Genome mining- and synthetic biology-enabled production of hypermodified peptides

被引：54

作者：

Bhushan, Agneya ^{[1
]}

Egli, Peter J. ^{[2
]}

Peters, Eike E. ^{[1
]}

Freeman, Michael F. ^{[3
,4
]}

Piel, Joern ^{[1
]}

机构：

[1] Swiss Fed Inst Technol, Inst Microbiol, Zurich, Switzerland

[2] Kantonsschule Obwalden, Sarnen, Switzerland

[3] Univ Minnesota Twin Cities, Dept Biochem Mol Biol, St Paul, MN USA

[4] Univ Minnesota Twin Cities, Biophys & BioTechnol Inst, St Paul, MN USA

来源：

NATURE CHEMISTRY | 2019年 / 11卷 / 10期

基金：

瑞士国家科学基金会;

关键词：

SECONDARY METABOLISM; POLYTHEONAMIDE B; BIOSYNTHESIS; DISCOVERY; METHYLATIONS; EXPRESSION; DIVERSITY; INSIGHTS;

D O I：

10.1038/s41557-019-0323-9

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

The polytheonamides are among the most complex and biosynthetically distinctive natural products known to date. These potent peptide cytotoxins are derived from a ribosomal precursor processed by 49 mostly non-canonical posttranslational modifications. As the producer is a 'microbial dark matter' bacterium only distantly related to any cultivated organism, >70-step chemical syntheses have been developed to access these unique compounds. Here, we mined prokaryotic diversity to establish a synthetic platform based on the new host Microvirgula aerodenitrificans that produces hypermodified peptides within two days. Using this system, we generated the aeronamides, new polytheonamide-type compounds with near-picomolar cytotoxicity. Aeronamides, as well as the polygeonamides produced from deep-rock biosphere DNA, contain the highest numbers of D-amino acids in known biomolecules. With increasing bacterial genomes being sequenced, similar host mining strategies might become feasible to access further elusive natural products from uncultivated life.

引用

页码：931 / 939

页数：9

共 56 条

[1]

[Anonymous], MSYSTEMS

[2] Ribosomally synthesized and post-translationally modified peptide natural products: overview and recommendations for a universal nomenclature [J].

Arnison, Paul G. ;

Bibb, Mervyn J. ;

Bierbaum, Gabriele ;

Bowers, Albert A. ;

Bugni, Tim S. ;

Bulaj, Grzegorz ;

Camarero, Julio A. ;

Campopiano, Dominic J. ;

Challis, Gregory L. ;

Clardy, Jon ;

Cotter, Paul D. ;

Craik, David J. ;

Dawson, Michael ;

Dittmann, Elke ;

Donadio, Stefano ;

Dorrestein, Pieter C. ;

Entian, Karl-Dieter ;

Fischbach, Michael A. ;

Garavelli, John S. ;

Goeransson, Ulf ;

Gruber, Christian W. ;

Haft, Daniel H. ;

Hemscheidt, Thomas K. ;

Hertweck, Christian ;

Hill, Colin ;

Horswill, Alexander R. ;

Jaspars, Marcel ;

Kelly, Wendy L. ;

Klinman, Judith P. ;

Kuipers, Oscar P. ;

Link, A. James ;

Liu, Wen ;

Marahiel, Mohamed A. ;

Mitchell, Douglas A. ;

Moll, Gert N. ;

Moore, Bradley S. ;

Mueller, Rolf ;

Nair, Satish K. ;

Nes, Ingolf F. ;

Norris, Gillian E. ;

Olivera, Baldomero M. ;

Onaka, Hiroyasu ;

Patchett, Mark L. ;

Piel, Joern ;

Reaney, Martin J. T. ;

Rebuffat, Sylvie ;

Ross, R. Paul ;

Sahl, Hans-Georg ;

Schmidt, Eric W. ;

Selsted, Michael E. .

NATURAL PRODUCT REPORTS, 2013, 30 (01) :108-160

[3] Reconstructing a hydrogen-driven microbial metabolic network in Opalinus Clay rock [J].

Bagnoud, Alexandre ;

Chourey, Karuna ;

Hettich, Robert L. ;

de Bruijn, Ino ;

Andersson, Anders F. ;

Leupin, Olivier X. ;

Schwyn, Bernhard ;

Bernier-Latmani, Rizlan .

NATURE COMMUNICATIONS, 2016, 7

[4] The biomass distribution on Earth [J].

Bar-On, Yinon M. ;

Phillips, Rob ;

Milo, Ron .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2018, 115 (25) :6506-6511

[5] Mechanistic Diversity of Radical S-Adenosylmethionine (SAM)-dependent Methylation [J].

Bauerle, Matthew R. ;

Schwalm, Erica L. ;

Booker, Squire J. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2015, 290 (07) :3995-4002

[6]

Bewley CA, 1998, ANGEW CHEM INT EDIT, V37, P2163, DOI 10.1002/(SICI)1521-3773(19980904)37:16<2162::AID-ANIE2162>3.0.CO

[7]

2-2

[8] Self-cleaving proteases [J].

Blair, Wade S. ;

Semler, Bert L. .

CURRENT OPINION IN CELL BIOLOGY, 1991, 3 (06) :1039-1045

[9] Eukaryotic opportunists dominate the deep-subsurface biosphere in South Africa [J].

Borgonie, G. ;

Linage-Alvarez, B. ;

Ojo, A. O. ;

Mundle, S. O. C. ;

Freese, L. B. ;

Van Rooyen, C. ;

Kuloyo, O. ;

Albertyn, J. ;

Pohl, C. ;

Cason, E. D. ;

Vermeulen, J. ;

Pienaar, C. ;

Litthauer, D. ;

Van Niekerk, H. ;

Van Eeden, J. ;

Lollar, B. Sherwood ;

Onstott, T. C. ;

Van Heerden, E. .

NATURE COMMUNICATIONS, 2015, 6

[10] Marine natural products [J].

Carroll, Anthony R. ;

Copp, Brent R. ;

Davis, Rohan A. ;

Keyzers, Robert A. ;

Prinsep, Michele R. .

NATURAL PRODUCT REPORTS, 2019, 36 (01) :122-173

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