The self-assembling zwitterionic form of<scp>L</scp>-phenylalanine at neutral pH

Mossou, Estelle; Teixeira, Susana; Mitchell, Edward P.; Mason, Sax A.; Adler‐Abramovich, Lihi; Gazit, Ehud; Forsyth, V. Trevor

doi:10.1107/s2053229614002563

Cited by 58 publications

(87 citation statements)

References 26 publications

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“…Figure shows different tryptophan crystal assemblies that were simulated. In the simulations, we assumed that the molecular structure of the fibril is essentially based on the molecular structure of the bulk crystal, in analogy to phenylalanine and diphenylalanine assemblies, which have related molecular structures in fibril and bulk crystal assemblies ,. However, the bulk structure in the experimentally observed linear fibrils might have some degree of folding or reorganization that allows it to maintain one dominant growth direction.…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

Formation of Apoptosis‐Inducing Amyloid Fibrils by Tryptophan

Shaham-Niv

Řehák

Vuković

et al. 2016

Israel Journal of Chemistry

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115

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Many major degenerative disorders are associated with the formation of amyloid fibrils by proteins and peptides. Recent studies have extended the repertoire of amyloidogenic building blocks to non‐proteinaceous entities, including amino acids and nucleobases. Here, based on the high propensity of tryptophan‐containing proteins and peptides to form amyloid fibrils, we explored the self‐assembly profile of this amino acid. We discovered that tryptophan forms fibrillary assemblies with a diameter of 15–75 nm. These fibrils bind the thioflavin T amyloid‐specific dye and show a typical spectrum of amyloid proteins upon binding. Furthermore, the assemblies show significant cytotoxicity triggered by an apoptosis mechanism, similar to that known for amyloids. As a control, the non‐amyloidogenic amino acid alanine was used under the same conditions and did not show any toxicity. Molecular dynamics simulations were used to explore the possible growth mechanism, molecular organization, and stability of tryptophan amyloidal fibrils. Taken together, we provide further extension to the amyloid hypothesis and additional indication for a knwon mechanism of toxicity for both amyloid‐associated and metabolic disorders.

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Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

Formation of Apoptosis‐Inducing Amyloid Fibrils by Tryptophan

Shaham-Niv

Řehák

Vuković

et al. 2016

Israel Journal of Chemistry

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115

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“…Additional high-resolution structural studies using X-ray crystallography were conducted to determine the ordering of phenylalanine in the aggregated zwitterionic form (Mossou et al 2014). Phenylalanine was crystallized at the same state in which it forms the cytotoxic, cell interacting assemblies.…”

Section: Mechanism Of Phenylalanine Assemblymentioning

confidence: 99%

Metabolite amyloids: a new paradigm for inborn error of metabolism disorders

Gazit

2016

J of Inher Metab Disea

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The formation of ordered amyloid assemblies is associated with major human degenerative disorders, including Alzheimer's disease, Parkinson's disease, and type 2 diabetes. Amyloid fibrils are elongated nanoscale structures that bind to specific dyes (including thioflavin T and Congo red). Amyloid fibrillar assemblies or their early intermediates are known to induce apoptotic cytotoxic effect. Until recently, amyloid fiber formation was observed only with proteins and peptides. We reported in 2012 that a single amino acid, phenylalanine, could also form typical amyloid fibrils with the same morphology, dye-binding specificity, and electron diffraction pattern as protein amyloids. X-ray crystallography demonstrated the formation of supramolecular β-sheet-like organization by phenylalanine at its zwitterionic form. Metabolite amyloids had pronounced cytotoxicity that could be depleted by treatment with antibodies raised against the phenylalanine structures. We suggested that the observed amyloid formation could explain some of the symptoms observed in phenylketonuria (PKU) upon the accumulation of phenylalanine. Follow-up studies by other groups revealed the ability of phenylalanine amyloids to bind to membranes, as observed with protein amyloids. Furthermore, the doxycycline amyloid formation inhibitor was shown to also affect the formation of phenylalanine amyloids. In 2015, it was reported that other metabolites involved in metabolic disorders, including adenine, uracil, tyrosine, and orotic acid, could form amyloid-like assemblies. It was further demonstrated that the assemblies induce apoptotic cell death. Taken together, we suggest a new hypothesis to understand the etiology of degenerative processes observed in inborn error of metabolism disorders and indicate new avenues for treatment.

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“…[14] X-ray crystallography of Phe in its zwitterionic state, under conditions allowing its fibrillization, confirmed the organization of the amino acid into an ordered β-sheet-like layered organization, which was stabilized by a network of hydrogen bonds and aromatic interactions. [15]…”

Section: Introductionmentioning

confidence: 99%

Amino Acid Based Self‐assembled Nanostructures: Complex Structures from Remarkably Simple Building Blocks

Chakraborty

Gazit

2018

ChemNanoMat

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Amino acids are the simplest biological building blocks capable of forming discreet nanostructures by supramolecular self-assembly. The understanding of the process of organization of amino acid nanostructures is of fundamental importance for the study of metabolic diseases as well as for materials science applications. Although peptide self-assembled structures have been the topic of many review articles, much less attention has been devoted to the ability of amino acid building blocks, both natural and synthetic, to form ordered assemblies with defined architectures and notable physical properties, by the process of self-association. Herein, we try to shed light on amino acid based nanostructures, their fabrication and implications. We discuss self-assembled nanostructures, including hydrogels with nanoscale order, obtained from both modified and unmodified single amino acids. We also envision some future prospects in this emerging field.

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The self-assembling zwitterionic form ofL-phenylalanine at neutral pH

Cited by 58 publications

References 26 publications

Formation of Apoptosis‐Inducing Amyloid Fibrils by Tryptophan

Formation of Apoptosis‐Inducing Amyloid Fibrils by Tryptophan

Metabolite amyloids: a new paradigm for inborn error of metabolism disorders

Amino Acid Based Self‐assembled Nanostructures: Complex Structures from Remarkably Simple Building Blocks

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