A monooxygenase catalyzes sequential dechlorinations of 2,4,6-trichlorophenol by oxidative and hydrolytic reactions. (1/10)

Ralstonia eutropha JMP134 2,4,6-trichlorophenol (2,4,6-TCP) 4-monooxygenase catalyzes sequential dechlorinations of 2,4,6-TCP to 6-chlorohydroxyquinol. Although 2,6-dichlorohydroxyquinol is a logical metabolic intermediate, the enzyme hardly uses it as a substrate, implying it may not be a true intermediate. Evidence is provided to support the proposition that the monooxygenase oxidized 2,4,6-TCP to 2,6-dichloroquinone that remained with the enzyme and got hydrolyzed to 2-chlorohydroxyquinone, which was chemically reduced by ascorbate and NADH to 6-chlorohydroxyquinol. When the monooxygenase oxidized 2,6-dichlorophenol, the product was 2,6-dichloroquinol, which was not further converted to 6-chlorohydroxyquinol, implying that the enzyme only converts 2,6-dichloroquinone to 6-chlorohydroxyquinol. Stoichiometric analysis indicated the consumption of one O2 molecule per 2,4,6-TCP converted to 6-chlorohydroxyquinol, ruling out the possibility of two oxidative reactions. Experiments with 18O-labeling gave direct evidence for the incorporation of oxygen from both O2 and H2O into the produced 6-chlorohydroxyquinol. A monooxygenase that catalyzes hydroxylation by both oxidative and hydrolytic reactions has not been reported to date. The ability of the enzyme to perform two types of reactions is not due to the presence of a second functional domain but rather is due to catalytic promiscuity, as a homologous monooxygenase converts 2,4,6-TCP to only 2,6-dichloroquinol. Employing both conventional catalysis and catalytic promiscuity of a single enzyme in two consecutive steps of a metabolic pathway has been unknown previously.  (+info)

A novel dual antagonist of thromboxane A2 and leukotriene D4 receptors: synthesis and structure-activity relationships of chloroquinolylvinyl derivatives. (2/10)

To discover an orally active thromboxane A(2) (TXA(2)) and leukotriene D(4) (LTD(4)) dual antagonist, we designed and synthesized chloroquinolylvinyl derivatives based on the structures of the TXA(2) antagonist daltroban and the LTD(4) antagonist montelukast. Among these derivatives, 4-{[(2-(4-chlorophenylsulfonylamino)-1-{3-[(E)-2-(7-chloro-2-quinolyl)vinyl]pheny l}ethyl)thio]methyl}benzoic acid (18d) showed potent inhibitory activity against U46619-induced aggregation of guinea pig platelets and LTD(4)-induced contraction in the guinea pig ileum, with IC(50) values of 340 nm and 0.40 nm, respectively. Oral administration of 18 d also inhibited both the LTD(4)-induced acceleration of plasma leakage to skin in guinea pig and the U46619-induced increase in airway resistance in guinea pig with ED(50) values of 0.47 mg/kg and 3.3 mg/kg, respectively.  (+info)

In vitro activities of cloxyquin (5-chloroquinolin-8-ol) against Mycobacterium tuberculosis. (3/10)

The in vitro activities of cloxyquin (5-chloroquinolin-8-ol) against 9 standard strains and 150 clinical isolates of Mycobacterium tuberculosis were studied. The MICs ranged from 0.062 to 0.25 microg/ml. The MIC(50) and MIC(90) were 0.125 and 0.25 microg/ml, respectively. These indicate that cloxyquin exhibited good antituberculosis activity, even for multidrug-resistant isolates.  (+info)

Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia. (4/10)

In subjects with schizophrenia, impairments in working memory are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC). This dysfunction appears to be due, at least in part, to abnormalities in gamma-aminobutyric acid (GABA)-mediated inhibitory circuitry. To test the hypothesis that altered GABA-mediated circuitry in the DLPFC of subjects with schizophrenia reflects expression changes of genes that encode selective presynaptic and postsynaptic components of GABA neurotransmission, we conducted a systematic expression analysis of GABA-related transcripts in the DLPFC of 14 pairs of schizophrenia and age-, sex- and post-mortem interval-matched control subjects using a customized DNA microarray with enhanced sensitivity and specificity. Subjects with schizophrenia exhibited expression deficits in GABA-related transcripts encoding (1) presynaptic regulators of GABA neurotransmission (67 kDa isoform of glutamic acid decarboxylase (GAD(67)) and GABA transporter 1), (2) neuropeptides (somatostatin (SST), neuropeptide Y (NPY) and cholecystokinin (CCK)) and (3) GABA(A) receptor subunits (alpha1, alpha4, beta3, gamma2 and delta). Real-time qPCR and/or in situ hybridization confirmed the deficits for six representative transcripts tested in the same pairs and in an extended cohort, respectively. In contrast, GAD(67), SST and alpha1 subunit mRNA levels, as assessed by in situ hybridization, were not altered in the DLPFC of monkeys chronically exposed to antipsychotic medications. These findings suggest that schizophrenia is associated with alterations in inhibitory inputs from SST/NPY-containing and CCK-containing subpopulations of GABA neurons and in the signaling via certain GABA(A) receptors that mediate synaptic (phasic) or extrasynaptic (tonic) inhibition. In concert with previous findings, these data suggest that working memory dysfunction in schizophrenia is mediated by altered GABA neurotransmission in certain DLPFC microcircuits.  (+info)

Reduction of dopamine synaptic activity: degradation of 50-kHz ultrasonic vocalization in rats. (5/10)

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Supramolecular synthon pattern in solid clioquinol and cloxiquine (APIs of antibacterial, antifungal, antiaging and antituberculosis drugs) studied by (3)(5)Cl NQR, (1)H-(1)(7)O and (1)H-(1)(4)N NQDR and DFT/QTAIM. (6/10)

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In situ formation of steroidal supramolecular gels designed for drug release. (7/10)

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In vitro activity of chlorhydroxyquinoline against mycoplasma species. (8/10)

The in vitro activities of 5-chloro-8-hydroxyquinoline (CHQ) against single strains of 12 different species of mycoplasma and the impacts of repeated exposure of these strains to CHQ on their susceptibility to this agent have been studied. On initial exposure, the minimal inhibitory concentrations for these strains ranged from 0.24 to 1.92 micrograms of CHQ per ml of test medium; activities remained unchanged during 10 serial transfers in CHQ-containing medium.  (+info)

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