A Novel Yeast Model for Tyrosine Accumulation and Self-Assembly

The term 'inborn error of metabolism' (IEM) encompasses thousands of genetic metabolic disorders caused due to a mutated enzyme-encoding gene and the consequent accumulation of a specific metabolic substrate. In most cases, the etiological link between metabolic alterations and the manifested disorders is still elusive. Following the extension of the generic amyloid hypothesis to include metabolites, which possess the ability to form nanofibrillar structures and display amyloid-like properties, a new paradigm for the pathophysiology of metabolic diseases was established. In this work, we seek to deepen our understanding regarding the structural features and mechanism of metabolite amyloid-like self-assembly in a living system and their pathological role in IEM patients. Furthermore, following the successful utilization of yeast to establish the first in vivo model for adenine accumulation and aggregation, we established an additional yeast model for tyrosine accumulation and self-assembly. By using strain partially blocked in the shikimate pathway, we observed non-linear dose-dependent growth inhibition upon tyrosine feeding which was shown to be associated with increased intracellular accumulation of tyrosine. The robust sensitivity to tyrosine was attributed to the formation of toxic tyrosine amyloid-like structures, as indicated by the staining with an amyloid-specific dye and specific antibodies raised against the tyrosine fibrils. Moreover, treatment with epigallocatechin gallate resulted in a significant reduction in the formation of the toxic tyrosine amyloid-like assemblies which further supports the notion that toxicity is triggered by tyrosine assemblies. This model can provide insights into the mechanism of metabolite self-assembly and platform to discover disease-modifying therapeutic avenues.