Jesús Cortés

EntreChem (Spain)

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Peter F. Leadlay

University of Cambridge

James Staunton

University of Cambridge

Luz Elena Núñez

EntreChem (Spain)

Francisco Morís

EntreChem (Spain)

Brian A.M. Rudd

Novacta (United Kingdom)

Michael J. Dawson

Bicycle Therapeutics (United Kingdom)

Steven Boakes

Speechmatics (United Kingdom)

Cármen Méndez

Universidad de Oviedo

BŘ

Bronislava Řežuchová

Slovak Academy of Sciences

Stephen Haydock

Taunton & Somerset NHS Foundation Trust

Cooperative Institutions

University of Cambridge

Universidad de Oviedo

Slovak Academy of Sciences

Universidad de León

Institute of Molecular Biology of the Slovak Academy of Sciences

University of Tübingen

Instituto de Biotecnología de León

Czech Academy of Sciences, Institute of Microbiology

Hertfordshire Community NHS Trust

GlaxoSmithKline (United Kingdom)

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Lantibiotics and Similar Peptides Produced by and Active on Gram-Positives: Discovery, Development and Perspectives

Springer eBooks (2013)

Jesús Cortés

Lantibiotics

Gram

n-gram

10.1007/978-3-642-39968-8_7

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Citations (2)

An efficient blue-white screening system for markerless deletions and stable integrations in Streptomyces chromosomes based on the blue pigment indigoidine biosynthetic gene bpsA

Applied Microbiology and Biotechnology (2018)

Bronislava Řežuchová Dagmar Homerová Beatrica Ševčı́ková Luz Elena Núñez Renáta Nováková

Multiple cloning site

mCherry

Gene cluster

Heterologous

10.1007/s00253-018-9393-7

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Citations (18)

A New Modular Polyketide Synthase in the Erythromycin Producer Saccharopolyspora erythraea

Microbial Physiology (2004)

Steven Boakes Markiyan Oliynyk Jesús Cortés Ines Böhm Brian A.M. Rudd

A previously unidentified set of genes encoding a modular polyketide synthase (PKS) has been sequenced in Saccharopolyspora erythraea, producer of the antibiotic erythromycin. This new PKS gene cluster (pke) contains four adjacent large open reading frames (ORFs) encoding eight extension modules, flanked by a number of other ORFs which can be plausibly assigned roles in polyketide biosynthesis. Disruption of the pke PKS genes gave S. erythraea mutant JC2::pSBKS6, whose growth characteristics and pattern of secondary metabolite production did not apparently differ from the parent strain under any of the growth conditions tested. However, the pke PKS loading module and individual pke acyltransferase domains were shown to be active when used in engineered hybrid PKSs, making it highly likely that under appropriate conditions these biosynthetic genes are indeed expressed and active, and synthesize a novel polyketide product.

Polyketide synthase

10.1159/000084562

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Citations (14)

The biosynthetic gene cluster for the polyketide immunosuppressant rapamycin.

Proceedings of the National Academy of Sciences (1995)

Torsten Schwecke Jesús F. Aparicio István Molnár Ariane König Lake Ee Khaw

The macrocyclic polyketides rapamycin and FK506 are potent immunosuppressants that prevent T-cell proliferation through specific binding to intracellular protein receptors (immunophilins). The cloning and specific alteration of the biosynthetic genes for these polyketides might allow the biosynthesis of clinically valuable analogues. We report here that three clustered polyketide synthase genes responsible for rapamycin biosynthesis in Streptomyces hygroscopicus together encode 14 homologous sets of enzyme activities (modules), each catalyzing a specific round of chain elongation. An adjacent gene encodes a pipecolate-incorporating enzyme, which completes the macrocycle. The total of 70 constituent active sites makes this the most complex multienzyme system identified so far. The DNA region sequenced (107.3 kbp) contains 24 additional open reading frames, some of which code for proteins governing other key steps in rapamycin biosynthesis.

Gene cluster

Polyketide synthase

Streptomyces hygroscopicus

Cloning (programming)

10.1073/pnas.92.17.7839

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Citations (437)

High-Quality Draft Genome Sequence of the Actinobacterium Nocardia terpenica IFM 0406, Producer of the Immunosuppressant Brasilicardins, Using Illumina and PacBio Technologies

Genome Announcements (2016)

Anina Buchmann Michael Eitel Pierre Koch Paul N. Schwarz Evi Stegmann

ABSTRACT The bacterium Nocardia terpenica IFM 0406 is known as the producer of the immunosuppressant brasilicardin A. Here, we report the completely sequenced genome of strain IFM 0406, which facilitates the heterologous expression of the brasilicardin biosynthetic gene cluster but also unveils the intriguing biosynthetic capacity of the strain to produce secondary metabolites.

Strain (injury)

Gene cluster

Heterologous

10.1128/genomea.01391-16

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Citations (16)

Genetic Engineering in Combination with Semi‐Synthesis Leads to a New Route for Gram‐Scale Production of the Immunosuppressive Natural Product Brasilicardin A

Angewandte Chemie (2021)

Alma Botas Michael Eitel Paul N. Schwarz Anina Buchmann Paula Costales

Abstract Brasilicardin A ( 1 ) consists of an unusual anti / syn / anti ‐perhydrophenanthrene skeleton with a carbohydrate side chain and an amino acid moiety. It exhibits potent immunosuppressive activity, yet its mode of action differs from standard drugs that are currently in use. Further pre‐clinical evaluation of this promising, biologically active natural product is hampered by restricted access to the ready material, as its synthesis requires both a low‐yielding fermentation process using a pathogenic organism and an elaborate, multi‐step total synthesis. Our semi‐synthetic approach included a) the heterologous expression of the brasilicardin A gene cluster in different non‐pathogenic bacterial strains producing brasilicardin A aglycone ( 5 ) in excellent yield and b) the chemical transformation of the aglycone 5 into the trifluoroacetic acid salt of brasilicardin A ( 1 a ) via a short and straightforward five‐steps synthetic route. Additionally, we report the first preclinical data for brasilicardin A.

Natural product

Aglycone

Trifluoroacetic acid

Gram

10.1002/ange.202015852

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Citations (1)

Novel octaketide macrolides related to 6-deoxyerythronolide B provide evidence for iterative operation of the erythromycin polyketide synthase

Chemistry & Biology (2000)

Barrie Wilkinson Graham Foster Brian A.M. Rudd NICHOLAS L. TAYLOR Andrew P. Blackaby

Polyketide synthase

10.1016/s1074-5521(00)00076-4

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Citations (80)

A Polylinker Approach to Reductive Loop Swaps in Modular Polyketide Synthases

ChemBioChem (2008)

Laurenz Kellenberger Ian S. Galloway Guido Sauter Günter A. Böhm Ulf Hanefeld

Abstract Multiple versions of the DEBS 1‐TE gene, which encodes a truncated bimodular polyketide synthase (PKS) derived from the erythromycin‐producing PKS, were created by replacing the DNA encoding the ketoreductase (KR) domain in the second extension module by either of two synthetic oligonucleotide linkers. This made available a total of nine unique restriction sites for engineering. The DNA for donor “reductive loops,” which are sets of contiguous domains comprising either KR or KR and dehydratase (DH), or KR, DH and enoylreductase (ER) domains, was cloned from selected modules of five natural PKS multienzymes and spliced into module 2 of DEBS 1‐TE using alternative polylinker sites. The resulting hybrid PKSs were tested for triketide production in vivo. Most of the hybrid multienzymes were active, vindicating the treatment of the reductive loop as a single structural unit, but yields were dependent on the restriction sites used. Further, different donor reductive loops worked optimally with different splice sites. For those reductive loops comprising DH, ER and KR domains, premature TE‐catalysed release of partially reduced intermediates was sometimes seen, which provided further insight into the overall stereochemistry of reduction in those modules. Analysis of loops containing KR only, which should generate stereocentres at both C‐2 and C‐3, revealed that the 3‐hydroxy configuration (but not the 2‐methyl configuration) could be altered by appropriate choice of a donor loop. The successful swapping of reductive loops provides an interesting parallel to a recently suggested pathway for the natural evolution of modular PKSs by recombination.

Multiple cloning site

Polyketide synthase

10.1002/cbic.200800332

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Citations (58)

Cloning and sequence analysis of genes involved in erythromycin biosynthesis in Saccharopolyspora erythraea: sequence similarities between EryG and a family of S-adenosylmethionine-dependent methyltransferases

MGG Molecular & General Genetics (1991)

Stephen Haydock James A. Dowson Namrita Dhillon Gareth A. Roberts Jesús Cortés

Gene cluster

10.1007/bf00290659

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Citations (159)