Abstract
The extension of the amyloid hypothesis to include non-protein metabolite assemblies invokes a paradigm for the pathology of inborn error of metabolism disorders. However, a direct demonstration of the assembly of metabolite amyloid-like structures has so far been provided only in vitro. Here, we established an in vivo model of adenine self-assembly in yeast, in which toxicity is associated with intracellular accumulation of the metabolite. Using a strain blocked in the enzymatic pathway downstream to adenine, we observed a non-linear dose-dependent growth inhibition. Both the staining with an indicative amyloid dye and anti-adenine assemblies antibodies demonstrated the accumulation of adenine amyloid-like structures, which were eliminated by lowering the supplied adenine levels. Treatment with a polyphenol inhibitor reduced the occurrence of amyloid-like structures while not affecting the dramatic increase in intracellular adenine concentration, resulting in inhibition of cytotoxicity, further supporting the notion that toxicity is triggered by adenine assemblies.
Highlights
The extension of the amyloid hypothesis to include non-protein metabolite assemblies invokes a paradigm for the pathology of inborn error of metabolism disorders
Both the adenine phosphoribosyltransferase (APRT) and adenosine deaminase (ADA) enzymes take part in adenine salvage in humans and mutations in their encoding genes can lead to the accumulation of adenine and its derivatives[22,23]
To verify that the toxic effect observed for the salvage mutant is due to disruption of the AAH1 and APT1 genes, single copy plasmids carrying both genes were introduced to the mutant cells by transformation
Summary
The extension of the amyloid hypothesis to include non-protein metabolite assemblies invokes a paradigm for the pathology of inborn error of metabolism disorders. Using a strain blocked in the enzymatic pathway downstream to adenine, we observed a non-linear dose-dependent growth inhibition Both the staining with an indicative amyloid dye and antiadenine assemblies antibodies demonstrated the accumulation of adenine amyloid-like structures, which were eliminated by lowering the supplied adenine levels. A paradigm for the pathophysiology of inborn error of metabolism disorders significantly extended the original hypothesis, showing that at millimolar pathological concentrations, the single phenylalanine amino acid can form nanofibrillar structures in aqueous solution and neutral pH in vitro[3]. These nonproteinaceous assemblies exhibit typical apple-green birefringence and clear fluorescence signal upon. Differential flexibility properties might explain the resistance of alpha-phenylglycine, that differs from phenylalanine by the absence of an additional flexible carbon extension, to fibril a WT aah1Δ apt1Δ aah1Δapt1Δ
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
