Terrequinone A biosynthesis through L-tryptophan oxidation, dimerization and bisprenylation

Nat Chem Biol. 2007 Sep;3(9):584-92. doi: 10.1038/nchembio.2007.20. Epub 2007 Aug 12.


The antitumor fungal metabolite terrequinone A, identified in extracts of Aspergillus sp., is biosynthesized by the five-gene cluster tdiA-tdiE. In this work, we have overproduced all five proteins (TdiA-TdiE) in the bacterial host Escherichia coli, fully reconstituting the biosynthesis of terrequinone A. This pathway involves aminotransferase activity, head-to-tail dimerization and bisprenylation of the scaffold to yield the benzoquinone natural product. We have established that TdiD is a pyridoxal-5'-phosphate-dependent L-tryptophan aminotransferase that generates indolepyruvate for an unusual nonoxidative coupling by the tridomain nonribosomal peptide synthetase TdiA. TdiC, an NADH-dependent quinone reductase, generates the nucleophilic hydroquinone for two distinct rounds of prenylation by the single prenyltransferase TdiB. TdiE is required to shunt the benzoquinone away from an off-pathway monoprenylated species by an as yet unknown mechanism. Overall, we have biochemically characterized the complete biosynthetic pathway to terrequinone A, highlighting the nonoxidative dimerization pathway and the unique asymmetric prenylation involved in its maturation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Aspergillus nidulans / enzymology*
  • Dimerization
  • Escherichia coli / genetics
  • Indoles / chemical synthesis*
  • Metabolic Networks and Pathways / genetics
  • Molecular Sequence Data
  • Multienzyme Complexes / genetics*
  • Oxidation-Reduction
  • Prenylation
  • Tryptophan / metabolism*


  • Antineoplastic Agents
  • Indoles
  • Multienzyme Complexes
  • terrequinone A
  • Tryptophan

Associated data

  • GENBANK/EF550581
  • GENBANK/EF550582
  • GENBANK/EF550583
  • GENBANK/EF550584
  • GENBANK/EF550585
  • PubChem-Substance/24844218
  • PubChem-Substance/24844219
  • PubChem-Substance/24844220
  • PubChem-Substance/24844221
  • PubChem-Substance/24844222
  • PubChem-Substance/24844223
  • PubChem-Substance/24844224
  • PubChem-Substance/24844225
  • PubChem-Substance/24844226
  • PubChem-Substance/24844227
  • PubChem-Substance/24844228
  • PubChem-Substance/24844229
  • PubChem-Substance/24844230
  • PubChem-Substance/24844231
  • PubChem-Substance/24844232
  • PubChem-Substance/24844233
  • PubChem-Substance/24844234
  • PubChem-Substance/24844235
  • PubChem-Substance/24844236
  • PubChem-Substance/24844237
  • PubChem-Substance/24844238
  • PubChem-Substance/24844239
  • PubChem-Substance/24844240