Haem polymerization in malaria

Bendrat, Klaus; Berger, Bradley J.; Cerami, Anthony

doi:10.1038/378138a0

Cited by 160 publications

(106 citation statements)

References 6 publications

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“…However, the involvement of the enzyme component was questioned later as the reaction was reported to occur even in the presence of preformed J3-haematin or malarial haemozoin [10]. A phospholipid component isolated from the non-infected as well as malaria-infected erythrocytes or malarial histidine-rich protein were also found to initiate the formation of haemozoin [11,12], Haemozoin is a polymer of haem units linked through an iron~zarboxylate bond between central iron of one haem and propionate side chain of the other [13]. Egan et al [14] have recently reported the formation of haemozoin/13-haematin to *Corresponding author.…”

Section: Introductionmentioning

confidence: 99%

Formation of haemozoin/β‐haematin under physiological conditions is not spontaneous

Pandey

Tekwani

1996

FEBS Letters

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Section: Introductionmentioning

confidence: 99%

Formation of haemozoin/β‐haematin under physiological conditions is not spontaneous

Pandey

Tekwani

1996

FEBS Letters

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“…An important step in elucidating the drug action mechanism of these antimalarials is the recent description of the heme aggregating ability of an unusual class of histidine-rich proteins, HRP I-IV, from P. falciparum, which have been cloned and overexpressed (22). These proteins may be the heme polymerase suggested by Slater and Cerami (2) or they may instead initiate heme aggregation (22) which can then be propagated by either enzymatic (2,23) or nonenzymatic (24 -27) heme-sequestering mechanisms. Regardless of these mechanistic details, it is clearly important to have a detailed structural understanding of the metabolic product of heme detoxification.…”

Section: X-ray Diffraction Of Hemozoin and ␤-Hematin 714mentioning

confidence: 99%

Characterization of the Products of the Heme Detoxification Pathway in Malarial Late Trophozoites by X-ray Diffraction

Bohle

Dinnebiér

Madsen

et al. 1997

Journal of Biological Chemistry

151

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In a process inhibited by the quinoline antimalarial drugs, Plasmodia detoxify heme released during the degradation of hemoglobin by aggregating it into malarial pigment, an insoluble crystalline heme coordination polymer. Synchrotron x-ray powder diffraction patterns for intact desiccated malarial trophozoites and synthetic ␤-hematin have been measured; both materials correspond to a single crystalline triclinic lattice with unit cell parameters a ‫؍‬ 12.2176(4), b ‫؍‬ 14.7184(5), c ‫؍‬ 8.0456(3) Å; ␣ ‫؍‬ 90.200(2), ␤ ‫؍‬ 96.806(3), ␥ ‫؍‬ 97.818(3)°a nd Z ‫؍‬ 2. These results unambiguously demonstrate that hemozoin crystallites are identical to synthetic ␤-hematin.Heme is a potent multifunction regulator whose biochemical levels and distribution are precisely controlled on both intraand extracellular levels (1). Efficient regulation of heme is particularly critical for intra-erythrocytic parasites such as plasmodia which process large quantities of heme in the postinvasion digestion of the erythrocyte's hemoglobin. Plasmodia, which lack heme oxygenases, detoxify heme by sequestering it into an insoluble heme aggregate termed malarial pigment or hemozoin (2). The quinoline-based family of antimalarials interfere with this process by an as yet unknown mechanism that has recently come under intense scrutiny as part of the effort to combat the spread of chloroquine-resistant strains of Plasmodium. A variety of spectroscopic and bioanalytical techniques indicate that hemozoin is similar to the synthetic aggregated heme phase ␤-hematin, which is thought to form strands of hemes linked by propionate oxygen-iron bonds as well as interstrand propionate hydrogen bonds, Fig. 1 (3-5). Characterization of the carboxylate stretching bands for the propionic acid side chains by IR and Raman spectroscopy provides the best evidence for the presence of iron-oxygen bonds to the propionate side chains (3-5). Unfortunately, crystallographic characterization of these heme aggregates has been hampered by the phase heterogeneity of many synthetic preparations as well as by the small size of the synthetic and natural crystallites isolated from either trophozoites and infected hosts (6). High resolution powder diffraction has been used extensively for the solution of many structural problems (7), and it can solve problems posed by diffraction from microcrystalline phases. In this communication we describe the characterization of ␤-hematin derived from both synthetic and natural sources and provide new unambiguous evidence that the heme aggregate present in late stage trophozoites is ␤-hematin. EXPERIMENTAL PROCEDURESCirca 3 ϫ 10 9 chloroquine-susceptible Plasmodium falciparum late trophozoites of the 3D7 clone (NF54 strain) were synchronized with sorbitol and allowed to achieve a 92% level of parasitemia (8). The resulting intact trophozites were isolated by rapid cooling in liquid nitrogen, and the frozen suspension of cells was lyophilized by freezedrying in vacuo at Ϫ10°C. In general this freeze-drying process required 12-14 h and res...

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“…Even long before the recent discoveries of the relationship between haemozoin and lipids, there had been a number of studies suggesting that lipids mediate its formation. The proposal was first made by Bendrat et al (1995) and subsequently supported by Dorn et al who showed that an acetonitrile extract of P. falciparum trophozoites supports haemozoin formation (Dorn et al 1998). Fitch and co-workers also demonstrated that chloroform extracts of infected and uninfected red blood cells, monooleoylglycerol (MOG) and DOG as well as certain fatty acids and detergents efficiently support its formation (Fitch et al 1999).…”

Section: Haemozoin Formation In Vivomentioning

confidence: 82%

Biomimetic Approaches to Understanding the Mechanism of Haemozoin Formation

Egan¹

2011

On Biomimetics

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Haem polymerization in malaria

Cited by 160 publications

References 6 publications

Formation of haemozoin/β‐haematin under physiological conditions is not spontaneous

Formation of haemozoin/β‐haematin under physiological conditions is not spontaneous

Characterization of the Products of the Heme Detoxification Pathway in Malarial Late Trophozoites by X-ray Diffraction

Biomimetic Approaches to Understanding the Mechanism of Haemozoin Formation

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