Organisation of the biosynthetic gene cluster for rapamycin in Streptomyces hygroscopicus: Analysis of genes flanking the polyketide synthase

István Molnár, Jesús F. Aparicio, Stephen F. Haydock, Lake Ee Khaw, Torsten Schwecke, Ariane König, James Staunton, Peter F. Leadlay

Research output: Contribution to journalArticle

111 Scopus citations

Abstract

Analysis of the gene cluster from Streptomyces hygroscopicus that governs the biosypthesis of the polyketide immunosuppressant rapamycin (Rp) has revealed that it contains three exceptionally large open reading frames (ORFs) encoding the modular polyketide synthase (PKS). Between two of these lies a fourth gene (rapP) encoding a pipecolate-incorporating enzyme that probably also catalyzes closure of the macrolide ring. On either side of these very large genes are ranged a total of 22 further ORFs before the limits of the cluster are reached, as judged by the identification of genes clearly encoding unrelated activities. Several of these ORFs appear to encode enzymes that would be required for Rp biosynthesis. These include two cytochrome P-450 monooxygenases (P450s), designated RapJ and RapN, an associated ferredoxin (Fd) RapO, and three potential SAM-dependent O-methyltransferases (MTases), RapI, RapM and RapQ. All of these are likely to be involved in 'late' modification of the macrocycle. The cluster also contains a novel gene (rapL) whose product is proposed to catalyze the formation of the Rp precursor, L-pipecolate, through the cyclodeamination of L-lysine. Adjacent genes have putative roles in Rp regulation and export. The codon usage of the PKS biosynthetic genes is markedly different from that of the flanking genes of the cluster.

Original languageEnglish (US)
Pages (from-to)1-7
Number of pages7
JournalGene
Volume169
Issue number1
DOIs
StatePublished - Feb 22 1996
Externally publishedYes

Keywords

  • Cyclodeaminase
  • Cytochrome P450
  • FK506
  • Methyltransferase
  • Peptide synthetase

ASJC Scopus subject areas

  • Genetics

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