Gene/Protein Disease Symptom Drug Enzyme Compound
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The epipolythiodioxopiperazine (ETP) gliotoxin mediates toxicity via its reactive thiol groups and thereby contributes to virulence of the human pathogenic fungus Aspergillus fumigatus. Self-intoxication of the mold is prevented either by reversible oxidation of reduced gliotoxin or by irreversible conversion to bis(methylthio)gliotoxin. The latter is produced by the S-methyltransferase TmtA and attenuates ETP biosynthesis. Here, we report the crystal structure of TmtA in complex with S-(5'-adenosyl)-l-homocysteine. TmtA features one substrate and one cofactor binding pocket per protein, and thus, bis-thiomethylation of gliotoxin occurs sequentially. Molecular docking of substrates and products into the active site of TmtA reveals that gliotoxin forms specific interactions with the protein surroundings, and free energy calculations indicate that methylation of the C10a-SH group precedes alkylation of the C3-SH site. Altogether, TmtA is well suited to selectively convert gliotoxin and to control its biosynthesis, suggesting that homologous enzymes serve to regulate the production of their toxic natural sulfur compounds in a similar manner.
ACS Chem Biol 2016 Apr 15
PMID:Sequential Inactivation of Gliotoxin by the S-Methyltransferase TmtA. 2680 94

Neuromodulators and neurotransmitters play important roles in neural network development. The quantitative changes of these signaling molecules often reflect their regulatory roles in physiological processes. Currently, several commercial tags (e.g., iTRAQ and TMT) have been widely used in proteomics. With reduced cost and higher labeling efficiency, we employed a set of custom-developed N, N-dimethyl leucine (DiLeu) 4-plex isobaric tandem mass tags as an attractive alternative for the relative quantitation of neuropeptides in brain tissue of American lobster Homarus americanus at multiple developmental stages. A general workflow for isobaric labeling of neuropeptides followed by LC-MS/MS analysis has been developed, including optimized sample handling procedures. Overall, we were able to quantify 18 trace-amount neuropeptides from 6 different families using a single adult brain as a control. The quantitation results indicated that the expressions of different neuropeptide families had significant changes over distinct developmental stages. Additionally, our data revealed intriguing elevated expression of neuropeptides in the early juvenile development stage. The methodology presented here advanced the workflow of DiLeu as an alternative labeling approach and the application of DiLeu-based quantitative peptidomics, which can be extended to areas beyond neuroscience.
ACS Chem Neurosci 2018 08 15
PMID:Relative Quantitation of Neuropeptides at Multiple Developmental Stages of the American Lobster Using N, N-Dimethyl Leucine Isobaric Tandem Mass Tags. 2935 24

Enrichment of modified peptides from global peptides is inevitable in mass spectrometric analysis protein modifications because of their importance in the study of cellular functions and low abundance in the global proteomic analysis. Recent advances in enrichment methods for modified peptides such as phosphopeptides and intact glycopeptides (IGPs) show that the methods for proteomic analyses of both protein modifications are robust. We have recently observed and reported a large number of IGPs from phosphoproteomic analysis using IMAC-based phosphopeptides enrichment procedure. To determine whether phosphorylated peptides could be specifically isolated from coenriched IGPs in IMAC experiments with different pH, IMAC procedures were performed at different pH conditions, and we found that the enrichment of phosphopeptides at pH 2.0 was the optimal condition for having the highest number of phosphopeptide identifications; however, coenrichment of phosphopeptides and glycopeptides was inevitable in the entire pH range. The hydrophilic enrichments of IGPs performed before or after IMAC enrichment were evaluated subsequently to determine the optimal workflow for simultaneous analyses of phosphopeptides and glycopeptides, and IMAC enrichment followed by hydrophilic enrichment was chosen as the optimized workflow. Applying the workflow to the TMT-labeled peptides from luminal and basal-like type of breast cancer patient-derived xenograft (PDX) models allowed quantitative analyses of phospho- and glycoproteomics with 17582 phosphopeptides and 3468 glycopeptides identified, and 1237 phosphopeptides and 236 glycopeptides showed significant expression differences between luminal and basal-like, respectively. This method allows simultaneous analyses of phosphoprotein and glycoprotein modifications, extending our understanding of roles of glycosylation and phosphorylation in biology and diseases.
ACS Chem Biol 2019 01 18
PMID:Developing Workflow for Simultaneous Analyses of Phosphopeptides and Glycopeptides. 3052 47