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

Arif Nurkanto; Ghulam Jeelani; Herbert J Santos; Yulia Rahmawati; Mihoko Mori; Yumi Nakamura; Kana Goto; Yoko Saikawa; Takeshi Annoura; Yuzuru Tozawa; Takaya Sakura; Daniel Ken Inaoka; Kazuro Shiomi; Tomoyoshi Nozaki

doi:10.3389/fcimb.2021.639065

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

Front Cell Infect Microbiol. 2021 Mar 9:11:639065. doi: 10.3389/fcimb.2021.639065. eCollection 2021.

Authors

Arif Nurkanto^{1

2}, Ghulam Jeelani², Herbert J Santos², Yulia Rahmawati², Mihoko Mori^{3

4}, Yumi Nakamura⁵, Kana Goto⁵, Yoko Saikawa⁵, Takeshi Annoura⁶, Yuzuru Tozawa⁷, Takaya Sakura⁸, Daniel Ken Inaoka⁸, Kazuro Shiomi³, Tomoyoshi Nozaki²

Affiliations

¹ Research Center for Biology, Indonesian Institute of Sciences (LIPI), Cibinong, Indonesia.
² Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
³ Kitasato Institute for Life Sciences, Kitasato University, Tokyo, Japan.
⁴ Biological Resource Center, National Institute of Technology and Evaluation (NITE), Chiba, Japan.
⁵ Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama, Japan.
⁶ Department of Parasitology, National Institute of Infectious Diseases (NIID), Tokyo, Japan.
⁷ Graduate School of Science and Engineering, Saitama University, Saitama, Japan.
⁸ Department of Molecular Infection Dynamics, School of Tropical Medicine and Global Health, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Japan.

Abstract

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.

Keywords: PfPanK1; PfPanK2; Plasmodium falciparum; coenzyme A; inhibitors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biological Products*
Erythrocytes
Pantothenic Acid
Phosphotransferases (Alcohol Group Acceptor)
Plasmodium falciparum*

Substances

Biological Products
Pantothenic Acid
Phosphotransferases (Alcohol Group Acceptor)
pantothenate kinase