by aspirin (ASA) of platelet aggregation and of the generation of thromboxane A2 from arachidonic acid (AA). We studied the ability of 2-hydroxybenzoic acid analogues to block ASA and to prevent the platelet desensitization due to a first exposure to AA. Inactivation was prevented when exposure to AA was done in the presence of reversible inhibitors of cyclo-oxygenase. Phenol, methyl salicylate and L8027 were thus strong inhibitors of AA-induced platelet activation and desensitization. The minimal structural requirement for inhibition of thromboxane A2 generation from AA was a phenol group as benzoic acid was fully inactive. 2-Hydroxybenzoic acid, and to some extent 2,6-dihydroxybenzoic acid were effective against ASA, the most active substances being methyl salicylate and L8027. The minimal structural requirement for blocking ASA was that 2-hydroxybenzoic acid, 2-methoxybenzoic acid should be devoid of activity, which highlights the fact that the hydroxyl group must be available. Our work favours the hypothesis that non-steroidal anti-inflammatory drugs react with two sites of cyclo-oxygenase, which were named the supplementary and the catalytic sites. The interaction of 2-hydroxybenzoic acid and of its analogues with the supplementary site is necessary but not sufficient for the efficacy of these compounds as cyclo-oxygenase inhibitors. The intensity of interaction with the supplementary site and the modifications of the catalytic site determine the potency of these compounds as cyclo-oxygenase inhibitors. For preventing ASA inactivation, an interaction with the supplementary sites is always necessary, but furthermore an appropriate group, preferentially in the position ortho to the hydroxyl, is needed.

Animals↗
PubMed1997

Structures of competitive inhibitor complexes of protocatechuate 3,4-dioxygenase: multiple exogenous ligand binding orientations within the active site.

Protocatechuate 3,4-dioxygenase (3,4-PCD) catalyzes the oxidative ring cleavage of 3,4-dihydroxybenzoate to produce beta-carboxy-cis, cis-muconate. Crystal structures of Pseudomonas putida3,4-PCD [quaternary structure of (alphabetaFe3+)12] complexed with seven competitive inhibitors [3-hydroxyphenylacetate (MHP), 4-hydroxyphenylacetate (PHP), 3-hydroxybenzoate (MHB), 4-hydroxybenzoate (PHB), 3-fluoro-4-hydroxybenzoate (FHB), 3-chloro-4-hydroxybenzoate (CHB), and 3-iodo-4-hydroxybenzoate (IHB)] are reported at 2.0-2.2 A resolution with R-factors of 0. 0.159-0.179. The inhibitors bind in a narrow active site crevasse lined with residues that provide a microenvironment that closely matches the chemical characteristics of the inhibitors. This results in as little as 20% solvent-exposed surface area for the higher-affinity inhibitors (PHB, CHB, and FHB). In uncomplexed 3,4-PCD, the active site Fe3+ is bound at the bottom of the active site crevasse by four endogenous ligands and a solvent molecule (Wat827). The orientations of the endogenous ligands are relatively unperturbed in each inhibitor complex, but the inhibitors themselves bind to or near the iron in a range of positions, all of which perturb the position of Wat827. The three lowest-affinity inhibitors (MHP, PHP, and IHB) yield distorted trigonal bipyramidal iron coordination geometry in which the inhibitor C4-phenolate group displaces the solvent ligand. MHB binds within the active site, but neither its C3-OH group nor the solvent molecule binds to the iron. The C4-phenolate group of the three highest-affinity inhibitors (PHB, CHB, and FHB) coordinates the Fe3+ adjacent to Wat827, resulting in a shift in its position to yield a six-coordinate distorted octahedral geometry. The range of inhibitor orientations may mimic the mechanistically significant stages of substrate binding to 3, 4-PCD. The structure of the final substrate complex is reported in the following paper [Orville, A. M., Lipscomb, J. D., & Ohlendorf, D. H. (1997) Biochemistry 36, 10052-10066].

Binding Sites↗
PubMed1995

Isolation and structural elucidation of pentacyclic triterpenoids from Maprounea africana.

Pentacyclic triterpenoids based on the taraxer-14-ene skeleton with a C-28 attached carboxylic acid group have been isolated from the roots of Maprounea africana. These compounds were identified as 1 beta,2 alpha-dihydroxyaleuritolic acid 2,3-bis-p-hydroxybenzoate [1], 2 alpha-hydroxyaleuritolic acid 3-p-hydroxybenzoate [2], 2 alpha-hydroxyaleuritolic acid 2,3-bis-p-hydroxybenzoate [4], aleuritolic acid 3-p-hydroxybenzoate [5], aleuritolic acid [6], and aleuritolic acid 3-acetate [7]. Compounds 1 and 2 are new triterpene esters. Compound 3 was previously reported as 7 beta-hydroxymaprounic acid 3-p-hydroxybenzoate [13]. However, based on detailed nmr studies, its structure has been revised.

Magnetic Resonance Spectroscopy↗
PubMed1984

Dissimilation of aromatic compounds in Rhodotorula graminis: biochemical characterization of pleiotropically negative mutants.

Microorganisms oxidize many aromatic compounds through the dihydroxylated intermediates catechol and protocatechuate and through the beta-ketoadipate pathway. The catabolic sequences used by the yeast Rhodotorula graminis for the dissimilation of aromatic compounds were elucidated after biochemical analysis of pleiotropically negative mutant strains. Growth properties of one mutant strain revealed that benzoate-4-hydroxylase was required for the utilization of phenylalanine, mandelate, and benzoate. Analysis of benzoate-4-hydroxylase- and p-hydroxybenzoate hydroxylase-deficient mutants provided genetic evidence that benzoate was hydroxylated in the para position forming p-hydroxybenzoate. Enzyme assays and growth studies with wild-type and mutant strains of R. graminis indicated that separate and highly specific hydroxylases oxidized p-hydroxybenzoate and m-hydroxybenzoate to protocatechuate. Examination of a protocatechuate 3,4-dioxygenase-deficient mutant demonstrated the role of the protocatechuate branch of the eucaryotic beta-ketoadipate pathway for the utilization of phenylalanine, mandelate, benzoate, and m-hydroxybenzoate. Salicylate, on the other hand, was shown to be metabolized through catechol. Thus, R. graminis differs from other yeasts such as Trichosporon cutaneum and Rhodotorula mucilaginosa in that it contains both branches of the beta-ketodipate pathway.

Enzyme Induction↗