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At least 1,171 records · Page 65Linked to original sources
PubMed2006

Effects of cyanobacterium Fischerella ambigua isolates and cell free culture media on zebrafish (Danio rerio) embryo development.

The toxic effects of several species of fresh water cyanobacteria, notably Microcystis species and associated toxins, the microcystins, Anabaena species (anatoxin), Nodularia sp. (nodularin), and Cylindrospermopsis raciborskii (cylindrospermopsin), are well known. Little, however, is known about the effects of secondary metabolites other than alkaloids. Early life stage tests with zebrafish (Danio rerio) were used to detect bioactive properties of compounds released by healthy cyanobacteria (Fischerella ambigua), particularly on the early developmental stages of fish. This approach, using F. ambigua is probably most valuable as it shows the toxicity of healthy growing cyanobacteria. The effects of cyanobacterial secondary metabolites on the embryonic stages of fish are of considerable interest as many aquatic creatures, particularly fish, are unable to avoid the potential toxins that may be released by undesirable algal blooms or as a result of allelopathic effects. In the current study, the zebrafish (D. rerio) was used as a model experimental system to investigate the effects of ambigols A and C, tjipanazole D and C, 2,4-dichlorobenzoic acid, cell free culture media, and media extracts of a terrestrial/fresh water strain of the cyanobacterium F. ambigua on embryo development. Fish embryo tests performed with the cell free culture medium showed that after 3h of exposure to undiluted culture medium all fish embryos died. At a tenfold dilution the process of epiboly (formation of the gastrula) was retarded in all embryos, lesions were observed, and their general development was significantly arrested, finally followed by death. The same tests performed with extracts (dichloromethane, n-butanol, and residual cell free culture medium) of the cell free culture medium, ambigol A, ambigol C, 2,4-dichlorobenzoic acid and tjipanazole D showed only ambigol A to have an influence on zebrafish development at concentrations>or=1 mg/l (2.06 microM). After 55 h all embryos showed pectoral oedema, irregularly shaped fin folds, bent tails, and unusual circular neoplasms in the dorsal tail fin fold. Due to the high concentration of ambigol A used in this assay these effects were considered to be of minor importance when compared to those of the culture medium.

Animals↗
PubMed2004

Fast determination of colchicine by TLC-densitometry from pharmaceuticals and vegetal extracts.

Colchicine, (S)-N-(5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo-(a(-heptalen-7-yl)-acetamide, is the main alkaloid contained in Colchicum autumnale (meadow saffron). There are known colorimetric, spectrophotometric, volumetric, potentiometric, voltametric, gravimetric and various chromatographic methods for quantitative determination of colchicine, each of them presenting a series of advantages and disadvantages. As an alternative, we proposed the use of a densitometric determination for colchicine allowing the determination of this alkaloid from pharmaceutical products, as well from seeds of meadow saffron. The total alkaloid extract was separated by Thin-Layer Chromatography using Silicagel 60F(254) layers and a mixture of chloroform:acetone:diethylamine (5:4:1) as mobile phase. The same conditions were used for the determination from pharmaceutical products. Densitometric measurements were carried out at the absorption maximum (350 nm) of colchicine, the determinations being made by reflectance and by fluorescence. The peaks were optimized regarding to their area and shape by varying four scanning parameters (slit width and height, number of measurements and scanning speed). We established the calibration plot using pure colchicine in the range 50-600 ng mL(-1). The proposed method could be widely used in the pharmaceutical industry for the quick and accurate quantitative determination of colchicine because it eliminates the interferences given by other bioactive or degradation compounds. The method was characterized by validation parameters (linearity, accuracy, fidelity, sensitivity) and it was established its performances in comparison with an HPLC method and an official quantitative determination from the Romanian Pharmacopoeia X edition respectively.

Chromatography, Thin Layer↗
PubMed2004

In vitro bioactivity of 17alpha-estradiol.

A miniaturised short-term in vitro assay based on the activation of the human estrogen receptor alpha and genetically modified yeast (Saccharomyces cerevisiae) cells was performed to explore the capacity of this system to monitor the bioactivity of estrogenic compounds, particularly 17alpha- and 17beta-estradiol. Together with the human estrogen receptor (hER)-alpha plasmid, the reporter plasmid containing a yeast-optimised version of the green fluorescent protein (yEGFP) linked to three repeats of the cis-acting estrogen hormone-responsive element (ERE) were expressed in a strain being deleted in the pleiotropic drug resistance transporters Pdr5, Snq2 and Yor1, known to facilitate efflux of organic compounds including steroids and chemotherapeutics. Agonists that bind to hER in vitro trigger estrogen receptor-mediated transcriptional activation of the GFP reporter gene monitored by fluorescence emission at 535 nm. The sensitivity of the assay was tested with various 17alpha- and 17beta-estradiol concentrations, yielding a detection limit of 5 pg/ml (0.018 nM) for the agonist 17beta-E2 in solvent and in human charcoal-stripped serum using a S. cerevisiae pdr5, snq2 and yor1 mutant strain. For 17alpha-estradiol only, at approximately 1500 pg/ml a similar fluorescence response compared to 100 pg/ml 17beta-E2 was observed implicating a much weaker potency of this stereoisomer. The specificity of the system was tested by expression of a truncated hER lacking the ligand-binding domain E and by administration of the androgen, 4-androsten 3,17 dione. Both controls did not yield an increase in fluorescence emission. This fluorescence emission assay enables detection of estrogenic biological activity induced by direct agonists, such as 17beta-E2 at concentrations similar to those found in human sera or by estrogen-like chemicals.

Biological Assay↗
PubMed2003

Tocolytic and toxic activity of papaya seed extract on isolated rat uterus.

Carica papaya L. seeds extracted with 80% ethanol (EEPS) caused concentration-dependent tocolysis of uterine strips isolated from gravid and non-gravid rats. Prostaglandin F2alpha and oxytocin-induced contractions of the isolated rat uterus were also inhibited in a concentration-dependent fashion by EEPS. Recoveries of the uterine activity after EEPS-induced uterine quiescence were very weak. Higher concentration of EEPS caused prompt uterine quiescence, which was also significantly irreversible. Pre-incubation of the rat uterus in Ringer Locke solution containing 10 mg/ml of EEPS for 1 hour prior to suspension in tissue baths led to significant depression of the spontaneous and KCl (60 mM)-induced uterine contractions relative to the solvent control (P<0.05). Cross sections of EEPS-pretreated non-gravid rat uterus (stained with hematoxyline and eosin) examined under light microscope revealed degeneration of the endometrium and myometrium with obvious cytoplasmic vacuolation indicating that EEPS could have direct toxic effect on the uterine tissues. Previous workers have reported benzyl isothiocyanate (BITC) as the main bioactive and anthelmintic compound in different extracts of papaya seeds. Using electron impact ionization methods, the presence of BITC in EEPS was also shown in this study. Mass spectra of both EEPS and standard BITC showed a base peak of benzyl/tropylium ion at m/z 91 (indicative of an aromatic compound) and the molecular ion peak of BITC (m/z 149). Our earlier studies have demonstrated BITC-induced functional and morphological derangement of isolated uterus. We thus conclude that at high concentration, EEPS is capable of causing irreversible uterine tocolysis probably due to the damaging effect of BITC (its chief phytochemical) on the myometrium.

Animals↗
PubMed2006

Harnessing endophytes for industrial microbiology.

Endophytic microorganisms exist within the living tissues of most plant species. They are most abundant in rainforest plants. Novel endophytes usually have associated with them novel secondary natural products and/or processes. Muscodor is a novel endophytic fungal genus that produces bioactive volatile organic compounds (VOCs). This fungus, as well as its VOCs, has enormous potential for uses in agriculture, industry and medicine. Muscodor albus produces a mixture of VOCs that act synergistically to kill a wide variety of plant and human pathogenic fungi and bacteria. This mixture of gases consists primarily of various alcohols, acids, esters, ketones and lipids. Artificial mixtures of the VOCs mimic the biological effects of the fungal VOCs when tested against a wide range of fungal and bacterial pathogens. Many practical applications for 'mycofumigation' by M. albus have been investigated and the fungus is now in the market place.

Anti-Bacterial Agents↗
PubMed2000

Effect of starvation and chlormethiazole on cytochrome P450s of rat nasal mucosa.

Cytochrome P450 (CYP) enzymes of nasal tissue are relatively resistant to induction by classical inducers. In the present study, the effects of starvation on the expression of CYP1A, 2A, 2B, 2C, 2E, 2G, and 3A subfamilies in the nasal mucosa of rat were studied. Fasting for 72 hr caused an increase in 2E1-dependent p-nitrophenol hydroxylase and 1A-dependent ethoxy- (or methoxy) resorufin dealkylase activities, but did not affect either 2A-linked coumarin hydroxylase or the testosterone hydroxylase activity, the latter reaction being a marker of several CYPs including 2G1. Whereas increases in 2E1- and 1A- associated catalytic activities were accompanied by a concomitant increase in the corresponding apoproteins as determined by immunoblotting, immunoactive protein bands reactive with antibodies raised against rat 1A1, 2B1, 2C11, 3A1 or rabbit nasal 2A10/11 and 2G1 were not altered. Fasting also increased CYP2E1 and CYP1A2 on the mRNA level, but did not alter CYP1A1 mRNA as determined by hybridization with cDNA probes selective for these cytochromes. A reiterative administration of chlormethiazole, a specific inhibitor of 2E1 in liver, strongly inhibited many CYPs, including 2E1, 1A2, 2G1, and 2A in the nasal mucosa, but did not influence expression of 2B or 3A as determined by immunoblotting or catalytic activities. The chlormethiazole-mediated inhibition of 1A1 and 2E1 was demonstrated to be at the mRNA level. These results suggest that fasting induces the gene expression of 2E1 and 1A2 and that the mechanisms involved in the regulation of CYPs in the nasal mucosa are tissue-specific. The inducibility of the above-mentioned isoforms may have a significant role in the clearance of drugs and bioactivation of inhaled compounds.

Animals↗
PubMed2002

Comparison of the total antioxidant content of 30 widely used medicinal plants of New Mexico.

Teas made from medicinal plants are commonly used by a majority of the inhabitants of New Mexico and Mexico to treat various ailments including infections, arthritis, heart disorders, headaches, fever, asthma and menstrual pain. However, little is known about the identity or chemical nature of the bioactive substances and compounds responsible for the therapeutic effects of the teas made from the leaves, seeds, flowers stems, and roots of these medicinal plants. Some of the beneficial effects of these teas may be attributable to antioxidants contained in the medicinal plants from which they are brewed. In the present study we collected 30 medicinal plants that are widely used in the Rio Grande Valley and, using a two-stage Trolox based assay, analyzed the total antioxidant capacity of aqueous extracts prepared from these plants. The antioxidant content of the aqueous extracts was substantial, ranging from 27 to 972 micromol Trolox equivalent per gram dry weight. An extract of the leaves of the plant Ilex paraguensis (Mate leaf) contained the highest amount of antioxidant, followed by the flowers of the Rosa sp. (Rosa de Castillo, 804 micromol/g), the bark of Chinchona sp. (Copalquin, 692 micromol/g), Rumex hymenosepalus stems (Cana Agria, 672 micromol/g) and the leaves of Marrubium vulgare (Mastranzo, 560 micromol/g). The plants that had the lowest antioxidant capacity were the seeds of Linum lewissii (Linasa, 29 micromol/g) and Yucca sp. plant root (Amole, 27 micromol/g). It will be useful to further analyze those plants that contain the most antioxidant activity in order to identify the active principles.

Antioxidants↗
PubMed1997

Evidence for a novel heme adduct generated by the in vitro reaction of 2,4,6-trinitrotoluene with human hemoglobin using electrospray ionization mass spectrometry.

The bioactivation of nitroaromatic compounds to highly reactive intermediates is responsible for the genotoxic and cytotoxic effects by reaction with DNA and proteins. Due to its continued use as a secondary explosive and its prevalence at contaminated sites, the mechanism of covalent binding of 2,4,6-trinitrotoluene (TNT), or its metabolites, to critical cellular proteins has been of interest. Herein, we report the in vitro reaction of TNT with human hemoglobin under anaerobic and reductive (using sodium hydrosulfite) conditions, yielding a novel adduct between a putative nitrosodinitrotoluene (MW = 211 Da) and the prosthetic heme group (iron protoporphyrin-IX or heme b). While the covalent modification of hemoglobin polypeptide chains by TNT has been established, to our knowledge, this is the first example of a heme-TNT related adduct. This finding could be of relevance in investigation of biotransformation of TNT in subjects exposed to TNT via skin exposure or inhalation.

Heme↗
PubMed2002

Medicinal bulbous plants of South Africa and their traditional relevance in the control of infectious diseases.

Natural products are becoming more important in modern-day society as man is moving away from synthetic products, which can be detrimental to the environment and human health. Scientific research on the healing properties and bioactivity of natural compounds, especially of plant origin, has been extensive particularly in the Western world. However, a rich heritage of floral biodiversity is found in developing countries. South Africa, a country with a strong history of traditional healing, hosts a variety of around 30000 plant species. Indigenous bulbous plants of importance to South African traditional healers mainly belong to the Amaryllidaceae and Hyacinthaceae families. A number of these plants have particular uses as disinfectants and anti-inflammatory agents, although there is still a lack of scientific research regarding their unique pharmacological compounds.

Communicable Diseases↗
PubMed2003

Modeling and molecular dynamics of glutamine transaminase K/cysteine conjugate beta-lyase.

The homodimeric, pyridoxal 5'-phosphate (PLP)-dependent enzyme glutamine transaminase K/cysteine conjugate beta-lyase (GTK/beta-lyase) has been implicated in the bioactivation of chemopreventive compounds. This paper describes the first homology model of rat renal GTK/beta-lyase and its active site residues, deduced from molecular dynamics (MD) simulations of the binding mode of 13 structurally diverse cysteine S-conjugates and amino acids after Amber-parametrization of PLP. Comparison with Thermus thermophilus aspartate aminotransferase (tAAT) and Trypanosoma cruzi tyrosine aminotransferase (tTAT), used as templates for modeling GTK/beta-lyase, showed that the PLP-binding site of GTK/beta-lyase is highly conserved. Binding of the ligand alpha-carboxylate-group occurred via the conserved residues Arg(432) and Asn(219), and Asn(50) and Gly(70). Two pockets accommodated the various ligand side chains. A small pocket, located directly above PLP, was of a highly hydrophobic and aromatic character. A larger pocket, formed partly by the substrate access channel, was more hydrophilic and notably involved the salt bridge partners Glu(54) and Arg(99*) (* denotes the other subunit). Ligand-binding residues included Leu(51), Phe(71), Tyr(135), Phe(373) and Phe(312*), and pi-stacking interactions were often observed. Tyr(135) and Asn(50) were prominent in hydrogen bonding with the sulfur-atom of cysteine S-conjugates. The observed binding mode of the ligands corresponded well with their experimentally determined inhibitory potency toward GTK/beta-lyase. The current homology model thus provides a starting point for further validation of the role of active site residues in ligand-binding by means of mutagenesis studies. Ultimately, insight in the binding of ligands to GTK/beta-lyase may result in the rational design of new ligands and selective inhibitors.

Amino Acid Sequence↗
PubMed2006

Cranberry phytochemicals: Isolation, structure elucidation, and their antiproliferative and antioxidant activities.

Bioactivity-guided fractionation of cranberries was used to determine the chemical identity of bioactive constituents. Twenty compounds were isolated using gradient solvent fractionation, silica gel and ODS columns, and preparative RP-HPLC. Their chemical structures were identified using HR-MS, 1D and 2D NMR, and X-ray diffraction analysis. Antiproliferative activities of isolated compounds against HepG2 human liver cancer and MCF-7 human breast cancer cells were evaluated. Among the compounds isolated, ursolic acid, quercetin, and 3,5,7,3',4'-pentahydroxyflavonol-3-O-beta-D-glucopyranoside showed potent antiproliferative activities against HepG2 cell growth, with EC50 values of 87.4 +/- 2.7, 40.9 +/- 1.1, and 49.2 +/- 4.9 microM, respectively. Ursolic acid, quercetin, and 3,5,7,3',4'-pentahydroxyflavonol-3-O-beta-D-glucopyranoside showed potent inhibitory activity toward the proliferation of MCF-7 cells, with EC50 values of 11.7 +/- 0.1, 137.5 +/- 2.6, and 23.9 +/- 3.9 microM, respectively. Quercetin, 3,5,7,3',4'-pentahydroxyflavonol-3-O-beta-D-glucopyranoside, 3,5,7,3',4'-pentahydroxyflavonol-3-O-beta-D-galactopyranoside, and 3,5,7,3',4'-pentahydroxyflavonol-3-O-alpha-l-arabinofuranoside showed potent antioxidant activities, with EC50 values of approximately 10 microM. These results showed cranberry phytochemical extracts have potent antioxidant and antiproliferative activities.

Antineoplastic Agents↗
PubMed1990

Synthesis and antineoplastic properties of ether-linked thioglycolipids.

Ether-linked glycero-alpha- and beta-D-glucopyranosides and glycero-1-thio-alpha- and beta-D-glucopyranosides have been synthesized by modifications of the Königs-Knorr procedure, and their antitumor activities have been evaluated. The bioactivities of these compounds have been evaluated in five different cell lines (WEHI 3B, C653, X63/OMIL3, R6X-B15, and HL-60) and compared with the activities of 1-O-hexadecyl-2-O-methyl-sn-3-glycerophosphocholine (GPC) and its enantiomer, 3-O-hexadecyl-2-O-methyl-sn-1-GPC. The results indicate that a alpha-D-thioglucopyranoside [1-O-hexadecyl-2-O-methyl-3-S-(alpha-D-1'- thioglucopyranosyl-sn-glycerol)] is selective with respect to its action on target cells, with high activity for killing of WEHI 3B and C653 cells as determined by inhibition of [3H]thymidine incorporation into DNA and HL-60 cell cytotoxicity, but unable to induce aggregation of rabbit platelets at 10(-5) M. The corresponding beta-linked thioglycolipid was ineffective with respect to cytotoxicity against each cell line tested, indicating the importance of configuration at the anomeric position; the beta-thioglycoside was also ineffective with respect to inducing platelet aggregation. 1-O-Hexadecyl-2-O-methyl-sn-3-GPC and 3-O-hexadecyl-2-O-methyl-sn-1-GPC were potent inhibitors of growth of each cell line tested but also caused rabbit platelet aggregation at concentrations greater than or equal to 10(-7) M. Thus, 3-S-(alpha-thioglycopyranosyl)-sn- glycerols bearing a long-chain O-alkyl group at the sn-1 position and a methoxy group at the sn-2 position of glycerol appear to be a promising class of antineoplastic agents with lower risk of inducing thrombosis than the widely studied platelet activating factor analogue, 1-O-octadecyl-2-O-methyl-rac-3-GPC.

Animals↗
PubMed1997

Evaluation of the antifungal activity of natural xanthones from Garcinia mangostana and their synthetic derivatives.

The antifungal activity of several xanthones isolated from the fruit hulls of Garcinia mangostana and some derivatives of mangostin against three phytopathogenic fungi, Fusarium oxysporum vasinfectum, Alternaria tenuis, and Dreschlera oryzae, has been evaluated. The natural xanthones showed good inhibitory activity against the three fungi. Substitution in the A and C rings has been shown to modify the bioactivities of the compounds.

Alkylation↗
PubMed1999

Gas exchange response to a PAF receptor antagonist, SR 27417A, in acute asthma: a pilot study.

The pathogenic role of platelet-activating factor (PAF) in asthma has been questioned due to the limited or negative efficacy of PAF antagonists; however, in acute asthma (AA), where the endogenous release of PAF may be enhanced, the effects of PAF antagonist receptors have not been investigated. It was postulated that inhaled PAF provokes gas exchange defects in mild asthma likely to be related to airway vascular leakage. The response to a potent, selective PAF receptor antagonist, SR 27471A, on pulmonary gas exchange was studied, more specifically ventilation-perfusion (VA'/Q') distributions, in patients with AA within 48 h of hospitalization. A randomized, double-blind, placebo-controlled, parallel group (n=6, each) design was used. After baseline measurements, either placebo or SR 27417A (20 mg, orally) was administered and measurements were repeated 3 h later. Conventional anti-asthma medication was not interrupted. Despite a near-complete inhibition of the in vitro, platelet aggregation tests by 40 nM PAF (mean+/-SEM from 72+/-9 to 6+/-2%) and 80 nM PAF (from 81+/-7 to 6+/-3% both p<0.01) by SR 27471A indicating a good bioactivity of the compound, no significant changes in baseline forced expiratory volume in one second, (40+/-6%), respiratory system resistance (6.2+/-0.7 cmH2O x L(-1) x s), alveolar-arterial pressure difference for oxygen (5.2+/-0.4 kPa), arterial oxygen tension (9.0+/-0.5 kPa) or VA'/Q' distributions, as expressed by the dispersion of pulmonary blood flow (LogSD Q, 1.07+/-0.09; normal values <0.60), were observed. It is concluded that SR 27417A has limited value when added to the conventional treatment of acute asthma. These findings minimize the potential pathogenic role of endogenous platelet-activating factor as a relevant mediator of airway inflammation during acute asthma.

Acute Disease↗
PubMed2003

Definitive identification of cysteine and glutathione complexes of bismuth by mass spectrometry: assessing the biochemical fate of bismuth pharmaceutical agents.

Solutions containing BiCl3, bismuth subsalicylate or Bi(NO3)3 with L-cysteine, DL-homocysteine, D-methionine or glutathione have been examined by electrospray mass spectrometry. Prominent peaks are assigned to bismuth complexes of these biomolecules and provide insight towards understanding the bioactivity of bismuth compounds.

Bismuth↗
PubMed1993

Protein kinase inhibitors in plants of the myrtaceae, proteaceae, and leguminosae.

Methanolic extracts of leaves, flowers, stems, bark, and other parts of representative plants of the Myrtaceae, specifically of the EUCALYPTUS, MELALEUCA, THRYPTOMENA, CALLISTOMEN, ACMENA, AND ANGOPHORA genera, variously contain high levels of inhibitors of plant Ca (2+)-dependent protein kinase (CDPK) and of Ca (2+)-calmodulin-dependent myosin light chain kinase (MLCK). In terms of the protein kinase inhibition unit (PKIU), defined as the amount in the standard protein kinase assays causing 50% inhibition of protein kinase activity, these inhibitor levels ranged from the non-detectable to 179,000 PKIU (gram fresh weight) (-1) [(g FW) (-1)] and there was no consistent pattern of inhibitor distribution. A variety of other plants tested had low or non-detectable levels of CDPK and MLCK inhibitors. Plants of the EUCALYPTUS, MELALEUCA, ANGOPHORA, and GREVILLEA genera contained inhibitors of the catalytic subunit of the cyclic AMP-dependent protein kinase (cAK), inhibitor levels ranging from 20,000 to 9,600,000 PKIU (g FW) (-1). In general, cAK inhibitor levels found in the Myrtaceae were mostly much higher than levels of CDPK and MLCK inhibitors and reversed phase HPLC of such plant extracts revealed a multiplicity of components associated with cAK inhibitory activity. These IN VITRO screening procedures enable rapid detection and quantitation of levels of bioactive plant defence compounds with medicinal potential.

Journal Article↗
PubMed1992

Mechanism of C8 alkylation of guanine residues by activated arylamines: evidence for initial adduct formation at the N7 position.

Aromatic amines are bioactivated to electrophilic compounds that react with DNA, predominantly at the C8 position of guanine bases. This site is weakly nucleophilic and it has been proposed that the C8 adduct is the final product after initial N7-adduct formation. To consider this possibility, we reacted several C8-substituted guanine derivatives with N-acetoxy-2-aminofluorene, prepared in situ from 2-acetylsalicylic acid and N-hydroxy-2-aminofluorene. With C8,N9-dimethylguanine, an adduct was isolated in good yield that was consistent, by NMR and mass spectral characterization, with a structure involving carcinogen substitution at the N7 position of guanine and linked through the 2-aminofluorenyl nitrogen--N-(C8,N9- dimethylguanin-N7-yl)-2-aminofluorene. This adduct could be easily reduced with NaBH4, consistent with the proposed N7-adduct structure. The same reaction was also carried out with C8-methylguanosine and C8-methyldeoxyguanosine and similar adducts were isolated. In contrast, C8-bromoguanosine reacted with N-acetoxy-2-aminofluorene to yield the C8-substituted arylamine adduct N-(guanosin-C8-yl)-2-aminofluorene directly. These products are uniquely consistent with a scheme in which C8-adduct formation is preceded by an initial electrophilic substitution on the N7 atom, which is postulated to be a general reaction for activated arylamines and heterocyclic amines.

Acetylation↗
PubMed2002

Structure of a human carcinogen-converting enzyme, SULT1A1. Structural and kinetic implications of substrate inhibition.

Sulfonation catalyzed by sulfotransferase enzymes plays an important role in chemical defense mechanisms against various xenobiotics but also bioactivates carcinogens. A major human sulfotransferase, SULT1A1, metabolizes and/or bioactivates many endogenous compounds and is implicated in a range of cancers because of its ability to modify diverse promutagen and procarcinogen xenobiotics. The crystal structure of human SULT1A1 reported here is the first sulfotransferase structure complexed with a xenobiotic substrate. An unexpected finding is that the enzyme accommodates not one but two molecules of the xenobiotic model substrate p-nitrophenol in the active site. This result is supported by kinetic data for SULT1A1 that show substrate inhibition for this small xenobiotic. The extended active site of SULT1A1 is consistent with binding of diiodothyronine but cannot easily accommodate beta-estradiol, although both are known substrates. This observation, together with evidence for a disorder-order transition in SULT1A1, suggests that the active site is flexible and can adapt its architecture to accept diverse hydrophobic substrates with varying sizes, shapes and flexibility. Thus the crystal structure of SULT1A1 provides the molecular basis for substrate inhibition and reveals the first clues as to how the enzyme sulfonates a wide variety of lipophilic compounds.

Amino Acid Sequence↗