The
essential amino acid histidine plays a central role in the manifestation of several metabolic processes, including
protein synthesis,
enzyme-catalysis, and key biomolecular interactions. However, excess accumulation of
histidine causes
histidinemia, which shows brain-related medical complications, and the molecular mechanism of such
histidine-linked complications is largely unknown. Here, we show that
histidine undergoes a self-assembly process, leading to the formation of
amyloid-like cytotoxic and catalytically active nanofibers. The kinetics of
histidine self-assembly was favored in the presence of Mg(II) and Co(II)
ions. Molecular dynamics data showed that preferential noncovalent interactions dominated by H-bonds between
histidine molecules facilitate the formation of
histidine nanofibers. The
histidine nanofibers induced
amyloid cross-seeding reactions in several
proteins and
peptides including pathogenic Aβ1-42 and brain extract components. Further, the
histidine nanofibers exhibited
oxidase activity and enhanced the oxidation of
neurotransmitters. Cell-based studies confirmed the cellular internalization of
histidine nanofibers in SH-SY5Y cells and subsequent cytotoxic effects through
necrosis and apoptosis-mediated cell death. Since several complications including behavioral abnormality, developmental delay, and neurological disabilities are directly linked to abnormal accumulation of
histidine, our findings provide a foundational understanding of the mechanism of
histidine-related complications. Further, the ability of
histidine nanofibers to catalyze
amyloid seeding and oxidation reactions is equally important for both biological and materials science research.