Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum.
Article Details
- CitationCopy to clipboard
Wang J, Zhang CJ, Chia WN, Loh CC, Li Z, Lee YM, He Y, Yuan LX, Lim TK, Liu M, Liew CX, Lee YQ, Zhang J, Lu N, Lim CT, Hua ZC, Liu B, Shen HM, Tan KS, Lin Q
Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum.
Nat Commun. 2015 Dec 22;6:10111. doi: 10.1038/ncomms10111.
- PubMed ID
- 26694030 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Artenimol 14-3-3 protein Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol 40S ribosomal protein S19 Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol 40S ribosomal protein S21 Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol 40S ribosomal protein S3 Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol 40S ribosomal protein S3a Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol 40S ribosomal protein S5, putative Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol 60S ribosomal protein L10, putative Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol 60S ribosomal protein L14, putative Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol 60S ribosomal protein L17, putative Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol 60S ribosomal protein L2 Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol 60S ribosomal protein L21 Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol 60S ribosomal protein L23 Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol 60S ribosomal protein L24, putative Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol 60S ribosomal protein L27 Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol 60S ribosomal protein L3 Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol 60S ribosomal protein L30e, putative Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol 60S ribosomal protein L4 Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Actin-1 Protein Plasmodium falciparum (isolate HB3) UnknownLigandDetails Artenimol Acyl-CoA synthetase Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Adenosine deaminase Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Adenosylhomocysteinase Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Anamorsin homolog Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Aspartate carbamoyltransferase Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol ATP-dependent RNA helicase UAP56 Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Autophagy-related protein 18, putative Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Calcium-dependent protein kinase 4 Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Calcium-transporting ATPase Protein Plasmodium falciparum (isolate K1 / Thailand) UnknownLigandDetails Artenimol cAMP-dependent protein kinase regulatory subunit Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Carbamoyl phosphate synthetase Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Casein kinase 2, alpha subunit Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Cell division cycle protein 48 homologue,putative Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Chaperone, putative Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Chloroquine resistance transporter Protein Plasmodium falciparum UnknownLigandDetails Artenimol Coatomer alpha subunit, putative Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Conserved Plasmodium membrane protein Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Dipeptidyl aminopeptidase 1 Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol DnaJ protein, putative Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Elongation factor 1-alpha Protein Plasmodium falciparum (isolate K1 / Thailand) UnknownLigandDetails Artenimol Elongation factor 1-gamma, putative Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Elongation factor 2 Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Endoplasmin homolog, putative Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Enolase Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Eukaryotic initiation factor 4A Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Eukaryotic translation initiation factor 3 subunit C Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Fructose-bisphosphate aldolase Protein Plasmodium falciparum UnknownLigandDetails Artenimol Glutamate dehydrogenase Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Glutamate--tRNA ligase Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Glutamine synthetase, putative Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Glyceraldehyde-3-phosphate dehydrogenase Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Glycophorin-binding protein Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol GTP-binding nuclear protein Ran Protein Plasmodium falciparum UnknownLigandDetails Artenimol Haloacid dehalogenase-like hydrolase Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol HAP protein Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Heat shock protein 110, putative Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Heat shock protein 90 Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Hexokinase Protein Plasmodium falciparum UnknownLigandDetails Artenimol High molecular weight rhoptry protein 2 Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol HSP40, subfamily A, putative Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Hypoxanthine-guanine-xanthine phosphoribosyltransferase Protein Plasmodium falciparum (isolate FCR-3 / Gambia) UnknownLigandDetails Artenimol Importin subunit alpha Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Importin-7, putative Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Inner membrane complex sub-compartment protein 3 Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Insulinase, putative Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Isoleucine--tRNA ligase, putative Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Knob-associated histidine-rich protein Protein Plasmodium falciparum UnknownLigandDetails Artenimol L-lactate dehydrogenase Protein Plasmodium falciparum (isolate CDC / Honduras) UnknownLigandDetails Artenimol Lysophospholipase, putative Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Mature parasite-infected erythrocyte surface antigen Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Merozoite surface protein 1 Protein Plasmodium falciparum (isolate CDC / Honduras) UnknownLigandDetails Artenimol Methionine--tRNA ligase Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Multidrug resistance protein Protein Plasmodium falciparum (isolate FC27 / Papua New Guinea) UnknownLigandDetails Artenimol Non-SERCA-type Ca2+-transporting P-ATPase Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Nucleoside transporter 2 Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Ornithine aminotransferase Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Parasite-infected erythrocyte surface protein Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Peptidyl-prolyl cis-trans isomerase Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Phosphoethanolamine N-methyltransferase Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Phosphoribosylpyrophosphate synthetase Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Plasmepsin IV Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Plasmepsin-1 Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Plasmepsin-2 Protein Plasmodium falciparum UnknownLigandDetails Artenimol Plasmodium exported protein Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Polyadenylate-binding protein Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Probable ATP-dependent 6-phosphofructokinase Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Proteasome subunit alpha type Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Protein disulfide-isomerase Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Protein transport protein SEC31 Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Purine nucleotide phosphorylase, putative Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Pyridoxal 5'-phosphate synthase subunit Pdx1 Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Pyruvate kinase Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Rhoptry neck protein 3 Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Ring-infected erythrocyte surface antigen Protein Plasmodium falciparum (isolate FC27 / Papua New Guinea) UnknownLigandDetails Artenimol S-adenosylmethionine synthase Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Sec62, putative Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Serine repeat antigen 5 Protein Plasmodium falciparum UnknownLigandDetails Artenimol Signal recognition particle receptor, beta subunit Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Skeleton-binding protein 1 Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Spermidine synthase Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol T-complex protein 1 subunit eta Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Thioredoxin peroxidase 1 Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Thioredoxin-like protein Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Thioredoxin-related protein, putative Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Threonine--tRNA ligase Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Tubulin alpha chain Protein Plasmodium falciparum (isolate K1 / Thailand) UnknownLigandDetails Artenimol Tubulin beta chain Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Ubiquitin-60S ribosomal protein L40 Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol Ubiquitin-conjugating enzyme E2 Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol V-type H(+)-translocating pyrophosphatase, putative Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails Artenimol V-type proton ATPase catalytic subunit A Protein Plasmodium falciparum (isolate 3D7) UnknownLigandDetails