Limits...
Extension of the generic amyloid hypothesis to nonproteinaceous metabolite assemblies.

Shaham-Niv S, Adler-Abramovich L, Schnaider L, Gazit E - Sci Adv (2015)

Bottom Line: Although the formation of these supramolecular entities has previously been associated with proteins and peptides, it was later demonstrated that even phenylalanine, a single amino acid, can form fibrils that have amyloid-like biophysical, biochemical, and cytotoxic properties.Moreover, the generation of antibodies against these assemblies in phenylketonuria patients and the correlating mice model suggested a pathological role for the assemblies.The formation of amyloid-like assemblies by metabolites implies a general phenomenon of amyloid formation, not limited to proteins and peptides, and offers a new paradigm for metabolic diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.

ABSTRACT
The accumulation of amyloid fibrils is the hallmark of several major human diseases. Although the formation of these supramolecular entities has previously been associated with proteins and peptides, it was later demonstrated that even phenylalanine, a single amino acid, can form fibrils that have amyloid-like biophysical, biochemical, and cytotoxic properties. Moreover, the generation of antibodies against these assemblies in phenylketonuria patients and the correlating mice model suggested a pathological role for the assemblies. We determine that several other metabolites that accumulate in metabolic disorders form ordered amyloid-like ultrastructures, which induce apoptotic cell death, as observed for amyloid structures. The formation of amyloid-like assemblies by metabolites implies a general phenomenon of amyloid formation, not limited to proteins and peptides, and offers a new paradigm for metabolic diseases.

No MeSH data available.


Related in: MedlinePlus

The organization and assembly of metabolites into ordered structures.(A) l-Phenylalanine self-assembles into well-ordered amyloid-like assemblies with typical nanofibrillar dimensions as observed by electron microscopy, ordered electron diffraction pattern [modified from (13)], and binding to amyloid-specific dyes (ThT and Congo red). The crystal structure of zwitterionic phenylalanine represents the same molecular spacing as of a hypothetical polyphenylalanine stand (in green) and may be regarded as a supramolecular strand-like organization. The assemblies formed are cytotoxic, and their deposition could be observed in the brains of PKU patients. The self-assembly could be inhibited by the d-phenylalanine stereoisomer (30). The cytotoxic effect could be prevented by depletion with specific antibodies raised toward the supramolecular assemblies (13). (B) Overall review of genetic inborn error of metabolism disorders and their related accumulating metabolites.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4643800&req=5

Figure 1: The organization and assembly of metabolites into ordered structures.(A) l-Phenylalanine self-assembles into well-ordered amyloid-like assemblies with typical nanofibrillar dimensions as observed by electron microscopy, ordered electron diffraction pattern [modified from (13)], and binding to amyloid-specific dyes (ThT and Congo red). The crystal structure of zwitterionic phenylalanine represents the same molecular spacing as of a hypothetical polyphenylalanine stand (in green) and may be regarded as a supramolecular strand-like organization. The assemblies formed are cytotoxic, and their deposition could be observed in the brains of PKU patients. The self-assembly could be inhibited by the d-phenylalanine stereoisomer (30). The cytotoxic effect could be prevented by depletion with specific antibodies raised toward the supramolecular assemblies (13). (B) Overall review of genetic inborn error of metabolism disorders and their related accumulating metabolites.

Mentions: Until recently, this visionary paradigm-shifting model for molecular association and energy landscape was limited to proteins and polypeptides (12). However, it was recently demonstrated that the single phenylalanine amino acid can form well-ordered amyloid-like fibrillar assemblies. These fibrils bind the amyloid-specific thioflavin T (ThT) and Congo red dyes. Moreover, the assemblies were found to have a significant cytotoxic effect allowing distinct immunogenicity, similar to amyloid deposits (13). In addition, single-crystal x-ray diffraction analysis of zwitterionic phenylalanine, under the condition in which it was found to form fibrillar assemblies, demonstrated a tight packing of the amino acid (14) in a pattern that resembles a β sheet secondary structure (Fig. 1A). This provided an important observation because conventional secondary structure evaluation methods such as circular dichroism and Fourier transform infrared spectroscopy are not applicable due to the absence of an amide chromophore. The observed formation of amyloid-like fibrils by phenylalanine was suggested to provide new mechanistic insights into the observed progression of pathology in phenylketonuria (PKU). Physiological accumulation of phenylalanine in body tissues, plasma, and urine is a characteristic of the PKU metabolic disorder (15). The cytotoxicity of the phenylalanine fibrils, which highly resembles that of amyloid fibrils, may provide an explanation for the mental retardation observed in PKU patients who do not maintain a restricted diet. The detection of phenylalanine assemblies in the brain of PKU model mice and individuals affected by the disorder supports this notion (Fig. 1A).


Extension of the generic amyloid hypothesis to nonproteinaceous metabolite assemblies.

Shaham-Niv S, Adler-Abramovich L, Schnaider L, Gazit E - Sci Adv (2015)

The organization and assembly of metabolites into ordered structures.(A) l-Phenylalanine self-assembles into well-ordered amyloid-like assemblies with typical nanofibrillar dimensions as observed by electron microscopy, ordered electron diffraction pattern [modified from (13)], and binding to amyloid-specific dyes (ThT and Congo red). The crystal structure of zwitterionic phenylalanine represents the same molecular spacing as of a hypothetical polyphenylalanine stand (in green) and may be regarded as a supramolecular strand-like organization. The assemblies formed are cytotoxic, and their deposition could be observed in the brains of PKU patients. The self-assembly could be inhibited by the d-phenylalanine stereoisomer (30). The cytotoxic effect could be prevented by depletion with specific antibodies raised toward the supramolecular assemblies (13). (B) Overall review of genetic inborn error of metabolism disorders and their related accumulating metabolites.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4643800&req=5

Figure 1: The organization and assembly of metabolites into ordered structures.(A) l-Phenylalanine self-assembles into well-ordered amyloid-like assemblies with typical nanofibrillar dimensions as observed by electron microscopy, ordered electron diffraction pattern [modified from (13)], and binding to amyloid-specific dyes (ThT and Congo red). The crystal structure of zwitterionic phenylalanine represents the same molecular spacing as of a hypothetical polyphenylalanine stand (in green) and may be regarded as a supramolecular strand-like organization. The assemblies formed are cytotoxic, and their deposition could be observed in the brains of PKU patients. The self-assembly could be inhibited by the d-phenylalanine stereoisomer (30). The cytotoxic effect could be prevented by depletion with specific antibodies raised toward the supramolecular assemblies (13). (B) Overall review of genetic inborn error of metabolism disorders and their related accumulating metabolites.
Mentions: Until recently, this visionary paradigm-shifting model for molecular association and energy landscape was limited to proteins and polypeptides (12). However, it was recently demonstrated that the single phenylalanine amino acid can form well-ordered amyloid-like fibrillar assemblies. These fibrils bind the amyloid-specific thioflavin T (ThT) and Congo red dyes. Moreover, the assemblies were found to have a significant cytotoxic effect allowing distinct immunogenicity, similar to amyloid deposits (13). In addition, single-crystal x-ray diffraction analysis of zwitterionic phenylalanine, under the condition in which it was found to form fibrillar assemblies, demonstrated a tight packing of the amino acid (14) in a pattern that resembles a β sheet secondary structure (Fig. 1A). This provided an important observation because conventional secondary structure evaluation methods such as circular dichroism and Fourier transform infrared spectroscopy are not applicable due to the absence of an amide chromophore. The observed formation of amyloid-like fibrils by phenylalanine was suggested to provide new mechanistic insights into the observed progression of pathology in phenylketonuria (PKU). Physiological accumulation of phenylalanine in body tissues, plasma, and urine is a characteristic of the PKU metabolic disorder (15). The cytotoxicity of the phenylalanine fibrils, which highly resembles that of amyloid fibrils, may provide an explanation for the mental retardation observed in PKU patients who do not maintain a restricted diet. The detection of phenylalanine assemblies in the brain of PKU model mice and individuals affected by the disorder supports this notion (Fig. 1A).

Bottom Line: Although the formation of these supramolecular entities has previously been associated with proteins and peptides, it was later demonstrated that even phenylalanine, a single amino acid, can form fibrils that have amyloid-like biophysical, biochemical, and cytotoxic properties.Moreover, the generation of antibodies against these assemblies in phenylketonuria patients and the correlating mice model suggested a pathological role for the assemblies.The formation of amyloid-like assemblies by metabolites implies a general phenomenon of amyloid formation, not limited to proteins and peptides, and offers a new paradigm for metabolic diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.

ABSTRACT
The accumulation of amyloid fibrils is the hallmark of several major human diseases. Although the formation of these supramolecular entities has previously been associated with proteins and peptides, it was later demonstrated that even phenylalanine, a single amino acid, can form fibrils that have amyloid-like biophysical, biochemical, and cytotoxic properties. Moreover, the generation of antibodies against these assemblies in phenylketonuria patients and the correlating mice model suggested a pathological role for the assemblies. We determine that several other metabolites that accumulate in metabolic disorders form ordered amyloid-like ultrastructures, which induce apoptotic cell death, as observed for amyloid structures. The formation of amyloid-like assemblies by metabolites implies a general phenomenon of amyloid formation, not limited to proteins and peptides, and offers a new paradigm for metabolic diseases.

No MeSH data available.


Related in: MedlinePlus