The final acylation step in taxol biosynthesis: cloning of the taxoid C13-side-chain N-benzoyltransferase from Taxus

Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9166-71. doi: 10.1073/pnas.082115799. Epub 2002 Jun 27.

Abstract

The formation of several acyl groups and an amide group of Taxol is catalyzed by regioselective CoA thioester-dependent acyltransferases. Several full-length acyltransferase sequences, obtained from a cDNA library constructed from mRNA isolated from Taxus cuspidata cells induced for Taxol production with methyl jasmonate, were individually expressed in Escherichia coli, from which a cDNA clone encoding a 3'-N-debenzoyl- 2'-deoxytaxol N-benzoyltransferase was identified. This recombinant enzyme catalyzes the stereoselective coupling of the surrogate substrate N-debenzoyl-(3'RS)-2'-deoxytaxol with benzoyl-CoA to form predominantly one 3'-epimer of 2'-deoxytaxol. The product 2'-deoxytaxol was confirmed by radio-HPLC,(1)H-NMR, and chemical ionization-MS. This enzymatic reaction constitutes the final acylation in the Taxol biosynthetic pathway. The full-length cDNA coding for the N-benzoyltransferase has an ORF of 1,323 nucleotides and encodes a 441-residue protein with a calculated molecular weight of 49,040. The recombinant enzyme expressed in E. coli has a pH optimum at 8.0, a k(cat) approximately 1.5 +/- 0.3 s(-1) and K(m) values of 0.42 mM and 0.40 mM for the N-deacylated taxoid and benzoyl-CoA, respectively. In addition to improving the production yields of Taxol in genetically engineered host systems, this enzyme provides a means of attaching modified aroyl groups to taxoid precursors for the purpose of improving drug efficacy.

Publication types

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

MeSH terms

  • Aldehyde-Ketone Transferases / genetics*
  • Aldehyde-Ketone Transferases / metabolism*
  • Amino Acid Sequence
  • Base Sequence
  • Cloning, Molecular
  • DNA, Plant / genetics
  • Escherichia coli / genetics
  • Mass Spectrometry
  • Molecular Sequence Data
  • Nuclear Magnetic Resonance, Biomolecular
  • Paclitaxel / biosynthesis*
  • Paclitaxel / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Taxus / enzymology
  • Taxus / genetics*
  • Taxus / metabolism*

Substances

  • DNA, Plant
  • Recombinant Proteins
  • Aldehyde-Ketone Transferases
  • taxoid C13-side-chain N-benzoyltransferase
  • Paclitaxel

Associated data

  • GENBANK/AF466397