Hemozoin: A Paradigm for Biominerals in Disease

Abstract

Biomineralization is the formation of organic–inorganic composites by organisms. Originally evolved as a protective mechanism, this complex process has also become a recognized contributor to several disease states, which range from kidney stone disease (nephrolithiasis) to parasitic diseases like malaria. The characteristic three‐step process for the formation of biominerals is defined by the supramolecular preorganization of a nucleating template, the interfacial molecular recognition of crystal nuclei and the cellular processing of resultant aggregates. Hemozoin formed in the heme detoxification pathway used by the malarial parasite Plasmodium falciparum represents a paradigm for pathogenic biominerals. Current research indicates that a supramolecular lipid template organizes heme released previously during hemoglobin catabolism. Nucleation and growth of the heme aggregate serves to protect the parasite from the toxic effects of free heme. Given the mechanisms of biomineralization, it is not surprising to discover that century‐old antimalarial compounds function by disrupting key interactions between the heme substrate and template. Subsequently, the heme‐aggregate is released into the host vasculature and deposits in patients' brains, spleens, and livers where it disrupts host innate immune response. The underlying basis of this immunomodulating activity seems to result from hemozoin mediated lipid peroxidation. Understanding the relationships between hemozoin formation and its pathogenic activity with the host immune response represents a significant challenge to chemical biology.

Crystallization of synthetic haemozoin (β-haematin) nucleated at the surface of lipid particles

“…Paradigms from the field of biomineralization suggest that the process involves the supramolecular preorganization of an organic matrix (e.g. lipids or proteins) that provides a foundation for the second order assembly for inorganic species1, 38. In malaria, a growing body of evidence suggests that a lipid rich environment is essential for the formation of haemozoin12–16.…”

“…lipids or proteins) that provides a foundation for the second-order assembly for inorganic species. 1, 38 In malaria, a growing body of evidence suggests that a lipid-rich environment is essential for the formation of haemozoin. 12-16 However, previous experimental data for bhaematin formation under physiological conditions could not account for the speed of haemozoin formation in vivo or provide details of the nucleation and crystal extension process.…”

Experimental and Time-Dependent Density Functional Theory Characterization of the UV–Visible Spectra of Monomeric and μ-Oxo Dimeric Ferriprotoporphyrin IX

“…Recently there has been a revival of interest in the aqueous solution chemistry of free ferriprotoporphyrin IX [Fe(III)PPIX; ferriheme]. This arises from its implication in heme acquisition by both mammalian and bacterial cells − and more especially heme detoxification in the malaria parasite and in other blood-feeding organisms. − For many years it was assumed that Fe(III)PPIX spontaneously forms a μ-oxo dimer, μ-[Fe(III)PPIX] 2 O, as the dominant species in aqueous solution . However, over the last 5 years three studies have clearly demonstrated that this is not the case. − Rather, in pure aqueous solution, it exists as a π–π dimer of H 2 O–, HO–Fe(III)PPIX or a dimer comprising one of each species, depending on pH .…”

“…There is a substantially larger contribution of charge transfer transitions in μ-[Fe(III)-PPIX] 2 O compared with H 2 O−Fe(III)PPIX in this part of the spectrum. The major contributing transitions are CT(7) and CT(8), which are π→d π transitions and CT(12), which is a π→d z 2 transition. The high energy shoulder of the Soret peak will not be discussed further, owing to the very large number of underlying excitations (see Scheme 2).…”

pH-Responsive Artemisinin Derivatives and Lipid Nanoparticle Formulations Inhibit Growth of Breast Cancer Cells In Vitro and Induce Down-Regulation of HER Family Members

“…ART contains an endoperoxide bridge (R-O-O-R') that is required for its anti-malarial activity. Malaria parasites digest hemoglobin as a carbon source, and accumulate a large amount of iron [8]–[10]. When ART encounters an iron atom, the endoperoxide group breaks up, and forms free radicals.…”