Plasmodium vivaxand human hexokinases share similar active sites but display distinct quaternary architectures

Abstract

Malaria is a devastating disease caused by a protozoan parasite. It affects over 300 million individuals and results in over 400 000 deaths annually, most of whom are young children under the age of five. Hexokinase, the first enzyme in glucose metabolism, plays an important role in the infection process and represents a promising target for therapeutic intervention. Here, cryo-EM structures of two conformational states of Plasmodium vivax hexokinase (PvHK) are reported at resolutions of ∼3 Å. It is shown that unlike other known hexokinase structures, PvHK displays a unique tetrameric organization (∼220 kDa) that can exist in either open or closed quaternary conformational states. Despite the resemblance of the active site of PvHK to its mammalian counterparts, this tetrameric organization is distinct from that of human hexokinases, providing a foundation for the structure-guided design of parasite-selective antimalarial drugs.

Protein kinases on carbon metabolism: potential targets for alternative chemotherapies against toxoplasmosis

“…The organization of the tetrameric structure in Plasmodium is related to the most extensive hydrophobic interactions in peripheral regions, generating solid interactions in the interfaces of the kinase. In contrast, these regions are replaced by polar residues ( Srivastava et al., 2020 ). Toxoplasma knockout parasites for HK cannot catalyze glucose phosphorylation, even under supplemented glucose conditions, displaying defects in the formation of tissue cysts in the nervous system of mice and alterations in the invasion process of new host cells ( Shukla et al., 2018 ).…”

Plasmodium Kinases as Potential Drug Targets for Malaria: Challenges and Opportunities

“… 45 Recently, structures of P. falciparum choline kinase ( Pf ChoK) and hexokinase have also been reported. 11 , 13 To our knowledge, no Plasmodium PIK structures have been elucidated to date.…”

“…High-resolution structures of at least 11 different Plasmodium protein kinases have been solved ( Pb CDPK1 (3Q5I), Pf CDPK2 (4MVF), Pf CDPK4 (4QOX, 4RGJ), Pf CK2 (5XVU), Pf CLK1 (3LLT), Pf MAPK2 (3NIE), Pb MAPK2 (3N9X), Pf PK5 (e.g., 1OB3), Pf PK7 (e.g., 2PMN), Pf PKG (5DYK), and Pv PKG (e.g., 5DZC). Recently, structures of P. falciparum choline kinase ( Pf ChoK) and hexokinase have also been reported. , To our knowledge, no Plasmodium PIK structures have been elucidated to date.…”

“…Here, we focus on protein and phosphoinositide kinases (PIKs). For information related to other kinases, such as choline kinase , and hexokinase (glucokinase), a reference is made to the specific literature. , In addition, a recent review from Cabrera and colleagues deals with Plasmodium kinases as drug targets and specific classes of inhibitors …”

Structural Analysis of Plasmodium falciparum Hexokinase Provides Novel Information about Catalysis Due to a Plasmodium-Specific Insertion

“…Pf HK exists as a single-copy gene on chromosome 6 without any isoenzymes [ 14 ]. Hexokinases are well conserved among Plasmodium , but the sequence identity to their human counterpart is lower than 32% [ 7 , 15 ]. Compared to other proteins within similar species, Pf HK contains 15 cysteines (~3%) and is therefore considered to be exceptionally cysteine-rich [ 16 ].…”