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I03-Macromolecular Crystallography	Structure of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase–dihydropteroate synthase from Plasmodium vivax sheds light on drug resistance Manickam Yogavel , Joanne E. Nettleship , Akansha Sharma , Karl Harlos , Abhishek Jamwal , Rini Chaturvedi , Manmohan Sharma , Vitul Jain , Jyoti Chhibber-Goel , Amit Sharma Journal Of Biological Chemistry DOI: 10.1074/jbc.RA118.004558 Diamond Proposal Number(s): [14744] Open Access Show Abstract ▼ Abstract: The genomes of the malaria-causing Plasmodium parasites encode a protein fused of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) and dihydropteroate synthase (DHPS) domains that catalyze sequential reactions in the folate biosynthetic pathway. Whereas higher organisms derive folate from their diet and lack the enzymes for its synthesis, most eubacteria and a number of lower eukaryotes including malaria parasites synthesize tetrahydrofolate via DHPS. Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) HPPK-DHPSs are currently targets of drugs like sulfadoxine (SDX). The SDX effectiveness as an antimalarial drug is increasingly diminished by rise and spread of drug resistance mutations. Here, we present the crystal structure of PvHPPK-DHPS in complex with four substrates/analogs, revealing the bifunctional PvHPPK-DHPS architecture in an unprecedented state of enzymatic activation. SDX’s effect on HPPK-DHPS is due to 4-amino benzoic acid (pABA) mimicry, and the PvHPPK-DHPS structure sheds light on the SDX-binding cavity as well as on mutations that effect SDX potency. We mapped five dominant drug resistance mutations in PvHPPK-DHPS: S382A, A383G, K512E/D, A553G, and V585A, most of which occur individually or in clusters proximal to the pABA-binding site. We found that these resistance mutations subtly alter the intricate enzyme/pABA/SDX interactions such that DHPS affinity for pABA is diminished only moderately, but its affinity for SDX is changed substantially. In conclusion, the PvHPPK-DHPS structure rationalizes and unravels the structural bases for SDX resistance mutations and highlights architectural features in HPPK-DHPSs from malaria parasites that can form the basis for developing next-generation anti-folate agents to combat malaria parasites.	Aug 2018

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I03-Macromolecular Crystallography

Structure of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase–dihydropteroate synthase from Plasmodium vivax sheds light on drug resistance

Manickam Yogavel , Joanne E. Nettleship , Akansha Sharma , Karl Harlos , Abhishek Jamwal , Rini Chaturvedi , Manmohan Sharma , Vitul Jain , Jyoti Chhibber-Goel , Amit Sharma

Journal Of Biological Chemistry

DOI: 10.1074/jbc.RA118.004558

Diamond Proposal Number(s): [14744]