(S,S)-2,3-Dihydroxy-2,3-dihydrobenzoic acid: microbial access with engineered cells of Escherichia coli and application as starting material in natural-product synthesis

Chemistry. 2003 Sep 5;9(17):4188-96. doi: 10.1002/chem.200204265.

Abstract

Cyclohexadiene-trans-5,6-diols such as (S,S)-2,3-dihydroxy-2,3-dihydrobenzoic acid (2,3-trans-CHD) have been shown to be of importance as chiral starting materials for the syntheses of bioactive substances, especially for the syntheses of carbasugars. By using methods of metabolic-pathway engineering, the Escherichia coli genes entB and entC, which encode isochorismatase and isochorismate synthase, were cloned and over-expressed in E. coli strains with a deficiency of entA, which encodes 2,3-dihydroxybenzoate synthase. A 30-fold increase in the corresponding EntB/EntC enzyme activities affects the accumulation of 2,3-trans-CHD in the cultivation medium. Although the strains did not contain deletions in chorismate-utilising pathways towards aromatic amino acids, neither chorismate nor any other metabolic intermediates were found as by-products. Fermentation of these strains in a 30 L pH-controlled stirred tank reactor showed that 2,3-trans-CHD could be obtained in concentrations of up to 4.6 g L(-1). This demonstrates that post-chorismate metabolites are accessible on a preparative scale by using techniques of metabolic-pathway engineering. Isolation and separation from fermentation salts could be performed economically in one step through anion-exchange chromatography or, alternatively, by reactive extraction. Starting from 2,3-trans-CHD as an example, we established short syntheses towards new carbasugar derivatives.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzoates / chemistry*
  • Benzoates / isolation & purification
  • Benzoates / metabolism*
  • Chorismic Acid / analogs & derivatives
  • Chorismic Acid / metabolism
  • Cyclohexanecarboxylic Acids / chemistry*
  • Cyclohexanecarboxylic Acids / isolation & purification
  • Cyclohexanecarboxylic Acids / metabolism*
  • Escherichia coli / cytology
  • Escherichia coli / genetics
  • Escherichia coli / metabolism*
  • Escherichia coli Proteins / genetics
  • Escherichia coli Proteins / metabolism
  • Esterification
  • Fermentation
  • Hydrolases / genetics
  • Hydrolases / metabolism
  • Intramolecular Transferases / genetics
  • Intramolecular Transferases / metabolism
  • Stereoisomerism

Substances

  • Benzoates
  • Cyclohexanecarboxylic Acids
  • Escherichia coli Proteins
  • Hydrolases
  • isochorismatase
  • Intramolecular Transferases
  • isochorismate synthase
  • Chorismic Acid