Pathogens of all kinds continue to represent major public health challenges and demand new therapeutic strategies. Our lab focuses on developing therapeutics that derive from mechanistic analysis of anaerobic enzymes. Two of our projects are based on the iron-sulfur cluster enzymes Viperin and MqnE. Viperin, an acronym derived from the enzymes conspicuous properties (virus-inhibitory protein, endoplasmic reticulum-associated, interferon inducible), is an interferon inducible protein found in all higher eukaryotes that inhibits the replication of a remarkable range of both RNA and DNA viruses. We recently discovered that viperin converts the ribonucleotide CTP to a novel compound 3ʹ-deoxy-3′,4ʹ-didehydro-CTP (ddhCTP) through a radical-based mechanism. Interestingly, bacterial, fungal, and archaeal viperin-like enzymes are divergent in substrate specificity, producing alternative ddh-nucleotide triphosphate (ddhNTP) products (i.e. ddhUTP, ddhGTP). Our recent studies understanding the mechanism by which viperin and viperin-like enzymes catalyze this reaction and the structural basis for their divergent nucleotide specificity will be the focus of Part 1 of my talk. Part 2 will focus on the enzyme MqnE from Helicobacter pylori, which is involved in menaquinone (MK) biosynthesis. MK is a soluble lipid cofactor needed for the respiratory chain in all anaerobic bacteria. MK can be synthesized by two pathways: the canonical pathway and the futalosine pathway. Fortunately, the futalosine pathway is only found in a narrow set of bacteria—including Helicobacter pylori—which are not normally found in the human digestive track, making this pathway an attractive target for the development of narrow spectrum antibiotics. Our research has focused on understanding the catalytic mechanism of this central enzyme and development of inhibitors against it, employing a combination of traditional enzymology, structural biology, and drug discovery.
