BodNatural Product FR900098 Analogs as Small Molecule Inhibitors for the Methylerythritol Phosphate (MEP) Pathway in Mycobacterium tuberculosis (Mtb) and Plasmodium falciparum (Pf)
Characterizing the mechanism of action of a novel enzyme that has a similar structure as other E3 ligases but exhibit different levels of activity
Darean will discusss Mycobacterium tuberculosis (Mtb) and Plasmodium falciparum (Pf), the methylerythritol phosphate (MEP) pathway is responsible for isoprene synthesis. The process and its products are vital tobacterial/parasitic metabolism. This pathway represents an attractive set of drug targets due to its essentiality in these pathogens but non-essentiality in humans. The second step in the MEP pathway is theconversion of 1-deoxy-D-xylulose-5-phosphate (DXP) to MEP and is catalyzed by 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr). Natural products fosmidomycin and FR900098 inhibit Dxr, howeverthey lack the required lipophilicity to reach the desired target inside the cell. Synthesized FR900098 analogs with lipophilic substitution in the position a to the phosphorous atom showed promise, resulting inincreased activity against Mtb and Pf. An a substitution, consisting of a 3,4-dichlorophenyl substituent, in combination with various O -linked alkylaryl substituents on the hydroxamate moiety is strategicallyutilized in the synthesis of a novel series of FR900098 analogs. The purpose of the O -linked alkylaryl substituents is to further enhance Dxr inhibition by extending into the bi-substrate NADPH binding pocket,thus blocking the binding of NADPH. This series of FR900098 analogs includes diammonium salts and both diethyl and dipivaloyloxymethyl (POM) prodrug esters. Data from these compounds suggest that thiscombination of substituents is advantageous in designing a new generation of antimicrobials.
Darean Bague received her B.S. in chemistry from Schreiner University in 2016, where she worked under Dr. Danette Vines synthesizing anticancer drug analogs and antibody-drug conjugates for breast cancer. She then attended Stephen F.Austin State University in Nacogdoches, Texas where she received her M.S. in chemistry doing research under Dr. Russell Franks focusing on novel synthesis of biodiesel from alternative renewable resources. Darean then joined the chemistry department at The George Washington University in 2018 and is working towards her PhD under the guidance of Dr. Cynthia Dowd.
Jessica will discuss Proteins with similar structure typically have similar functions. In the MID1 protein, there are two domains with similar structure, but exhibit different levels of activity. These domains have E3 ligase activities that direct cellular proteins for degradation and recycling. The MID1 RING and B-box1 domains catalyze the covalent attachment of a ubiquitin protein to a substrate protein. Despite having the same structure, the B-box1 catalyzes monoubiquitination compared with polyubiquitination by the RING domain. NMR binding studies reveal that the B-box1 domain binds the E2 enzyme, which is essential for ubiquitination, on a different surface compared with the way typical RING E3 domains interact with the E2. This interaction provides insight into why B-box1 exhibits monoubiquitination activity. To confirm that the difference in interaction affects the reaction, thiolysis reactions show that the mechanism of interaction is critical for nucleophilic attack of the thioester bond between the E2 and Ub proteins by amino group of lysine. These studies can be extrapolated to explain why some RING E3 ligases have exhibited weaker ubiquitination activity compared with others.
Jessica graduated from the University of Delaware in 2016 with a bachelor of science degree in Chemistry. After working at Charles River Laboratories, she joined Prof. Massiah's laboratory to study protein-protein interactions involved in the ubiquitin proteasome pathway.
This Seminar will be on Zoom. The Zoom link will be added the week of the Seminar