People
Post Doctoral Researchers
All electron transfer in biological systems is a result of simple oxidation and reduction reactions. Understanding the mechanisms of these reactions is critical to understanding how enzymes function. We have developed a computational protein design protocol that identifies electroactive sites in enzymes, which can be targeted for further study and mutation. It should be possible to control the distance of electron transfer through mutation of individual proton acceptors and create disease state model proteins. Understanding the true importance of proton acceptors in proteins systems has important implications in photosystem II, proteins implicated in neurological disorders, and for the fundamental research of biochemistry and electrochemistry.
Graduate Students
I am studying the cause and effects of histone and DNA methylation in vivo. Methylation of histones and DNA is associated with inhibition of gene expression; inappropriate expression of methyltransferases may cause cancer to develop. For example, overexpression of methyltransferases may cause tumor suppressor genes to be methylated, preventing these genes from being expressed and leading to the development of cancer. Studying DNA and protein methylation will lead to a clearer understanding of cancer development.
Congratulations to Helena for successfully defending her dissertation !!!!
My research focuses on the synthesis and study of cyclic peptide antibiotics. Through chemical synthesis, these antibiotics can be diversified to increase their potency, discover new classes of antibiotics, or broaden their therapeutic scope. I am also interested in studying the mechanism of action of poorly characterized cyclic peptide antibiotics so that we can design more potent antibiotics.
I am currently investigating the mechanisms of enzymes in the non-ribosomal peptide synthesis. These antibiotics are produced by non-ribosomal peptide synthetases and fatty acid biosynthetic. My work at the moment is focused on the study of enzymes involved in interesting chemical reactions found during the biosynthesis of these peptide antibiotics.
My work focuses on the combination of synthetic organic chemistry and biological systems. I have started out with a project synthesizing potential mechanism-based inhibitors of human histone lysine-specific demethylase (LSD1). This flavin-dependent enzyme specifically demethylates at lysine 4 of histone 3, and selective inhibitors could have important implications on gene regulation. I am currently moving my focus towards a natural product that has shown promising preliminary bioactivity both as an antibiotic and a cancer therapeutic. This project concentrates on the total chemical synthesis of this compound and the mechanism of action.
I work on targeting the peptidoglycan recycling pathway for the battle against bacterial infection. I am currently working with an enzyme that, when targeted, could play a role in impeding cell wall biosynthesis. This enzyme's mechanism is unknown so the first aim of my project is to the remedy that. In addition to mechanistic studies, structure elucidation of this enzyme is a major goal. Eventually, I would also like to get a structure of the enzyme bound to its substrate, which could then lead to structure-based drug design. In a nutshell, my project combines organic synthesis with structural biology and crystallography.
I am working on elucidating the biosynthetic mechanism of Ramoplanin, an antibiotic produced by Actinoplanes. Ramoplanin A2 is produced by non-ribosmal peptide synthetases and fatty acid biosynthetic genes. The exact mechanism and order of the transformations are being studied as well as the substrate specificity.
LSD1, lysine specific histone demethylase, is able to demethylate nucleosomal substrates when associated with CoREST, a transcriptional corepressor protein. My research mainly focuses on the molecular mechanism that underlies the role of CoREST on LSD1 activity. With understanding of the function of CoREST, the specific sites of interaction between LSD1 and CoREST will be determined, which consequently gives an idea of how to design a small molecule that inhibits the interaction between them. The inhibition of the interacting sites downregulates LSD1 activity, being able to prevent certain types of cancer.
Sortase enzymes covalently link proteins secreted by gram-positive bacteria to cell wall peptidoglycan subunits. Sortase C in Streptococcus pyogenes (Group A Strep) is a pilin polymerase that is encoded in a pilin gene region (FCT region) and covalently links together pilin subunits. Pili are important virulence factors that are hair-like extensions away from the bacterial surface and are usually adhesive to host cells. This allows bacteria to interact with their environment at a distance and provides possible targets for new antibiotics in this time of growing antibiotic resistance. Pilin polymerizing sortases are the only known sortases to covalently link proteins to other proteins. The study of the mechanism and specificity of these enzymes is the focus of my research. In particular, I am studying Sortase C2 and its substrates Tee3 (structural pilin subunit) and Cpa (adhesive pilin subunit) from a FCT-3 containing GAS strain
I am working on inhibiting the enzyme sortase A. Sortase enzymes perform a transpeptidation reaction on a conserved peptide domain. Currently, I am researching small molecule inhibitors which will prevent the enzyme from functioning. Without sortase activity, many gram-positive bacteria will be unable to bind virulence factors or perform other necessary functions.