Elsevier

Life Sciences

Volume 51, Issue 26, 1992, Pages 2073-2078
Life Sciences

Heme polymerase: Modulation by chloroquine treatment of a rodent malaria

https://doi.org/10.1016/0024-3205(92)90158-LGet rights and content

Abstract

The biosynthesis of the β-hematin of malarial pigment (hemozoin) is catalyzed by a newly discovered enzyme, heme polymerase, which is described for Plasmodium berghei in this report. This novel enzyme is present in the insoluble fraction of hemolysates of infected erythrocytes but is not present in normal erythrocytes. The substrate is ferriprotoporphyrin IX (FP) released from hemoglobin. At pH 5 and 37° C the enzyme is saturated by 100 μM FP. The pH optimum is between 5 and 6 and the reaction is linear for 6 hours. All heme polymerase activity is destroyed by heating at 100° C for 3 minutes. Chloroquine treatment of malarious mice reduces by 80 percent the activity of this enzyme, without inhibiting release of FP from hemoglobin, and thereby causes excess nonpolymerized, nonhemozoin FP to accumulate. Since the accumulated FP is accessible to bind chloroquine, we propose that it is the mediator of the antimalarial activity of chloroquine.

References (14)

  • C.D. Fitch et al.

    J. Biol. Chem.

    (1987)
  • C.D. Fitch

    Parasitol. Today

    (1986)
  • A.F.G. Slater et al.

    Nature

    (1992)
  • C.D. Fitch
  • E.W. McChesney et al.
  • C.D. Fitch et al.

    Mem. Inst. Oswaldo Cruz

    (1986)
  • D. Balasubramanian et al.

    Science

    (1984)
There are more references available in the full text version of this article.

Cited by (70)

  • Recent advances in biological activities of rhodium complexes: Their applications in drug discovery research

    2021, European Journal of Medicinal Chemistry
    Citation Excerpt :

    Malarial hemozoin may play a vital role as a target in disease pathogenesis and antimalarial drugs developments. Chloroquine in cell-free extracts [82] and in both Plasmodium falci-parum [83] and Plasmodium berghei [84,85] inhibits the synthesis of hemozoin. Smith et al. demonstrated that the biological activity of a series of cyclometalated Rh(III) complexes (Fig. 19) was enhanced via increased lipophilicity when endowed with an organosilane entity.

  • Using a genome-scale metabolic network model to elucidate the mechanism of chloroquine action in Plasmodium falciparum

    2017, International Journal for Parasitology: Drugs and Drug Resistance
    Citation Excerpt :

    Chloroquine was the first-line malaria treatment for many decades until drug-resistant P. falciparum strains became common. The drug causes a dose-dependent decrease in hemozoin formation (Chou and Fitch, 1992; Slater and Cerami, 1992) and an associated increase in toxic free heme in the food vacuole of the parasite (Combrinck et al., 2013; Loria et al., 1999). Over the past few decades, researchers have proposed many different mechanisms for chloroquine action, including 1) DNA intercalation (Meshnick, 1990), 2) alteration of digestive food vacuole pH (Yayon et al., 1985), 3) inhibition of heme polymerase (Yayon et al., 1985), and 4) formation of a toxic chloroquine-ferriprotoporphyrin IX complex (Sugioka et al., 1987).

  • The antimalarial drugs chloroquine and primaquine inhibit pyridoxal kinase, an essential enzyme for vitamin B6 production

    2014, FEBS Letters
    Citation Excerpt :

    However, there is still argument that other target molecules mediate the antimalarial effects since the effective concentrations of inhibitors are relatively high and direct association of chloroquine and primaquine with malaria quinone reductase and malaria aldehyde dehydrogenase and inhibition of these malaria enzymes by the quinoline derivatives have not been demonstrated. On the other hand, it has also been reported that chloroquine binds to heme and inhibits heme polymerase activity in the malaria protozoan, which is critical for heme intoxication [5]. The inhibition of heme polymerization might account for the mechanism of action of chloroquine as an antimalarial agent, although the corresponding enzyme mediating heme polymerization has not been identified.

  • Malarial hemozoin: From target to tool

    2014, Biochimica et Biophysica Acta - General Subjects
    Citation Excerpt :

    The accumulation of heme causes severe damage to the parasite, leading to its death [107]. Based on what little was known about the mechanism of action of CQ, several studies focused on testing its role as a possible inhibitor of hemozoin (ferriprotoporphyrin IX) crystallization [36,108,109]. They concluded that chloroquine does inhibit hemozoin formation by interfering in its assembly, be it initiated by hemozoin or by trophozoite extracts [36,109,110].

View all citing articles on Scopus
View full text