Understanding thioamitide biosynthesis using pathway engineering and untargeted metabolomics.

Chemical Science
T. H. EylesAndrew W Truman

Abstract

Thiostreptamide S4 is a thioamitide, a family of promising antitumour ribosomally synthesised and post-translationally modified peptides (RiPPs). The thioamitides are one of the most structurally complex RiPP families, yet very few thioamitide biosynthetic steps have been elucidated, even though the biosynthetic gene clusters (BGCs) of multiple thioamitides have been identified. We hypothesised that engineering the thiostreptamide S4 BGC in a heterologous host could provide insights into its biosynthesis when coupled with untargeted metabolomics and targeted mutations of the precursor peptide. Modified BGCs were constructed, and in-depth metabolomics enabled a detailed understanding of the biosynthetic pathway to thiostreptamide S4, including the identification of a protein critical for amino acid dehydration that has homology to HopA1, an effector protein used by a plant pathogen to aid infection. We use this biosynthetic understanding to bioinformatically identify diverse RiPP-like BGCs, paving the way for future RiPP discovery and engineering.

References

Jan 9, 1996·Proceedings of the National Academy of Sciences of the United States of America·V LarionovM A Resnick
Jan 16, 1999·Chemistry & Biology·D M DaigleG D Wright
Feb 4, 2003·Proceedings of the National Academy of Sciences of the United States of America·Bertolt GustKeith F Chater
Jul 24, 2003·Acta Crystallographica. Section D, Biological Crystallography·Michael BlaesseStefan Steinbacher
Mar 30, 2004·Journal of the American Society for Mass Spectrometry·Kelly A Newton, Scott A McLuckey
Jun 3, 2004·Genome Research·Gavin E CrooksSteven E Brenner
Jan 6, 2005·The Journal of Biological Chemistry·Hee-Jeon HongMark J Buttner
Mar 30, 2006·The Journal of Antibiotics·Yoichi HayakawaKazuo Shin-ya
May 19, 2010·Proceedings of the National Academy of Sciences of the United States of America·Bo LiWilfred A van der Donk
Sep 2, 2010·Proceedings of the National Academy of Sciences of the United States of America·Jan Claesen, Mervyn Bibb
Feb 24, 2011·Microbial Biotechnology·Juan Pablo Gomez-Escribano, Mervyn J Bibb
Aug 2, 2011·Chemistry & Biology·Juan E VelásquezWilfred A van der Donk
Jul 12, 2013·BMC Evolutionary Biology·Sébastien HalaryEric Bapteste
May 29, 2014·ACS Chemical Biology·Manuel A OrtegaWilfred A van der Donk
Feb 15, 2015·Journal of Structural Biology·Yangshin ParkSangkee Rhee
Jul 5, 2016·Angewandte Chemie·William J K CroneAndrew W Truman
Jan 31, 2017·Chemical Reviews·Lindsay M RepkaWilfred A van der Donk
Oct 6, 2017·ACS Chemical Biology·Louise KjaerulffRolf Müller
Nov 14, 2017·Journal of the American Chemical Society·Xing ChenE James Petersson
Mar 7, 2018·Proceedings of the National Academy of Sciences of the United States of America·Nilkamal MahantaDouglas A Mitchell
Mar 24, 2018·Science·Grace E KenneyAmy C Rosenzweig
Jun 20, 2018·Nature Chemical Biology·Vincent WiebachRoderich D Süssmuth
Jul 10, 2018·Journal of the American Chemical Society·Christopher J SchwalenDouglas A Mitchell
Jan 11, 2019·Journal of Industrial Microbiology & Biotechnology·Maximilian J HelfJörn Piel
Apr 30, 2019·Nucleic Acids Research·Kai BlinTilmann Weber
Jun 12, 2019·ACS Chemical Biology·Kei KudoHaruo Ikeda
May 15, 2020·Angewandte Chemie·Francisco Javier Ortiz-LópezOlga Genilloud

❮ Previous
Next ❯

Software Mentioned

RiPPER
decRiPPter
antiSMASH

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.