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Rapid Generation of Amyloid from Native Proteins In vitro
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Catalysis driven by an amyloid-substrate complex.

Taka Sawazaki1, Daisuke Sasaki1, Youhei Sohma1

  • 1Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Wakayama Medical University, Wakayama 640-8156, Japan.

Proceedings of the National Academy of Sciences of the United States of America
|May 1, 2024
PubMed
Summary
This summary is machine-generated.

A novel amyloid catalyst system (CASL) activates ammonium ions for amine modification reactions under acidic conditions. This breakthrough enables common chemical transformations previously hindered by low pH.

Keywords:
amyloidamyloid catalystcatalysisnucleophilic reaction

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Area of Science:

  • Chemical Biology
  • Organic Chemistry
  • Biocatalysis

Background:

  • Amine modification is crucial in chemistry and biology.
  • Alkyl amines are poorly nucleophilic in acidic buffers due to ammonium ion formation.
  • Existing methods struggle with amine modification under acidic, biorelevant conditions.

Purpose of the Study:

  • To develop a novel catalytic system for amine modification in acidic buffer.
  • To overcome the limitations of ammonium ion nucleophilicity at acidic pH.
  • To demonstrate the versatility of amyloid catalysts in promoting amine transformations.

Main Methods:

  • Development of a catalysis driven by amyloid-substrate complex (CASL) system.
  • Utilizing a specific amyloid catalyst (NL6) derived from islet amyloid polypeptide (IAPP).
  • Employing crystallographic analysis and chemical modification studies to elucidate the catalytic mechanism.

Main Results:

  • CASL effectively promotes various amine modifications (acylation, arylation, cyclization, alkylation) in acidic buffer.
  • The carbonyl oxygen of the Phe-Gly amide bond in NL6 is key for activating substrate amines via hydrogen bonding.
  • Selective conversion of substrates with similar amine reactivity was achieved using amyloid catalysts.
  • Demonstrated the utility of CASL for amine modifications under acidic conditions.

Conclusions:

  • CASL represents a unique molecular transformation system for amine modification.
  • Amyloid catalysts can activate ammonium ions, enabling reactions previously difficult at acidic pH.
  • This method offers a new approach for amine functionalization in chemistry and biology.