Unusual Aggregates Formed by the Self-Assembly of Proline, Hydroxyproline, and Lysine

Abstract

There is a plethora of significant research that illustrates toxic self-assemblies formed by the aggregation of single amino acids, such as phenylalanine, tyrosine, tryptophan, cysteine, and methionine, and their implication on the etiology of inborn errors of metabolisms (IEMs), such as phenylketonuria, tyrosinemia, hypertryptophanemia, cystinuria, and hypermethioninemia, respectively. Hence, studying the aggregation behavior of single amino acids is very crucial from the chemical neuroscience perspective to understanding the common etiology between single amino acid metabolite disorders and amyloid diseases like Alzheimer's and Parkinson's. Herein we report the aggregation properties of nonaromatic single amino acids L-proline (Pro), Lhydroxyproline (Hyp), and L-lysine hydrochloride (Lys). The morphologies of the self-assembled structures formed by Pro, Hyp, and Lys were extensively studied by various microscopic techniques, and controlled morphological transitions were observed under varied concentrations and aging times. The mechanism of structure formation was deciphered by concentration-dependent 1 H NMR analysis, which revealed the crucial role of hydrogen bonding and hydrophobic interactions in the structure formation of Pro, Hyp, and Lys. MTT assays on neural (SHSY5Y) cell lines revealed that aggregates formed by Pro, Hyp, and Lys reduced cell viability in a dose-dependent manner. These results may have important implications in the understanding of the patho-physiology of disorders such as hyperprolinemia, hyperhydroxyprolinemia, and hyperlysinemia since all these IEMs are associated with severe neurodegenerative symptoms, including intellectual disability, seizures, and psychiatric problems. Our future studies will endeavor to study these biomolecular assemblies in greater detail by immuno-histochemical analysis and advanced biophysical assays.

Advances in Self‐Assembly of Metabolite Nanostructures: Physiology, Pathology and Nanotechnology

“…[7] Other amino acids known to accumulate in various IEM disorders, including tyrosine, proline, hydroxyproline and lysine, were shown to form ordered aggregates structures exerting a cytotoxic effect towards cultured cells. [34,35] Additional nonaromatic metabolites such as cysteine and methionine, both known to accumulate in specific IEM disorders, produce toxic amyloid-like fibrillar structures in neutral aqueous conditions due to hydrogen bonding and thiol interactions, as confirmed by ThT and Congo red binding assays. [36] Homocysteine, a non-coded amino acid, can self-assemble into well-organized fibrillar supramolecular structures.…”

“…For example, high concentrations of phenylalanine may be associated with the brain dysfunction observed in PKU patients, an IEM disorder resulting from impaired phenylalanine metabolism [7] . Other amino acids known to accumulate in various IEM disorders, including tyrosine, proline, hydroxyproline and lysine, were shown to form ordered aggregates structures exerting a cytotoxic effect towards cultured cells [34,35] . Additional nonaromatic metabolites such as cysteine and methionine, both known to accumulate in specific IEM disorders, produce toxic amyloid‐like fibrillar structures in neutral aqueous conditions due to hydrogen bonding and thiol interactions, as confirmed by ThT and Congo red binding assays [36] …”

Toxic Metabolites and Inborn Errors of Amino Acid Metabolism: What One Informs about the Other

“…Along similar lines, phenylalanine also forms amyloid-like fibrillar deposits [125], which not only may explain some of the neuropathological symptoms of PKU but also suggest that elevated levels of phenylalanine could contribute to AD and other neurodegenerative disorders. Along these lines, there are links between tyrosine metabolism and tyrosine hydroxylase and PD [158,159], as well as hyperlysinemia and hyperprolinemia with AD [160].…”

Controlled aggregation properties of single amino acids modified with protecting groups

“…19 Kuo and coworkers recently employed the selfassembly of polypeptide diblock copolymers for the fabrication of high capacitance microporous carbon. [20][21][22] Our group is interested in studying the self-assembly of single amino acids, [23][24][25][26] peptides, [27][28][29][30][31][32] and heterocyclic compounds. [33][34][35] Hence, motivated by our previous research interest wherein we illustrated the self-assembly of single amino acids, [23][24][25][26] we were curious to study the self-assembled structure formation by modified single amino acids as well.…”

“…[20][21][22] Our group is interested in studying the self-assembly of single amino acids, [23][24][25][26] peptides, [27][28][29][30][31][32] and heterocyclic compounds. [33][34][35] Hence, motivated by our previous research interest wherein we illustrated the self-assembly of single amino acids, [23][24][25][26] we were curious to study the self-assembled structure formation by modified single amino acids as well. Therefore, we comprehensively assessed the self-assembling properties of single amino acids by functionalizing them with various protecting groups.…”