Novel Steroid Inhibitors of Glucose 6-Phosphate Dehydrogenase

Hamilton, Niall M.; Dawson, Martin D.; Fairweather, Emma; Hamilton, Nicola; Hitchin, James R.; James, Dominic I.; Jones, Stuart; Jordan, Allan M.; Lyons, Amanda; Small, Helen; Thomson, Graeme; Waddell, Ian D.; Ogilvie, Donald

doi:10.1021/jm300317k

Cited by 58 publications

(55 citation statements)

References 42 publications

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“…14B). The proton NMR spectrum of the isolated P450 17A1 product also matched a previously reported NMR spectrum of synthetic 16␣-hydroxy-DHEA (45).…”

Section: P450 17a1 Reactions With Iodosylbenzene-preliminarysupporting

confidence: 82%

Mechanism of 17α,20-Lyase and New Hydroxylation Reactions of Human Cytochrome P450 17A1

Yoshimoto

Gonzalez

Auchus

et al. 2016

Journal of Biological Chemistry

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We propose three mechanisms that can involve the FeO 3؉ entity and that explain the 18 O label in the acetic acid, two involving the intermediacy of an acetyl radical and one a steroid 17,20-dioxetane. P450 17A1 was found to perform 16-hydroxylation reactions on its 17␣-hydroxylated products to yield 16,17␣-dihydroxypregnenolone and progesterone, suggesting the presence of an active perferryloxo active species of P450 17A1 when its lyase substrate is bound. The 6␤-hydroxylation of 16␣,17␣-dihydroxyprogesterone and the oxidation of both 16␣,17␣-dihydroxyprogesterone and 16␣,17␣-dihydroxypregnenolone to 16-hydroxy lyase products were also observed. We provide evidence for the contribution of a compound I mechanism, although contribution of a ferric peroxide pathway in the 17␣,20-lyase reaction cannot be excluded. Cytochrome P450 (P450)3 enzymes catalyze oxidations of more chemicals than any other group of proteins (1). The list of reactions includes aliphatic and aromatic hydroxylations, heteroatom oxidations, epoxidations, and reactions involving both ring formation and cleavage (2-4). Many P450 reactions are important in the biosynthesis and degradation of steroids and sterols (4, 5), including several critical C-C bond cleavage reactions, i.e. those catalyzed by P450s 11A1, 17A1 (Fig. 1), 19A1, and 51A1 (6, 7).The mechanisms of the C-C cleavage reactions have been the subject of considerable interest and debate. One of the questions with P450s 17A1, 19A1, and 51A1 has been whether the active oxidant is a ferric peroxide (FeO 2 Ϫ ), which is an early intermediate following oxygen addition to the iron (Fig. 2, step 4) or the FeO 3ϩ species (Fig. 2, step 6), often referred to as compound I (4, 10, 11). With P450s 17A1 and 19A1, a variety of approaches has been applied, including theoretical calculations, biomimetic models, spectroscopy, substrate atom labeling, and kinetics (12-32).These C-C bond cleavage reactions are complex, and many of the results are ambiguous; also, a "mixed" mechanism would not be discerned in many of these experiments. One powerful approach originally used by Akhtar and co-workers (27-31) analyzes the actual reaction and can provide discrimination between the nucleophilic FeO 2 Ϫ and electrophilic FeO 3ϩ reactions (Fig. 2), based on the incorporation of 18 O label from O 2 into the carboxylic acid products (Fig. 3) (7). However, these experiments are complicated due to the ubiquitous presence of formic acid (P450 19A1 and 51A1 reactions) and acetic acid (P450 17A1) in laboratory settings. Thus, the data from such experiments are interpreted with the most confidence when the steroid substrates are labeled with 2 H or 13 C isotopes to facilitate analysis (15,33). Even then, the mass spectrometry results can be problematic, particularly if a shift of only one atomic mass unit is introduced and isotopologues derived from 18 O incorporation are not discriminated from molecules containing natural abundance 13 C atoms (33). The incorporation of one atom of 18 O label from O 2 into formic acid (F...

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“…14B). The proton NMR spectrum of the isolated P450 17A1 product also matched a previously reported NMR spectrum of synthetic 16␣-hydroxy-DHEA (45).…”

Section: P450 17a1 Reactions With Iodosylbenzene-preliminarysupporting

confidence: 82%

Mechanism of 17α,20-Lyase and New Hydroxylation Reactions of Human Cytochrome P450 17A1

Yoshimoto

Gonzalez

Auchus

et al. 2016

Journal of Biological Chemistry

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“…In contrast, G6PD-deficient tumor cell lines showed relatively slow growth and enhanced apoptosis [41]. Previous studies also reported G6PD inhibitory properties for few compounds such as steroids and derivatives [42,43], chalcones [28], catechin gallates [44], and some phenolic molecules [45].…”

Section: Resultsmentioning

confidence: 96%

Compounds from <em>Terminalia mantaly</em> L. (Combretaceae) Stem Bark Exhibit Potent Inhibition against some Pathogenic Yeasts and Enzymes of Metabolic Significance<strong></strong>

Tchuenmogne

Ngouana

Gohlke

et al. 2016

Preprint

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“…The first one relies on cell treatment with the steroid hormone dehydroepiandrosterone (DHEA). In DHEA-treated cells, inhibition of glucose-6-phosphate dehydrogenase activity resulted in decreased levels of NADPH, an essential cofactor that helps maintain glutathione (GSH) in its reduced antioxidant form (54). Thus, decreased levels of GSH weaken the cell's antioxidant defense system.…”

Section: Analysis Of Binding Of Recombinant Egfp-ply and Egfp-⌬6plymentioning

confidence: 99%

Red Blood Cell Susceptibility to Pneumolysin

Bokori-Brown

Petrov

Khafaji

et al. 2016

Journal of Biological Chemistry

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This study investigated the effect of the biochemical and biophysical properties of the plasma membrane as well as membrane morphology on the susceptibility of human red blood cells to the cholesterol-dependent cytolysin pneumolysin, a key virulence factor of Streptococcus pneumoniae, using single cell studies. We show a correlation between the physical properties of the membrane (bending rigidity and surface and dipole electrostatic potentials) and the susceptibility of red blood cells to pneumolysin-induced hemolysis. We demonstrate that biochemical modifications of the membrane induced by oxidative stress, lipid scrambling, and artificial cell aging modulate the cell response to the toxin. We provide evidence that the diversity of response to pneumolysin in diabetic red blood cells correlates with levels of glycated hemoglobin and that the mechanical properties of the red blood cell plasma membrane are altered in diabetes. Finally, we show that diabetic red blood cells are more resistant to pneumolysin and the related toxin perfringolysin O relative to healthy red blood cells. Taken together, these studies indicate that the diversity of cell response to pneumolysin within a population of human red blood cells is influenced by the biophysical and biochemical status of the plasma membrane and the chemical and/or oxidative stress pre-history of the cell.The interaction of toxins with their target cells is generally characterized by a dose-response curve that is sigmoidal in shape (1). This shape is taken to reflect the differing susceptibilities of individual cells within the population. The fact that red blood cells (RBCs), with their less developed glycocalyx compared with other cell types (2), exhibit such a response is evidence that the initial interaction between the toxin and the plasma membrane is subject to, and probably the main determinant of, such variability. Therefore, it is important to understand the biochemical and biophysical factors affecting toxin-membrane interactions and the resulting variability of susceptibility within the same cell population.Individual RBCs within a population differ significantly (3) with respect to their shape, volume, and surface area. Some of these changes are related to cell age, due to the variety of mechanical and chemical stresses that an RBC undergoes in its life span of ϳ120 days (4, 5), and others can be associated with diseases, such as diabetes and with acute conditions, such as sepsis, among many others (6), and thus are likely to be present in the membranes of many other cell types.Previous work on bulk cell preparations revealed that in addition to its normal discocytic shape, the RBC at rest can assume a variety of other distinct shapes, such as echinocytes and acanthocytes, characterized by exterior projections, and stomatocytes with cup-shaped invaginations (7). Many of these unusual shapes appear in normal blood at a frequency of about 1%. However, during blood bank storage and in many inflammatory, degenerative, and microvascular disorders, the frequ...

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Novel Steroid Inhibitors of Glucose 6-Phosphate Dehydrogenase

Cited by 58 publications

References 42 publications

Mechanism of 17α,20-Lyase and New Hydroxylation Reactions of Human Cytochrome P450 17A1

Mechanism of 17α,20-Lyase and New Hydroxylation Reactions of Human Cytochrome P450 17A1

Compounds from <em>Terminalia mantaly</em> L. (Combretaceae) Stem Bark Exhibit Potent Inhibition against some Pathogenic Yeasts and Enzymes of Metabolic Significance<strong></strong>

Red Blood Cell Susceptibility to Pneumolysin

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