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

Abstract

The incorrect metabolic breakdown of the nonaromatic 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.

A Mechanoelastic Glimpse on Hyaluronan-Coated Extracellular Vesicles

“…This could be linked to returning back to the same local environment around ACYMAN in the EV system. Next, to gain a better understanding of LMW-HA-induced flexibility/rigidity on HA-EVs, we performed fluorescence anisotropy. − The faster component (φ1) (equation S1) was attributed to the local motion of the probe molecule (ACYMAN), whereas the longer nanosecond component (φ2) carried the information regarding the segmental motion of the ACYMAN as it is inside the EVs. After Hyals treatment to the LMW-HA-EVs, time-resolved fluorescence anisotropy of ACYMAN on EVs (average rotational time scale, ⟨τr⟩ ≈ 1910 ps) became significantly retarded compared to that of the LMW-HA-EVs (average rotational time scale, ⟨τr⟩ ≈ 1440 ps) (Table ) (insets of Figure ) (Table S1).…”

The Metabolostasis Network and the Cellular Depository of Aggregation‐Prone Metabolites

“…Later studies demonstrated that these phenomena are not unique to phenylalanine but are shared among metabolites in general. Proteinogenic and non‐proteinogenic amino acids, nucleobases, various metabolic intermediates, and even sphingolipids were shown to form ordered amyloid‐like assemblies with structural and biological properties similar to those observed for phenylalanine structures [9, 16–28] . The formed assemblies also show clear biological and chemical properties as observed for phenylalanine‐ and protein‐based amyloid fibrils.…”

“…Proteinogenic and non-proteinogenic amino acids, nucleobases, various metabolic intermediates, and even sphingolipids were shown to form ordered amyloid-like assemblies with structural and biological properties similar to those observed for phenylalanine structures. [9,[16][17][18][19][20][21][22][23][24][25][26][27][28] The formed assemblies also show clear biological and chemical properties as observed for phenylalanine-and protein-based amyloid fibrils. These include nano-scale morphology, dyebinding properties, and apoptosis-inducing activity.…”

“…[8] Such arrangements may provide a mechanistic explanation for the high toxicity of the assemblies, possibly mediated by membrane destabilization and demyelination. [9][10][11] The cytotoxic effect of the assemblies formed by the physiological enantiomer of phenylalanine (L-Phe) could be modulated by various small molecules including the D-enantiomer of phenylalanine (D-Phe), [12] doxycycline, [13] various polyphenols such as epigallocatechin gallate (EGCG) and tannic acid, [14] and chemical chaperons. [15] Later studies demonstrated that these phenomena are not unique to phenylalanine but are shared among metabolites in general.…”

“…Follow‐up studies using ion mobility mass spectrometry have shown the formation of soluble oligomers by phenylalanine, where the structures are stabilized by electrostatic interactions of the positively charged amino group and the negatively charged carboxy group, with the hydrophobic aromatic groups directed towards the solvent [8] . Such arrangements may provide a mechanistic explanation for the high toxicity of the assemblies, possibly mediated by membrane destabilization and demyelination [9–11] . The cytotoxic effect of the assemblies formed by the physiological enantiomer of phenylalanine (L‐Phe) could be modulated by various small molecules including the D‐enantiomer of phenylalanine (D‐Phe), [12] doxycycline, [13] various polyphenols such as epigallocatechin gallate (EGCG) and tannic acid, [14] and chemical chaperons [15] …”