Theories on malarial pigment formation and XXXX action.

@entity1 @entity1522 @entity3793 @entity8774 @entity26 @entity50125 @entity3964 @entity311 @entity503 @entity3338 @entity68
Haeme metabolism remains a vulnerable problem for the intraerythrocytic @entity3964 which catabolises haemoglobin as a source of @entity1522 in an acidic, @entity26 -rich lysosome-like digestive vacuole. Haeme monomer, capable of generating @entity26 radicals, transforms into an inert crystal named malarial pigment or haemozoin by forming unique dimers that then crystalise. Laveran first described pigmented bodies in @entity1 to define a protozoan as the aetiologic agent of @entity311 . The trail of @entity311 pigment enabled Ross to implicate the mosquito in the life cycle of @entity3964 . In 1991, Slater and Cerami postulated a unique @entity68 - @entity3338 bond between two haemes in haemozoin crystals based on infrared and X-ray spectroscopy data. Additionally, parasite extracts were shown to possess a 'haeme polymerase' enzymatic activity as the process of crystal formation was then termed. Importantly, the @entity50125 , such as choloroquine, inhibit haemozoin formation. A @entity3964 derived @entity3793 -rich protein II, which binds haeme and initiates haemozoin formation, is present in the digestive vacuole. Pfhistidine-rich protein II and Pfhistidine-rich protein III are sufficient, but not necessary for haemozoin formation as a laboratory clone lacking both still makes the haeme crystals. The reduvid bug, and the Schistosoma and Haemoproteus genera also make haemozoin. Recently, Bohle and coworkers used X-ray diffraction to document the iron-carboxylate bond in intact desiccated parasites and to show that a Fe1-O41 head to tail haeme dimer is the unit building block of haemozoin. The role of the @entity3964 histidine-rich protein family members, lipids or potential novel proteins in the exact molecular assembly of the large molecular weight haeme crystals in the protein rich digestive vacuole needs to be solved. Accurate experimental determination of the role of haemozoin formation and inhibition as the target of @entity503 is fundamental to determination of the mechanism of @entity8774 drug action and resistance. The enhanced understanding of the biosynthetic pathway leading to haemozoin formation using functional proteomic tools and the mechanisms through which existing antimalarial drugs affect @entity3964 haeme chemistry will help design improved chaemotherapeutic agents.
