The Malaria Pigment Hemozoin Comprises at Most Four Different Isomer Units in Two Crystalline Models: Chiral as Based on a Biochemical Hypothesis or Centrosymmetric Made of Enantiomorphous Sectors

Hemozoin is a crystalline byproduct formed upon hemoglobin digestion in Plasmodium-infected blood cells. Based on X-ray powder diffraction (XRPD), hemozoin and its synthetic analogue β-hematin are very similar in structure, consisting of cyclic dimers (cd) of ferriprotoporphyrin IX [Fe(3+)-PPIX] molecules coordinated via Fe–O(propionate) bonds. Enantiofacial symmetry of Fe(3+)-PPIX implies formation of four different stereoisomeric dimers, two centrosymmetric (1), labeled cd11 and cd12, and two enantiomeric, cd2(+) and cd2(−), in which the Fe(3+)PPIX moieties are related by pseudo-2-fold symmetry. Only the cd11 stereoisomer was reported as the repeat unit in the initial structural elucidation of β-hematin and refinement of hemozoin. Our recent study of β-hematin, employing a combination of XRPD and density functional theory (DFT), revealed besides the published phase, characterized in terms of a disordered cd11/cd2(±) mixture, which is diffractionally equivalent to a cd11/cd12 mixture, a minor phas...