Site-specific enzymatic hydrolysis of taxanes at C-10 and C-13

J Biol Chem. 1994 Sep 2;269(35):22145-9.

Abstract

The production of large amounts of paclitaxel for use as an anticancer treatment has been a challenging problem because of the low concentration of the compound in yew trees and its occurrence as part of a mixture of other taxanes. Two novel enzymes were isolated to facilitate the production of 10-deacetylbaccatin III, a precursor used for semisynthesis of paclitaxel and analogs. A strain of Nocardioides albus (SC13911) was isolated from soil and found to produce an extracellular enzyme that specifically removed the C-13 side chain from paclitaxel, cephalomannine, 7-beta-xylosyltaxol, 7-beta-xylosyl-10-deacetyltaxol, and 10-deacetyltaxol. The enzyme was purified to near homogeneity to give a polypeptide with 47,000 M(r) on a sodium dodecyl sulfate gel. A strain of Nocardioides luteus (SC13912) isolated from soil was found to produce an intracellular 10-deacetylase that removed the 10-acetate from baccatin III and paclitaxel. The 10-deacetylase was purified to give a polypeptide with 40,000 M(r) on a sodium dodecyl sulfate gel. Treatment of extracts prepared from a variety of yew cultivars with the C-13-deacylase and C-10-deacetylase converted a complex mixture of taxanes primarily to 10-deacetylbaccatin III and increased the amount of this key precursor by 4-24 times.

MeSH terms

  • Bridged Bicyclo Compounds / chemistry
  • Bridged Bicyclo Compounds / metabolism
  • Bridged-Ring Compounds*
  • Carboxylic Ester Hydrolases / isolation & purification
  • Carboxylic Ester Hydrolases / metabolism*
  • Chromatography, High Pressure Liquid
  • Electrophoresis, Polyacrylamide Gel
  • Hydrolysis
  • Nocardiaceae / enzymology
  • Paclitaxel / metabolism*
  • Substrate Specificity
  • Taxoids*

Substances

  • Bridged Bicyclo Compounds
  • Bridged-Ring Compounds
  • Taxoids
  • taxane
  • C-10-deacetylase
  • C-13-deacylase
  • Carboxylic Ester Hydrolases
  • Paclitaxel