Development of an internally quenched fluorogenic substrate for kinetic analysis of thioesterases.
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Esterases↗
Biomedical subjects
Zachary Q Beck
Publications and source records attributed to Zachary Q Beck.
Chemoenzymatic synthesis of cryptophycin/arenastatin natural products.
Microbially derived modular polyketide synthase and nonribosomal peptide synthetase biosynthetic pathways are a rich source of novel natural products. Development of these systems for the engineered biosynthesis of diverse secondary metabolites continues to progress as a robust source of chemical diversity. Recent efforts that employ individual enzymes and catalytic domains for the production or modification of small molecules have met with growing success. In this study, the thioesterase domain from the cryptophycin biosynthetic pathway was isolated and its function evaluated with a series of linear chain elongation intermediates in developing a novel chemoenzymatic synthesis of the cryptophycin/arenastatin class of antitumor agents. The results show the high efficiency of the thioesterase in generating the 16-membered depsipeptide ring of this important natural product system. Moreover, analysis of selected substrates revealed considerable tolerance for structural variation within the seco-cryptophycin unit C beta-alanine residue, but strict structural requirements at the phenyl group position of the unit A delta-hydroxy octadienoate chain elongation intermediates.
Amino Acid Sequence↗
Defining HIV-1 protease substrate selectivity.
The Aspartyl protease of HIV-1 offers an excellent target for the development of specific drugs against the virus. Drugs against protease and reverse transcriptase form the basis for Highly Active Anti-Retroviral Therapy (HAART) that has been successful in improving survival rates and quality of life for HIV infected individuals. However, resistance development to these drugs is a continuing problem, demanding development of additional drugs and approaches to fight virus infection. A thorough understanding of the molecular basis for substrate and inhibitor specificity is critical to defining mechanisms of evasion by drug-resistant mutants as well as for the rational design of drugs able to inhibit a broad spectrum of HIV-1 variants. In this article, we describe characteristics of the protease structure and what is known regarding substrate diversity and mechanisms of cleavage. Approaches to defining substrate diversity are described as an approach to identifying optimal templates for broad-based inhibitor development.
Animals↗