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Enzymatic-synthesis of a bacterial polyketide from acetyl and malonyl coenzyme-a

Academic Article
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Overview

authors

  • Shen, Ben
  • Hutchinson, C. R.

publication date

  • December 1993

journal

  • Science  Journal

abstract

  • Microorganisms and plants manufacture a large collection of medically and commercially useful natural products called polyketides by a process that resembles fatty acid biosynthesis. Genetically engineered microorganisms with modified polyketide synthase (PKS) genes can produce new metabolites that may have new or improved pharmacological activity. A potentially general method to prepare cell-free systems for studying bacterial type II PKS enzymes has been developed that facilitates the purification and reconstitution of their constituent proteins. Selective expression of different combinations of the Streptomyces glaucescens tetracenomycin (Tcm) tcmJKLMN genes in a tcmGHIJKLMNO null background has been used to show that the Tcm PKS consists of at least the TcmKLMN proteins. Addition of the TcmJ protein to the latter four enzymes resulted in a greater than fourfold increase of overall activity and thus represents the optimal Tcm PKS. Polyclonal antibodies raised against each of the TcmKLMN proteins strongly inhibit the Tcm PKS, as do known inhibitors targeted to the active site Cys and Ser residues of a fatty acid synthase. This system exhibits a strict starter unit specificity because neither propionyl, butyryl, or isobutyryl coenzyme A substitute for acetyl coenzyme A in assembly of the Tcm decaketide. Because the Tcm PKS activity is significantly diminished by removal of the TcmM acyl carrier protein and can be restored by addition of separately purified TcmM to two different types of TcmM-deficient PKS, it should be possible to use such preparations to assay for each of the constituents of the Tcm PKS.

subject areas

  • Acetyl Coenzyme A
  • Amino Acid Sequence
  • Anthracenes
  • Antibody Specificity
  • Fatty Acid Synthases
  • Malonyl Coenzyme A
  • Molecular Sequence Data
  • Multienzyme Complexes
  • Streptomyces
  • Substrate Specificity
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Identity

International Standard Serial Number (ISSN)

  • 0036-8075

Digital Object Identifier (DOI)

  • 10.1126/science.8248801

PubMed ID

  • 8248801
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Additional Document Info

start page

  • 1535

end page

  • 1540

volume

  • 262

issue

  • 5139

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