Effects of Amino Acids on Malarial Heme Crystallization

Abstract

To gain insight into the mechanism of malarial hemozoin formation and to explore various biological groups for screening novel antimalarial drugs, we examined the effects of amino acids on the formation of b b-hematin (BH), which is a synthetic heme crystal structurally identical to hemozoin, in vitro. Our results showed that BH formation was significantly inhibited by basic amino acids (arginine, lysine, and histidine), probably due to the abilities of these amino acids to complex with heme. The results suggest an involvement in the improvement of the blood-schizonticidal activity of 8-quinolinamine when conjugated with basic amino acids. In addition, cysteine also inhibited BH formation, possibly due to its ability to reduce heme iron or decompose heme in acidic conditions. In contrast, BH formation was enhanced by amino acids with high hydrophobicity values (leucine, isoleucine, valine, methionine, and phenylalanine), with the exception of tryptophan at high temperature but was not affected in Tween-induced BH formation under normal physiological conditions. The present results can lead to further research on the development of new antimalarials by conjugating these amino acids, especially basic amino acids, with other substances, or by forming complex or small peptides that could have special effects on BH formation.

Phospholipid Membrane-Mediated Hemozoin Formation: The Effects of Physical Properties and Evidence of Membrane Surrounding Hemozoin

“…The differences in morphology between dioleoyl-PC and dipalmitoyl-PC vesicles were probably due to their different physical properties, in particular the different states – fluid or gel – caused by the differences in T m values. Moreover, since the hydrophobic interactions between their inducers and heme have been proposed as an important force in the creation of a precursor heme dimer [38], [45], [54], [55], it was interesting to explore the correlation between the physical properties of phospholipids and their ability to induce BH. Our results demonstrated that phospholipids could induce BH formation only in the fluid phase, and could not do so in the gel phase.…”

Synthesis, antiprotozoal, antimicrobial, β-hematin inhibition, cytotoxicity and methemoglobin (MetHb) formation activities of bis(8-aminoquinolines)

“…In another report, effects of amino acids on the formation of β -hematin (BH) was investigated, and results showed that BH formation was significantly inhibited by basic amino acids due to their abilities to complex with heme 31. Therefore, synthesized bisquinolines were assayed for inhibition of BH formation according to a procedure reported earlier 32.…”

Interplay between Plasmodium falciparum haemozoin and l-arginine: implication for nitric oxide production

“…Coincidentally, there is an association between severe malaria and Plasmodium falciparum haemozoin (HZ), a by-product of digested haemoglobin from P. falciparum infected erythrocytes, released into the bloodstream upon cell rupture [ 19 – 22 ]. Increase of l -Arg breakdown (free or intra-erythrocyte) has been reported elsewhere [ 23 ], while another report shows that l -Arg inhibits the formation of the synthetic pigment crystal (beta-hematin, βH) [ 24 ]. There is no information so far about a possible interaction between l -Arg and HZ.…”

“…Thus, an interaction between HZ and l -Arg can be expected. Indeed, Uyen and colleagues showed that basic amino acids, such as l -Arg or l -Lysine ( l -Lys), inhibit the formation of βH [ 24 ], the synthetic crystal made only of the haem portion of HZ, indirectly demonstrating the interaction of l -Arg with haem. However, in the present experiments, synthetic βH, differently from native HZ, was not able to reduce NO production even at the dose of 60 µM (Additional files 3 , 4 ) suggesting that the l -Arg–HZ interaction requires also a component of HZ, not yet identified.…”