Expanding metabolism for biosynthesis of nonnatural alcohols

Kechun Zhang, Michael R. Sawaya, David S. Eisenberg, James C. Liao

Research output: Contribution to journalArticlepeer-review

294 Scopus citations


Nature uses a limited set of metabolites to perform all of the biochemical reactions. To increase the metabolic capabilities of biological systems, we have expanded the natural metabolic network, using a nonnatural metabolic engineering approach. The branched-chain amino acid pathways are extended to produce abiotic longer chain keto acids and alcohols by engineering the chain elongation activity of 2-isopropylmalate synthase and altering the substrate specificity of downstream enzymes through rational protein design. When introduced into Escherichia coli, this nonnatural biosynthetic pathway produces various long-chain alcohols with carbon number ranging from 5 to 8. In particular, we demonstrate the feasibility of this approach by optimizing the biosynthesis of the 6-carbon alcohol, (S)-3-methyl-1-pentanol. This work demonstrates an approach to build artificial metabolism beyond the natural metabolic network. Nonnatural metabolites such as long chain alcohols are now included in the metabolite family of living systems.

Original languageEnglish (US)
Pages (from-to)20653-20658
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number52
StatePublished - Dec 30 2008


  • Chain elongation
  • Long chain alcohols
  • Metabolic engineering
  • Protein engineering


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