Ergothioneine biosynthetic methyltransferase EgtD reveals the structural basis of aromatic amino acid betaine biosynthesis

Chembiochem. 2015 Jan 2;16(1):119-25. doi: 10.1002/cbic.201402522. Epub 2014 Nov 17.

Abstract

Ergothioneine is an N-α-trimethyl-2-thiohistidine derivative that occurs in human, plant, fungal, and bacterial cells. Biosynthesis of this redox-active betaine starts with trimethylation of the α-amino group of histidine. The three consecutive methyl transfers are catalyzed by the S-adenosylmethionine-dependent methyltransferase EgtD. Three crystal structures of this enzyme in the absence and in the presence of N-α-dimethylhistidine and S-adenosylhomocysteine implicate a preorganized array of hydrophilic interactions as the determinants for substrate specificity and apparent processivity. We identified two active site mutations that change the substrate specificity of EgtD 10(7)-fold and transform the histidine-methyltransferase into a proficient tryptophan-methyltransferase. Finally, a genomic search for EgtD homologues in fungal genomes revealed tyrosine and tryptophan trimethylation activity as a frequent trait in ascomycetous and basidomycetous fungi.

Keywords: amino acids; betaines; biosynthesis; ergothioneine; hypaphorine; methyltransferases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Ascomycota / enzymology*
  • Ascomycota / genetics
  • Basidiomycota / enzymology*
  • Basidiomycota / genetics
  • Betaine / chemistry*
  • Betaine / metabolism
  • Catalytic Domain
  • Crystallography, X-Ray
  • Ergothioneine / chemistry*
  • Ergothioneine / metabolism
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Fungal Proteins / chemistry*
  • Fungal Proteins / genetics
  • Fungal Proteins / metabolism
  • Gene Expression
  • Histidine / chemistry
  • Histidine / metabolism
  • Methyltransferases / chemistry*
  • Methyltransferases / genetics
  • Methyltransferases / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • S-Adenosylhomocysteine / chemistry
  • S-Adenosylhomocysteine / metabolism
  • S-Adenosylmethionine / chemistry
  • S-Adenosylmethionine / metabolism
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Substrate Specificity
  • Tryptophan / chemistry
  • Tryptophan / metabolism

Substances

  • Fungal Proteins
  • Recombinant Proteins
  • Betaine
  • Histidine
  • S-Adenosylmethionine
  • Tryptophan
  • S-Adenosylhomocysteine
  • Ergothioneine
  • Methyltransferases