Structural Biology Commons^™

Exploring The Limitations Of Substrate Scope In Dimethylallyltryptophan Synthases, Evan T. Miller

Theses and Dissertations--Pharmacy

Natural products (NPs), are the largest source of bioactive compounds in Nature, and are essential to the treatment of human disease. Nearly 50% of drugs approved for use from 1981 to 2019 owe some aspect of their development to NPs, either in terms of their structure, pharmacophore, or mechanism of action. However, NPs are difficult to structurally optimize. Chemoenzymatic methods for NP derivatization have been increasingly seen as practical alternatives to traditional synthetic methods. Prenyltransferases (PTs) are involved in the primary and secondary metabolism of plants, bacteria, and fungi, and they are key enzymes in the biosynthesis of many clinically …

Building Tools For Improved Modulation Of The Human Gabaa Receptor, A Central Nervous System Target For The Treatment Of Anxiety, Garrett Edward Zinck

Theses and Dissertations--Pharmacy

In the U.S., anxiety is recognized as an increasing range of mentally and physically debilitating psychiatric health disorders with significant economic repercussions. Over the last 20 years, several novel anti-anxiety therapies have entered the drug development pipeline, but none have made it to market.

The work in this dissertation focused on structurally modifying valerenic acid (VA), a structurally unique carboxylated sesquiterpene acid found in Valeriana officinalis. VA is putatively reported to have allosteric modulatory activity of the human GABA_A receptor, a ligand-gated ion channel responsible for attenuating neurotransmissions. Structural modeling of VA’s GABA_A receptor interaction suggests that …

Interactions Of Post-Pks Enzymes Of The Mithramycin Biosynthetic Pathway, Ryan Wheeler

Theses and Dissertations--Pharmacy

Combinatorial biosynthesis is a powerful tool for generating new, more active drug analogues to combat disease. But in order for combinatorial biosynthesis to be employed to its full potential, a deep understanding of the enzymes that produce the parent molecule must be had. The goals of the work presented in this thesis are to characterize the reaction catalyzed by MtmW, the final enzyme in the mithramycin (MTM) biosynthetic pathway, and to discover the interaction between MtmW and MtmOIV.

MtmW is an aldol-ketoreductase responsible for reducing the most distal carbonyl on the MTM pentyl side chain. It forms an octamer that …

Toward An Enzyme-Coupled, Bioorthogonal Platform For Methyltransferases: Probing The Specificity Of Methionine Adenosyltransferases, Tyler D. Huber

Theses and Dissertations--Pharmacy

Methyl group transfer from S-adenosyl-l-methionine (AdoMet) to various substrates including DNA, proteins, and natural products (NPs), is accomplished by methyltransferases (MTs). Analogs of AdoMet, bearing an alternative S-alkyl group can be exploited, in the context of an array of wild-type MT-catalyzed reactions, to differentially alkylate DNA, proteins, and NPs. This technology provides a means to elucidate MT targets by the MT-mediated installation of chemoselective handles from AdoMet analogs to biologically relevant molecules and affords researchers a fresh route to diversify NP scaffolds by permitting the differential alkylation of chemical sites vulnerable to NP MTs that are unreactive to …

Chemoenzymatic Studies To Enhance The Chemical Space Of Natural Products, Jhong-Min Chen

Theses and Dissertations--Pharmacy

Natural products provide some of the most potent anticancer agents and offer a template for new drug design or improvement with the advantage of an enormous chemical space. The overall goal of this thesis research is to enhance the chemical space of two natural products in order to generate novel drugs with better in vivo bioactivities than the original natural products.

Polycarcin V (PV) is a gilvocarcin-type antitumor agent with similar structure and comparable bioactivity with the principle compound of this group, gilvocarcin V (GV). Modest modifications of the polyketide-derived tetracyclic core of GV had been accomplished, but the most …

Investigating Structure And Protein-Protein Interactions Of Key Post-Type Ii Pks Tailoring Enzymes, Theresa E. Downey

Theses and Dissertations--Pharmacy

Type II polyketide synthase (PKS) produced natural products have proven to be an excellent source of pharmacologically relevant molecules due to their rich biological activities and chemical scaffolds. Type II-PKS manufactured polyketides share similar polycyclic aromatic backbones leaving their diversity to stem from various chemical additions and alterations facilitated by post-PKS tailoring enzymes. Evidence suggests that post-PKS tailoring enzymes form complexes in order to facilitate the highly orchestrated process of biosynthesis. Thus, protein-protein interactions between these enzymes must play crucial roles in their structures and functions. Despite the importance of these interactions little has been done to study them. In …