Heme-Artemisinin Adducts Are Crucial Mediators of the Ability of Artemisinin to Inhibit Heme Polymerization

Kannan, R; Sahal, Dinkar; Chauhan, V. S.

doi:10.1016/s1074-5521(02)00117-5

Cited by 78 publications

(76 citation statements)

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“…We have shown previously that the haem-artemisinin adduct, or 'haemart', is a crucial mediator of the ability of artemisinin to inhibit haem polymerization [9]. Here we show that the reaction of artemisinin with haem in Hb is much faster than with free haem.…”

Section: Introductionmentioning

confidence: 46%

“…Protein estimation was done using the bicinchonic acid method (Pierce, Rockford, IL, U.S.A.). Haemin was recrystallized as described previously [9]. Human Hb used in the experiments was purified from blood following the procedure described by Roy and Acharya [23].…”

Section: Methodsmentioning

confidence: 99%

“…Protein concentration was estimated by measuring absorbance at 540 nm (0.8 absorbance unit = 1 mg/ml). Recombinant PfHRP II was expressed and purified as described previously [9].…”

Section: Methodsmentioning

confidence: 99%

“…Haemozoin, which was previously thought to be a polymer, is now known to be a dimer with hydrogen bonding between the dimer units in the crystal. Several antimalarial drugs, including chloroquine and artemisinin, recognize haem as a target molecule and are known to inhibit the formation of haemozoin [8,9]. The mechanism of biosynthesis of haemozoin, a process unique to the parasite, is not clearly understood, and the search for a haem polymerase has not been fruitful.…”

Section: Introductionmentioning

confidence: 99%

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Reaction of artemisinin with haemoglobin: implications for antimalarial activity

Kannan

Kumar

Sahal

et al. 2005

Biochemical Journal

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Elucidation of the principal targets of the action of the antimalarial drug artemisinin is an ongoing pursuit that is important for understanding the action of this drug and for the development of more potent analogues. We have examined the chemical reaction of Hb with artemisinin. The protein-bound haem in Hb has been found to react with artemisinin much faster than is the case with free haem. It appears that the uptake of Hb and the accumulation of artemisinin into the food vacuole, together with the preferred reactivity of artemisinin with haem in Hb, may make Hb the primary target of artemisinin's antimalarial action. Both monoalkylated (HA) and dialkylated (HAA) haem derivatives of artemisinin have been isolated. These 'haemarts' bind to PfHRP II (Plasmodium falciparum histidine-rich protein II), inhibiting haemozoin formation, and possess a significantly decreased ability to oxidize ascorbic acid. The accelerated formation of HAA from Hb is expected to decrease the ratio of haem to its alkylated derivatives. The haemarts that are generated from 'haemartoglobins' may bring about the death of malaria parasite by a two-pronged effect of stalling the formation of haemozoin by the competitive inhibition of haem binding to its templates and creating a more reducing environment that is not conducive to the formation of haemozoin.

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Section: Introductionmentioning

confidence: 46%

Section: Methodsmentioning

confidence: 99%

“…Protein concentration was estimated by measuring absorbance at 540 nm (0.8 absorbance unit = 1 mg/ml). Recombinant PfHRP II was expressed and purified as described previously [9].…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Reaction of artemisinin with haemoglobin: implications for antimalarial activity

Kannan

Kumar

Sahal

et al. 2005

Biochemical Journal

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“…Formation of non-polymerizable alkylated heme derivatives has been demonstrated in vitro and evidence has been provided that C-centered radicals derived from artemisinin act as alkylating agents [14,15]. Furthermore, it has been shown that covalent artemisinin-heme adducts mimick heme in binding to the enzyme histidine-rich protein II and as such have the ability to inhibit heme polymerization [16]. Recently, evidence has been obtained that iron-activated artemisinin-type drugs act by alkylating an essential enzyme of Plasmodium falciparum, i.e., a sarco/endoplasmic reticulum Ca 2ϩ -ATPase ortholog [17].…”

mentioning

confidence: 99%

Characterization of noncovalent complexes of antimalarial agents of the artemisinin-type and Fe(III)-heme by electrospray mass spectrometry and collisional activation tandem mass spectrometry

Pashynska

Heuvel

Claeys

et al. 2004

J. Am. Soc. Mass Spectrom.

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In this study, we demonstrate, using electrospray ionization mass spectrometry (ESI-MS) and collision-induced dissociation tandem mass spectrometry (ESI-MS/CID/MS), that stable noncovalent complexes can be formed between Fe(III)-heme and antimalarial agents, i.e., quinine, artemisinin, and the artemisinin derivatives, dihydroartemisinin, ␣-and ␤-artemether, and ␤-arteether. Differences in the binding behavior of the examined drugs with Fe(III)-heme and the stability of the drug-heme complexes are demonstrated. The results show that all tested antimalarial agents form a drug-heme complex with a 1:1 stoichiometry but that quinine also results in a second complex with the heme dimer. ESI-MS performed on mixtures of pairs of various antimalarial agents with heme indicate that quinine binds preferentially to Fe(III)-heme, while ESI-MS/CID/MS shows that the quinine-heme complex is nearly two times more stable than the complexes formed between heme and artemisinin or its derivatives. Moreover, it is found that dihydroartemisinin, the active metabolite of the artemisinin-type drugs in vivo, results in a Na ϩ -containing heme-drug complex, which is as stable as the heme-quinine complex. The efficiency of drug-heme binding of artemisinin derivatives is generally lower and the decomposition under CID higher compared with quinine, but these parameters are within the same order of magnitude. These results suggest that the efficiency of antimalarial agents of the artemisinin-type to form noncovalent complexes with Fe(III)-heme is comparable with that of the traditional antimalarial agent, quinine. Our study illustrates that electrospray ionization mass spectrometry and collision-induced dissociation tandem mass spectrometry are suitable tools to probe noncovalent interactions between heme and antimalarial agents. The results obtained provide insights into the underlying molecular modes of action of the traditional antimalarial agent quinine and of the antimalarials of the artemisinin-type which are currently used to treat severe or multidrug-resistant malaria. (J Am Soc Mass Spectrom 2004, 15, 1181-1190

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BiomimeticFe(II) Chemistry and Synthetic Studies on Antimalarial and Antitumour Endoperoxides

Chadwick

Rawe

2009

Patai's Chemistry of Functional Groups

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Introduction Endoperoxide‐Containing Antimalarials The Role of Iron The Biological Targets of Antimalarial Endoperoxides Semi‐Synthetic Artemisinin Derivatives Synthetic Endoperoxides Antimalarial Activities of Synthetic Endoperoxide Antimalarials Endoperoxide Containing Compounds with Antitumour Activity

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Heme-Artemisinin Adducts Are Crucial Mediators of the Ability of Artemisinin to Inhibit Heme Polymerization

Cited by 78 publications

References 40 publications

Reaction of artemisinin with haemoglobin: implications for antimalarial activity

Reaction of artemisinin with haemoglobin: implications for antimalarial activity

Characterization of noncovalent complexes of antimalarial agents of the artemisinin-type and Fe(III)-heme by electrospray mass spectrometry and collisional activation tandem mass spectrometry

BiomimeticFe(II) Chemistry and Synthetic Studies on Antimalarial and Antitumour Endoperoxides

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