Intrinsic property of phenylalanine to trigger protein aggregation and hemolysis has a direct relevance to phenylketonuria

Abstract

Excess accumulation of phenylalanine is the characteristic of untreated Phenylketonuria (PKU), a well-known genetic abnormality, which triggers several neurological, physical and developmental severities. However, the fundamental mechanism behind the origin of such diverse health problems, particularly the issue of how they are related to the build-up of phenylalanine molecules in the body, is largely unknown. Here, we show cross-seeding ability of phenylalanine fibrils that can effectively initiate an aggregation process in proteins under physiological conditions, converting native protein structures to β-sheet assembly. The resultant fibrils were found to cause severe hemolysis, yielding a plethora of deformed erythrocytes that is highly relevant to phenylketonuria. Unique arrangement of zwitterionic phenylalanine molecules in their amyloid-like higher order entities is predicted to promote both hydrophobic and electrostatic interaction, sufficient enough to trap proteins and to preferentially interact with the membrane components of RBCs. Since the prevalence of hemolysis and amyloid related psychoneurological severities are mostly observed in PKU patients, we propose that the inherent property of phenylalanine fibrils to trigger hemolysis and to induce protein aggregation may have direct relevance to the disease mechanism of PKU.

Seeding of proteins into amyloid structures by metabolite assemblies may clarify certain unexplained epidemiological associations

“…Recent studies demonstrated that metabolites could cross-seed proteins [ 23 ]. Phenylalanine formed fibrils initiated the aggregation of several non-amyloidogenic proteins under physiological conditions [ 23 ].…”

“…Recent studies demonstrated that metabolites could cross-seed proteins [ 23 ]. Phenylalanine formed fibrils initiated the aggregation of several non-amyloidogenic proteins under physiological conditions [ 23 ]. Globular proteins, including lysozyme, serum albumin, insulin, myoglobin and cytochrome c , spontaneously self-assembled into amyloid fibrils in the presence of phenylalanine seeds [ 23 ].…”

“…Phenylalanine formed fibrils initiated the aggregation of several non-amyloidogenic proteins under physiological conditions [ 23 ]. Globular proteins, including lysozyme, serum albumin, insulin, myoglobin and cytochrome c , spontaneously self-assembled into amyloid fibrils in the presence of phenylalanine seeds [ 23 ]. Another observation was the accelerated aggregation of a soluble mixture of amino acids following the addition of phenylalanine fibrils [ 23 ].…”

“…Globular proteins, including lysozyme, serum albumin, insulin, myoglobin and cytochrome c , spontaneously self-assembled into amyloid fibrils in the presence of phenylalanine seeds [ 23 ]. Another observation was the accelerated aggregation of a soluble mixture of amino acids following the addition of phenylalanine fibrils [ 23 ]. Additional study demonstrated the cross-seeding of proteins by homogentisic acid (HGA), a metabolite related to alkaptonuria [ 24 ], a rare IEM disorder which was lately classified as secondary amyloidosis.…”

Peer Review #1 of "Emergence of visible light optical properties of L-phenylalanine aggregates (v0.2)"

“…Eventually it was demonstrated by Adler-Abramovich et al that even unmodified monomeric Phe is capable of forming fibrillar aggregates (Adler-Abramovich et al, 2012), which share similarities to amyloids. The amyloidogenic nature of Phe fibrils were supported by experimental data, showing the presence of beta-sheet conformation (by CD) (Smith et al, 2008), and other amyloid-specific properties, such as ThT and Congo Red binding ability and even seeding potential (Singh et al, 2014;Shaham-Niv et al, 2015;Anand et al, 2017). Different models of aggregate assembly and structure types were also presented.…”