Amyloids Formed by Nonaromatic Amino Acid Methionine and Its Cross with Phenylalanine Significantly Affects Phospholipid Vesicle Membrane: An Insight into Hypermethioninemia Disorder

The incorrect metabolic breakdown of the non-aromatic amino acid methionine (Met) leads to the disorder called hypermethioninemia via an unknown mechanism. To understand the molecular level pathogenesis of this disorder, we prepared a DMPC lipid membrane, the mimicking setup of the cell membrane, and explored the effect of the millimolar level of Met on it. We found that Met forms toxic fibrillar aggregates that disrupt the rigidity of the membrane bilayer, and increases the dynamic response of water molecules surrounding the membrane as well as the heterogeneity of the membrane. Such aggregates strongly deform red blood cells. This opens the requirement to consider therapeutic antagonists either to resist or to inhibit the toxic amyloid aggregates against hypermethioninemia. Moreover, such disrupting effect on membrane bilayer and cytotoxicity along with deformation effect on RBC by the cross amyloids of Met and Phenylalanine (Phe) was found to be most virulent. This exclusive observation of the enhanced virulent effect of the cross amyloids is expected to be an informative asset to explain the coexistence of two amyloid disorders.

Automated summary

The incorrect metabolism of amino acid methionine leads to hypermethioninemia, but the underlying mechanism is unknown. By studying a lipid membrane mimicking the cell membrane, it was found that methionine forms toxic aggregates that disrupt the rigidity of the membrane and increase its heterogeneity, resulting in deformation of red blood cells. Furthermore, the cross amyloids of methionine and phenylalanine were found to have the most virulent effect on the membrane bilayer and cytotoxicity.