Abstract：
:The Plasmodium falciparum malarial parasite genome appears to encode one and only one phosphatidylinositol 3'-kinase (PI3K), and sequence analysis suggests that the enzyme is a "class III"- or "Vps34"-type PI3K. PfVps34 has generated excitement as a possible druggable target and potentially a key target of artemisinin-based antimalarials. In this study, we optimize the PfVps34 gene for heterologous expression in yeast, purify the protein to homogeneity, use a recently validated quantitative assay for phosphatidylinositol 3'-phosphate production from phosphatidylinositol ( Hassett et al., companion paper; DOI 10.1021/acs.biochem.7b00416 ) to quantify activity and drug inhibition of that activity, and investigate the importance of key residues in the enzyme's catalytic and "N-lobe" domains. Data suggest that PfVps34 is indeed inhibited by artemisinin and related drugs but only under conditions that cleave the drugs' endoperoxide bridge to generate reactive alkylating agents.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Hassett MR,Sternberg AR,Riegel BE,Thomas CJ,Roepe PDdoi
10.1021/acs.biochem.7b00416subject
Has Abstractpub_date
2017-08-22 00:00:00pages
4335-4345issue
33eissn
0006-2960issn
1520-4995journal_volume
56pub_type
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