ORCID

http://orcid.org/0000-0002-5529-3280

Date of Award

Summer 8-15-2021

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Microbiology & Microbial Pathogenesis)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Malaria is an enormous financial and public health burden for much of the world, infecting over 200 million and killing over 400,000 people every year. While much progress has been made combating malaria in the past few decades, those advances have slowed in recent years, partially due to the emergence of resistance to all known antimalarials used to date. To achieve the goal of eliminating malaria as a major global health problem, new therapeutics need to be developed, targeting novel categories of parasite biology. One poorly understood area of parasite biology is the regulation of various metabolic pathways. We have recently identified a superfamily of proteins, named haloacid dehalogenase (HAD) proteins, that are implicated in resistance to metabolic inhibitors and regulation of essential metabolic pathways in Plasmodium falciparum malaria parasites. Here, we investigate how HAD2 (PF3D7_1226300) regulates metabolism of the isoprenoid biosynthesis pathway, using biochemical, metabolomic, and genetic tools. We find that HAD2 is a phosphatase with a preference for triose phosphates. We then investigate the related HAD proteins—HAD4 (PF3D7_1118400), Lipin (PF3D7_0303200), and HAD5 (PF53D7_1017400)—for their roles in regulating parasite metabolism and the implications for future drug design. We find that HAD4 and Lipin are dispensable for growth in asexual malaria parasites. Lipin disruption causes significant growth reduction and accumulation of lipid species, while HAD4 is a dispensable nucleotide phosphatase. We also find that HAD5 is a phosphomannomutase that is essential for parasite egress and invasion. We solve the three-dimensional crystal structure of HAD5 and demonstrate our ability to selectively inhibit it compared to human phosphomannomutases. All of these findings add to our understanding of metabolic regulation in malaria parasites, illuminating key ways that targeting different metabolic pathways could work synergistically in development of novel antimalarial therapeutic strategies.

Language

English (en)

Chair and Committee

Daniel E. Goldberg

Committee Members

Tamara Doering, Jeffrey Henderson, Christina Stallings, Audrey Odom John,

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