Characterization of Plasmodium falciparum Pantothenate Kinase and Identification of Its Inhibitors From Natural Products

Frontiers in Cellular and Infection Microbiology

Kana Goto¹  Yoko Saikawa¹  Yumi Nakamura¹  Herbert J. Santos²  Yulia Rahmawati²  Tomoyoshi Nozaki²  Ghulam Jeelani²  Daniel Ken Inaoka³  Takaya Sakura³  Takeshi Annoura⁴  Yuzuru Tozawa⁵  Kazuro Shiomi⁶  Mihoko Mori⁷  Arif Nurkanto⁸ 

[1]Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama, Japan

[2]Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

[3]Department of Molecular Infection Dynamics, School of Tropical Medicine and Global Health, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Japan

[4]Department of Parasitology, National Institute of Infectious Diseases (NIID), Tokyo, Japan

[5]Graduate School of Science and Engineering, Saitama University, Saitama, Japan

[6]Kitasato Institute for Life Sciences, Kitasato University, Tokyo, Japan

[7]Kitasato Institute for Life Sciences, Kitasato University, Tokyo, Japan

[8]Biological Resource Center, National Institute of Technology and Evaluation (NITE), Chiba, Japan

[9]Research Center for Biology, Indonesian Institute of Sciences (LIPI), Cibinong, Indonesia

[10]Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

关键词: coenzyme A;    Pf;    Pf;    Plasmodium falciparum;    inhibitors;   

DOI  :  10.3389/fcimb.2021.639065

来源: Frontiers

【 摘 要 】

Coenzyme A (CoA) is a well-known cofactor that plays an essential role in many metabolic reactions in all organisms. In Plasmodium falciparum, the most deadly among Plasmodium species that cause malaria, CoA and its biosynthetic pathway have been proven to be indispensable. The first and rate-limiting reaction in the CoA biosynthetic pathway is catalyzed by two putative pantothenate kinases (PfPanK1 and 2) in this parasite. Here we produced, purified, and biochemically characterized recombinant PfPanK1 for the first time. PfPanK1 showed activity using pantetheine besides pantothenate, as the primary substrate, indicating that CoA biosynthesis in the blood stage of P. falciparum can bypass pantothenate. We further developed a robust and reliable screening system to identify inhibitors using recombinant PfPanK1 and identified four PfPanK inhibitors from natural compounds.

【 授权许可】

CC BY