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Plasmodium vivax and 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.

SUBMITTER: Srivastava SS

PROVIDER: S-EPMC7201273 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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<i>Plasmodium vivax</i> and human hexokinases share similar active sites but display distinct quaternary architectures.

Srivastava Shanti Swaroop SS Darling Joseph E JE Suryadi Jimmy J Morris James C JC Drew Mark E ME Subramaniam Sriram S

IUCrJ 20200326 Pt 3

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 <i>Plasmodium vivax</i> hexokinase (PvHK) are reported at resolutions of ...[more]

PMID: 32431829

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Project description:Plasmodium vivax has the widest geographic distribution of the human malaria parasites and nearly 2.5 billion people live at risk of infection. The control of P. vivax in individuals and populations is complicated by its ability to relapse weeks to months after initial infection. Strains of P. vivax from different geographical areas are thought to exhibit varied relapse timings. In tropical regions strains relapse quickly (three to six weeks), whereas those in temperate regions do so more slowly (six to twelve months), but no comprehensive assessment of evidence has been conducted. Here observed patterns of relapse periodicity are used to generate predictions of relapse incidence within geographic regions representative of varying parasite transmission.A global review of reports of P. vivax relapse in patients not treated with a radical cure was conducted. Records of time to first P. vivax relapse were positioned by geographic origin relative to expert opinion regions of relapse behaviour and epidemiological zones. Mixed-effects meta-analysis was conducted to determine which geographic classification best described the data, such that a description of the pattern of relapse periodicity within each region could be described. Model outputs of incidence and mean time to relapse were mapped to illustrate the global variation in relapse.Differences in relapse periodicity were best described by a historical geographic classification system used to describe malaria transmission zones based on areas sharing zoological and ecological features. Maps of incidence and time to relapse showed high relapse frequency to be predominant in tropical regions and prolonged relapse in temperate areas.The results indicate that relapse periodicity varies systematically by geographic region and are categorized by nine global regions characterized by similar malaria transmission dynamics. This indicates that relapse may be an adaptation evolved to exploit seasonal changes in vector survival and therefore optimize transmission. Geographic patterns in P. vivax relapse are important to clinicians treating individual infections, epidemiologists trying to infer P. vivax burden, and public health officials trying to control and eliminate the disease in human populations.

Dataset Information

Plasmodium vivax and human hexokinases share similar active sites but display distinct quaternary architectures.

Publications

<i>Plasmodium vivax</i> and human hexokinases share similar active sites but display distinct quaternary architectures.

Similar Datasets

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