Idiosyncratic reactions and metabolism of sulfur-containing drugs

Zuniga, Freddi I; Loi, Danmy; Ling, Kah Hiing John; Tang-Liu, Diane

doi:10.1517/17425255.2012.668528

Cited by 33 publications

(19 citation statements)

References 101 publications

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“…A potential limitation of compound A is that its reaction with glutathione may indicate a lack of specificity. Many drugs that target sulfhydryl groups are in fact nonspecific and may react with reactive cysteines on other proteins (Zuniga et al, 2012). There are, however, many examples of sulfhydryltargeting drugs in current use.…”

Section: Discussionmentioning

confidence: 99%

“…Because of their reversibility after DTT treatment, these new compounds likely activate LCAT by forming a mixed disulfide with LCAT by S-methylating Cys31. Again, a limitation of this new class of compounds is that many drugs that target sulfhydryl groups are nonspecific and may react with reactive cysteines on other proteins (Zuniga et al, 2012). Previous studies of the N-methylthio class of lactams have shown that the N-S bond is relatively resistant to cleavage by most types of nucleophiles but is susceptible to thiophiles (Woulfe et al, 1985;Shah and Cama, 1987).…”

Section: Discussionmentioning

confidence: 99%

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Lecithin:Cholesterol Acyltransferase Activation by Sulfhydryl-Reactive Small Molecules: Role of Cysteine-31

Freeman

Demosky

Konaklieva

et al. 2017

J Pharmacol Exp Ther

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Lecithin:cholesterol acyltransferase (LCAT) catalyzes plasma cholesteryl ester formation and is defective in familial lecithin:cholesterol acyltransferase deficiency (FLD), an autosomal recessive disorder characterized by low high-density lipoprotein, anemia, and renal disease. This study aimed to investigate the mechanism by which compound A [3-(5-(ethylthio)-1,3,4-thiadiazol-2-ylthio)pyrazine-2-carbonitrile], a small heterocyclic amine, activates LCAT. The effect of compound A on LCAT was tested in human plasma and with recombinant LCAT. Mass spectrometry and nuclear magnetic resonance were used to determine compound A adduct formation with LCAT. Molecular modeling was performed to gain insight into the effects of compound A on LCAT structure and activity. Compound A increased LCAT activity in a subset (three of nine) of LCAT mutations to levels comparable to FLD heterozygotes. The site-directed mutation LCAT-Cys31Gly prevented activation by compound A. Substitution of Cys31 with charged residues (Glu, Arg, and Lys) decreased LCAT activity, whereas bulky hydrophobic groups (Trp, Leu, Phe, and Met) increased activity up to 3-fold ( < 0.005). Mass spectrometry of a tryptic digestion of LCAT incubated with compound A revealed a +103.017 adduct on Cys31, consistent with the addition of a single hydrophobic cyanopyrazine ring. Molecular modeling identified potential interactions of compound A near Cys31 and structural changes correlating with enhanced activity. Functional groups important for LCAT activation by compound A were identified by testing compound A derivatives. Finally, sulfhydryl-reactive-lactams were developed as a new class of LCAT activators. In conclusion, compound A activates LCAT, including some FLD mutations, by forming a hydrophobic adduct with Cys31, thus providing a mechanistic rationale for the design of future LCAT activators.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Lecithin:Cholesterol Acyltransferase Activation by Sulfhydryl-Reactive Small Molecules: Role of Cysteine-31

Freeman

Demosky

Konaklieva

et al. 2017

J Pharmacol Exp Ther

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“…37,38 Sulfur atom has been thought to be the site of bioactivation of these organosulfur compounds resulting in conceivably toxic metabolites. 39 Biological oxidations of small molecules such as N-acetylthiourea, N-methylthiourea show that sulfur is a soft nucleophile, and is easily oxidized by oxidants such as iodine, HOBr and HOCl, which are found in the physiological environment albeit in low concentrations. 40 The difference in oxidative environment and oxidizing species has a large bearing on the intermediates and subsequent products.…”

Section: Introductionmentioning

confidence: 99%

Oxyhalogen-sulfur chemistry: Kinetics and mechanism of oxidation of n-acetylthiourea by aqueous bromate and acidified bromate

Chipiso¹,

Mbiya²,

Tran³

et al. 2016

S.Afr.j.chem.

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“…Table 1 lists some important characteristics of the microarray platforms analyzed in this work. These characteristics can affect microarray performance [7-10]. The length of probes represents a tradeoff between sensitivity and specificity, with longer probes being generally more sensitive and shorter being more specific.…”

Section: Introductionmentioning

confidence: 99%

Empirical comparison of cross-platform normalization methods for gene expression data

2011

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BackgroundSimultaneous measurement of gene expression on a genomic scale can be accomplished using microarray technology or by sequencing based methods. Researchers who perform high throughput gene expression assays often deposit their data in public databases, but heterogeneity of measurement platforms leads to challenges for the combination and comparison of data sets. Researchers wishing to perform cross platform normalization face two major obstacles. First, a choice must be made about which method or methods to employ. Nine are currently available, and no rigorous comparison exists. Second, software for the selected method must be obtained and incorporated into a data analysis workflow.ResultsUsing two publicly available cross-platform testing data sets, cross-platform normalization methods are compared based on inter-platform concordance and on the consistency of gene lists obtained with transformed data. Scatter and ROC-like plots are produced and new statistics based on those plots are introduced to measure the effectiveness of each method. Bootstrapping is employed to obtain distributions for those statistics. The consistency of platform effects across studies is explored theoretically and with respect to the testing data sets.ConclusionsOur comparisons indicate that four methods, DWD, EB, GQ, and XPN, are generally effective, while the remaining methods do not adequately correct for platform effects. Of the four successful methods, XPN generally shows the highest inter-platform concordance when treatment groups are equally sized, while DWD is most robust to differently sized treatment groups and consistently shows the smallest loss in gene detection. We provide an R package, CONOR, capable of performing the nine cross-platform normalization methods considered. The package can be downloaded at http://alborz.sdsu.edu/conor and is available from CRAN.

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Idiosyncratic reactions and metabolism of sulfur-containing drugs

Cited by 33 publications

References 101 publications

Lecithin:Cholesterol Acyltransferase Activation by Sulfhydryl-Reactive Small Molecules: Role of Cysteine-31

Lecithin:Cholesterol Acyltransferase Activation by Sulfhydryl-Reactive Small Molecules: Role of Cysteine-31

Oxyhalogen-sulfur chemistry: Kinetics and mechanism of oxidation of n-acetylthiourea by aqueous bromate and acidified bromate

Empirical comparison of cross-platform normalization methods for gene expression data

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