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News & Views |
Discovering cryptic natural products by substrate manipulation
Cryptic halogenation reactions result in natural products with diverse structural motifs and bioactivities. However, these halogenated species are difficult to detect with current analytical methods because the final products are often not halogenated. An approach to identify products of cryptic halogenation using halide depletion has now been discovered, opening up space for more effective natural product discovery.
- Ludek Sehnal
- , Libera Lo Presti
- & Nadine Ziemert
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Chemoenzymatic synthesis of fluorinated polyketides
The introduction of fluorine into a drug molecule can alter the biological responses to it, including modulating bioavailability, pharmacokinetics and selectivity. Now, a hybrid polyketide/fatty acid synthase multienzyme has been designed to incorporate fluorinated precursors during polyketide biosynthesis in an approach that provides new chemoenzymatic access to fluorinated natural compounds.
- Alexander Rittner
- , Mirko Joppe
- & Martin Grininger
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Unnatural biosynthesis by an engineered microorganism with heterologously expressed natural enzymes and an artificial metalloenzyme
Natural products are produced by living organisms practising nature’s chemical transformations. Now, an unnatural product has been generated by creating hybrid biosynthetic microorganisms. These microorganisms combine an unnatural chemical transformation—catalysis by an artificial metalloenzyme containing an iridium-based, unnatural cofactor—with a natural biosynthetic pathway within the same cell.
- Jing Huang
- , Zhennan Liu
- & John F. Hartwig
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A dual transacylation mechanism for polyketide synthase chain release in enacyloxin antibiotic biosynthesis
Enacyloxin IIa is an antibiotic, assembled by a modular polyketide synthase, with promising activity against the Gram-negative bacterium Acinetobacter baumannii. Now, it has been shown that the enacyloxin IIa polyketide chain is released via transfer to a separately encoded carrier protein by a non-elongating ketosynthase domain, followed by condensation with 3,4-dihydroxycyclohexane carboxylic acid by a non-ribosomal peptide synthetase condensation domain.
- Joleen Masschelein
- , Paulina K. Sydor
- & Gregory L. Challis
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Modification and de novo design of non-ribosomal peptide synthetases using specific assembly points within condensation domains
Non-ribosomal peptide synthetases have now been modified and de novo non-ribosomal peptide synthetases constructed using new assembly points within condensation domains. This approach enabled the production of new-to-nature peptides, including some carrying synthetic amino acids, as well as the generation of peptide libraries.
- Kenan A. J. Bozhüyük
- , Annabell Linck
- & Helge B. Bode
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Nonribosomal biosynthesis of backbone-modified peptides
Nonribosomal peptide synthetases (NRPSs) produce vital natural products but have proven recalcitrant to biosynthetic engineering. Now, a combination of yeast surface display and fluorescence-activated cell sorting (FACS) has been used to reprogram an L-Phe-incorporating module for β-Phe. The resulting module is highly selective and functions efficiently in NRPS pathways.
- David L. Niquille
- , Douglas A. Hansen
- & Donald Hilvert