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Mechanistic And Structure-Function Analysis Of Thymidylate Synthase-Dihydrofolate Reductase From Protozoal Parasites: Implications For The Development Of Non-Active Site Inhibitors, Chloé E. Atreya

Yale Medicine Thesis Digital Library

A major advance in the field of bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) is the recent crystallization of two apicomplexan TS-DHFR enzymes, from Cryptosporidium hominis and Plasmodium falciparum, which demonstrate significant structural differences from the well-known kinetoplastid TS-DHFR structure (Leishmania major ). A principal finding of this dissertation research is that the significant structural differences between the apicomplexa and kinetoplastid bifunctional TS-DHFR enzymes translate as significant mechanistic differences between parasite classes and among parasites within the same class.An in depth mechanistic analysis of C. hominis TS-DHFR and a preliminary analysis of the P. falciparum enzyme were completed. Results with C. hominis …