Haem-activated Promiscuous Targeting of Artemisinin in Plasmodium Falciparum

Overview

Journal Nat Commun

Specialty Biology

Date 2015 Dec 24

PMID 26694030

Citations 225

Authors

Jigang Wang

Chong-Jing Zhang

Wan Ni Chia

Cheryl C Y Loh

Zhengjun Li

Yew Mun Lee

Yingke He

Li-Xia Yuan

Teck Kwang Lim

Min Liu

Chin Xia Liew

Yan Quan Lee

Jianbin Zhang

Nianci Lu

Chwee Teck Lim

Zi-Chun Hua

Bin Liu

Han-Ming Shen

Kevin S W Tan

Qingsong Lin

Affiliations

Soon will be listed here.

Abstract

The mechanism of action of artemisinin and its derivatives, the most potent of the anti-malarial drugs, is not completely understood. Here we present an unbiased chemical proteomics analysis to directly explore this mechanism in Plasmodium falciparum. We use an alkyne-tagged artemisinin analogue coupled with biotin to identify 124 artemisinin covalent binding protein targets, many of which are involved in the essential biological processes of the parasite. Such a broad targeting spectrum disrupts the biochemical landscape of the parasite and causes its death. Furthermore, using alkyne-tagged artemisinin coupled with a fluorescent dye to monitor protein binding, we show that haem, rather than free ferrous iron, is predominantly responsible for artemisinin activation. The haem derives primarily from the parasite's haem biosynthesis pathway at the early ring stage and from haemoglobin digestion at the latter stages. Our results support a unifying model to explain the action and specificity of artemisinin in parasite killing.

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