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   analysis reveals that the conformation of this flexible loop and the
   binding affinities of triclosan to each of these enzymes are strongly
   correlated.
   [27]PDF (572 K)
   [28]Kinetic mechanism of NADH-enoyl-ACP reductase from Bras...
   FEBS Letters

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   You are entitled to access the full text of this document  [29]Kinetic
   mechanism of NADH-enoyl-ACP reductase from Brassica napus  Original
   Research Article
   FEBS Letters, Volume 484, Issue 2, 3 November 2000, Pages 65-68
   Tony Fawcett, Catherine L. Copse, J. William Simon, Antoni R. Slabas
   Abstract
   Enoyl-ACP reductase, a component of fatty acid synthase, is a target
   for anti-microbial agents and herbicides. Here we demonstrate the
   kinetic mechanism to be a compulsory-order ternary complex with NADH
   binding before the acyl substrate. Matrix-assisted laser desorption
   ionisation mass spectrometry analysis of enzymatically and synthesised
   crotonyl-ACP substrate showed the former to contain a single acyl
   group, whereas the latter contained up to four additional
   crotonylations. The use of authentic crotonyl-ACP will be important in
   future kinetic and crystallographic studies.
   [30]PDF (132 K)
   [31]Common themes in redox chemistry emerge from the X-ray ...
   Structure

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   You are entitled to access the full text of this document  [32]Common
   themes in redox chemistry emerge from the X-ray structure of oilseed
   rape (Brassica napus) enoyl acyl carrier protein reductase  Original
   Research Article
   Structure, Volume 3, Issue 9, September 1995, Pages 927-938
   John B Rafferty, J.William Simon, Clair Baldock, Peter J Artymiuk,
   Patrick J Baker, Antoine R Stuitje, Antoni R Slabas, David W Rice
   Abstract
   Background: Enoyl acyl carrier protein reductase (ENR) catalyzes the
   NAD(P)H-dependent reduction of trans-Δ2-enoyl acyl carrier protein, an
   essential step in de novo fatty acid biosynthesis. Plants contain both
   NADH-dependent and separate NADPH-dependent ENR enzymes which form part
   of the dissociable type II fatty acid synthetase. Highly elevated
   levels of the NADH-dependent enzyme are found during lipid deposition
   in maturing seeds of oilseed rape (Brassica napus).

   Results The crystal structure of an ENR–NAD binary complex has been
   determined at 1.9 å resolution and consists of a homotetramer in which
   each subunit forms a single domain comprising a seven-stranded parallel
   β sheet flanked by seven α helices. The subunit has a topology highly
   reminiscent of a dinucleotide-binding fold. The active site has been
   located by difference Fourier analysis of data from crystals
   equilibrated in NADH.

   Conclusion The structure of ENR shows a striking similarity with the
   epimerases and short-chain alcohol dehydrogenases, in particular,
   3α,20β-hydroxysteroid dehydrogenase (HSD). The similarity with HSD
   extends to the conservation of a catalytically important lysine that
   stabilizes the transition state and to the use of a tyrosine as a base
   — with subtle modifications arising from differing requirements of the
   reduction chemistry.
   [33]PDF (1680 K)
   [34]Triclosan: release from transdermal adhesive formulatio...
   International Journal of Pharmaceutics

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   [35]Triclosan: release from transdermal adhesive formulations and in
   vitro permeation across human epidermal membranes  Original Research
   Article
   International Journal of Pharmaceutics, Volume 235, Issues 1-2, 20
   March 2002, Pages 229-236
   Paula Chedgzoy, Gareth Winckle, Charles M. Heard
   Abstract
   Malarial resistance is an escalating global problem and consequently
   new and more efficacious treatments to combat malaria are urgently
   needed. The transdermal delivery of anti-malarials may provide an
   effective alternative or adjunct to conventional regimens. Triclosan is
   widely used as an anti-bacterial agent and it has recently been
   demonstrated that this compound has anti-malarial properties. Its high
   lipophilicity makes it a potential candidate for delivery across the
   skin and this paper examines in vitro the potential for the transdermal
   delivery of triclosan from ‘drug-in-glue’ formulations. Model patches
   were prepared using DuroTak® 2287, 2516 and 2051 acrylic polymer
   adhesives loaded with 0, 30 and 50 mg per 0.785 cm^−2 triclosan and
   dissolution was measured over a 12-h period. There was no apparent
   difference between the adhesives at the 30 mg patch loading, but at 50
   mg, the trend for increased release was 2051>2516>2287. No significant
   burst effect was apparent. Patches of 50 mg per 0.785 cm^2 were then
   used to determine the permeation of triclosan across heat-separated
   human epidermal membranes in Franz diffusion cells, over a period of 48
   h. The above general trend was reflected in the steady state flux
   values obtained: 2051:16.91 μg cm^−2 h^−1 (S.E.M. 1.29), 2516:15.05 μg
   cm^−2 h^−1 (S.E.M. 1.00), 2287 12.83 μg cm^−2 h^−1 (S.E.M. 2.81).
   Although pharmacokinetic data are not currently available to permit
   calculation of an efficacious patch size, the transdermal delivery of
   triclosan is feasible.
   [36]PDF (148 K)
   [37]Enoyl-ACP Reductase (FabI) of Haemophilus influenzae: S...
   Archives of Biochemistry and Biophysics

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   [38]Enoyl-ACP Reductase (FabI) of Haemophilus influenzae: Steady-State
   Kinetic Mechanism and Inhibition by Triclosan and
   Hexachlorophene  Original Research Article
   Archives of Biochemistry and Biophysics, Volume 390, Issue 1, 1 June
   2001, Pages 101-108
   Jovita Marcinkeviciene, Wenjun Jiang, Lisa M. Kopcho, Gregory Locke,
   Ying Luo, Robert A. Copeland
   Abstract
   Steady-state kinetics, equilibrium binding, and primary substrate
   kinetic isotope effect studies revealed that the reduction of
   crotonyl-CoA by NADH, catalyzed by Haemophilus influenzae enoyl-ACP
   reductase (FabI), follows a rapid equilibrium random kinetic mechanism
   with negative interaction among the substrates. Two biphenyl
   inhibitors, triclosan and hexachlorophene, were studied in the context
   of the kinetic mechanism. IC[50] values for triclosan in the presence
   and absence of NAD^+ were 0.1 ± 0.02 and 2.4 ± 0.02 μM, respectively,
   confirming previous observations that the E–NAD^+ complex binds
   triclosan more tightly than the free enzyme. Preincubation of the
   enzyme with triclosan and NADH suggested that the E–NADH complex is the
   active triclosan binding species as well. These results were reinforced
   by measurement of binding kinetic transients. Intrinsic protein
   fluorescence changes induced by binding of 20 μM triclosan to E,
   E–NADH, E–NAD^+, and E–crotonyl-CoA occur at rates of 0.0124 ± 0.001,
   0.0663 ± 0.002, 0.412 ± 0.01, and 0.0069 ± 0.0001 s^−1, respectively.
   The rate of binding decreased with increasing crotonyl-CoA
   concentrations in the E-crotonyl-CoA complex, and the extrapolated rate
   at zero concentration of crotonyl-CoA corresponded to the rate observed
   for the binding to the free enzyme. This suggests that triclosan and
   the acyl substrate share a common binding site. Hexachlorophene
   inhibition, on the other hand, was NAD^+- and time-independent; and the
   calculated IC[50] value was 2.5 ± 0.4 μM. Steady-state inhibition
   patterns did not allow the mode of inhibition to be unambiguously
   determined, but binding kinetics suggested that free enzyme, E–NAD^+,
   and E–crotonyl-CoA have similar affinity for hexachlorophene, since the
   k[obs]s were in the same range of 20–24 s^−1. When the E–NADH complex
   was mixed with hexachlorophene ligand, concentration-independent
   fluorescence quenching at 480 nm was observed, suggesting at least
   partial competition between NADH and hexachlorophene for the same
   binding site. Mutual exclusivity studies, together with the
   above-discussed results, indicate that triclosan and hexachlorophene