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

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

Research output: Contribution to journalArticle

110 Citations (Scopus)

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

Fingerprint

Polyketide Synthases
Streptomyces
Sirolimus
Multigene Family
Open Reading Frames
Genes
Polyketides
Ferredoxins
Macrolides
Methyltransferases
Enzymes
Immunosuppressive Agents
Codon
Cytochrome P-450 Enzyme System
Lysine

Keywords

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

ASJC Scopus subject areas

  • Genetics

Cite this

Organisation of the biosynthetic gene cluster for rapamycin in Streptomyces hygroscopicus : Analysis of genes flanking the polyketide synthase. / Molnar, Istvan; Aparicio, Jesús F.; Haydock, Stephen F.; Khaw, Lake Ee; Schwecke, Torsten; König, Ariane; Staunton, James; Leadlay, Peter F.

In: Gene, Vol. 169, No. 1, 22.02.1996, p. 1-7.

Research output: Contribution to journalArticle

Molnar, Istvan ; Aparicio, Jesús F. ; Haydock, Stephen F. ; Khaw, Lake Ee ; Schwecke, Torsten ; König, Ariane ; Staunton, James ; Leadlay, Peter F. / Organisation of the biosynthetic gene cluster for rapamycin in Streptomyces hygroscopicus : Analysis of genes flanking the polyketide synthase. In: Gene. 1996 ; Vol. 169, No. 1. pp. 1-7.
@article{150ae9f3b63a4c949399f7cb1f322b28,
title = "Organisation of the biosynthetic gene cluster for rapamycin in Streptomyces hygroscopicus: Analysis of genes flanking the polyketide synthase",
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.",
keywords = "Cyclodeaminase, Cytochrome P450, FK506, Methyltransferase, Peptide synthetase",
author = "Istvan Molnar and Aparicio, {Jes{\'u}s F.} and Haydock, {Stephen F.} and Khaw, {Lake Ee} and Torsten Schwecke and Ariane K{\"o}nig and James Staunton and Leadlay, {Peter F.}",
year = "1996",
month = "2",
day = "22",
doi = "10.1016/0378-1119(95)00799-7",
language = "English (US)",
volume = "169",
pages = "1--7",
journal = "Gene",
issn = "0378-1119",
publisher = "Elsevier",
number = "1",

}

TY - JOUR

T1 - Organisation of the biosynthetic gene cluster for rapamycin in Streptomyces hygroscopicus

T2 - Analysis of genes flanking the polyketide synthase

AU - Molnar, Istvan

AU - Aparicio, Jesús F.

AU - Haydock, Stephen F.

AU - Khaw, Lake Ee

AU - Schwecke, Torsten

AU - König, Ariane

AU - Staunton, James

AU - Leadlay, Peter F.

PY - 1996/2/22

Y1 - 1996/2/22

N2 - 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.

AB - 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.

KW - Cyclodeaminase

KW - Cytochrome P450

KW - FK506

KW - Methyltransferase

KW - Peptide synthetase

UR - http://www.scopus.com/inward/record.url?scp=0029883934&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029883934&partnerID=8YFLogxK

U2 - 10.1016/0378-1119(95)00799-7

DO - 10.1016/0378-1119(95)00799-7

M3 - Article

C2 - 8635730

AN - SCOPUS:0029883934

VL - 169

SP - 1

EP - 7

JO - Gene

JF - Gene

SN - 0378-1119

IS - 1

ER -