Presenter Information

Xhulio ArolliFollow

Major

Chemistry

Anticipated Graduation Year

2020

Access Type

Open Access

Abstract

Gcn5-Related N-acetyltransferase enzymes (GNATs) are part of a superfamily of enzymes that participate in acyl-transfer reactions and play a key role in a wide variety of biological processes including histone modification, protein acetylation, xenobiotic metabolism, and other cellular processes. The acyl group transfer ability of these enzymes gives them important roles in metabolic and cellular processes, gene regulation, transcription, detoxification, drug resistance, and post-translational protein modifications. In addition, they play a role in aminoglycoside antibiotic resistance, and thus inhibitors may provide an avenue to combat resistant bacteria. We have studied the docking and synthesis of alternate substrates for Gcn5-Related N-acetyltransferases (GNATs) enzyme PA3944 derived from Pseudomonas aeruginosa. The substrate binding site of most GNAT enzymes is adjacent to the binding site of its cofactor acetyl CoA which is highly conserved, which makes predicting enzyme-cofactor binding interactions in GNAT more straightforward. On the other hand, the highly selective substrate binding site is different for each GNAT making it is much more difficult to predict the substrate-enzyme binding interactions. Understanding the key substrate-GNAT specificity elements is critical for modulating GNAT enzymes toward the discovery of new medicines including antibiotics with a new mechanism of action.

Community Partners

San Francisco State University, San Francisco

Faculty Mentors & Instructors

Thahani S. Habeeb Mohammad, Daniel P. Becker, Department of Chemistry and Biochemistry

Supported By

Cory Reidl, Misty Kuhn, Department of Chemistry and Biochemistry

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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Molecular Docking and Synthesis of GNAT PA3944 Substrates and Inhibitors

Gcn5-Related N-acetyltransferase enzymes (GNATs) are part of a superfamily of enzymes that participate in acyl-transfer reactions and play a key role in a wide variety of biological processes including histone modification, protein acetylation, xenobiotic metabolism, and other cellular processes. The acyl group transfer ability of these enzymes gives them important roles in metabolic and cellular processes, gene regulation, transcription, detoxification, drug resistance, and post-translational protein modifications. In addition, they play a role in aminoglycoside antibiotic resistance, and thus inhibitors may provide an avenue to combat resistant bacteria. We have studied the docking and synthesis of alternate substrates for Gcn5-Related N-acetyltransferases (GNATs) enzyme PA3944 derived from Pseudomonas aeruginosa. The substrate binding site of most GNAT enzymes is adjacent to the binding site of its cofactor acetyl CoA which is highly conserved, which makes predicting enzyme-cofactor binding interactions in GNAT more straightforward. On the other hand, the highly selective substrate binding site is different for each GNAT making it is much more difficult to predict the substrate-enzyme binding interactions. Understanding the key substrate-GNAT specificity elements is critical for modulating GNAT enzymes toward the discovery of new medicines including antibiotics with a new mechanism of action.