Epoxomicin and Eponemycin Biosynthesis Involves gem-Dimethylation and an Acyl-CoA Dehydrogenase-Like Enzyme

Chembiochem : a European Journal of Chemical Biology
Judith ZettlerLeonard Kaysser

Abstract

The α',β'-epoxyketone moiety of proteasome inhibitors confers high binding specificity to the N-terminal threonine in catalytic proteasome β-subunits. We recently identified the epoxomicin and eponemycin biosynthetic gene clusters and have now conducted isotope-enriched precursor feeding studies and comprehensive gene deletion experiments to shed further light on their biosynthetic pathways. Leucine and two methyl groups from S-adenosylmethionine were readily incorporated into the epoxyketone warhead, suggesting decarboxylation of the thioester intermediate. Formation of the α',β'-epoxyketone is likely mediated by conserved acyl-CoA dehydrogenase-like enzymes, as indicated by complete loss of epoxomicin and eponemycin production in the respective knockout mutants. Our results clarify crucial questions in the formation of epoxyketone compounds and lay the foundation for in vitro biochemical studies on the biosynthesis of this pharmaceutically important class of proteasome inhibitors.

References

Nov 1, 1992·The Journal of Antibiotics·M HanadaT Oki
Dec 25, 1974·Journal of the American Chemical Society·A I ScottP J Whitman
Feb 4, 2003·Proceedings of the National Academy of Sciences of the United States of America·Bertolt GustKeith F Chater
Jan 20, 2004·European Journal of Biochemistry·Sandro Ghisla, Colin Thorpe
Aug 25, 2004·Organic & Biomolecular Chemistry·Kerstin HeroldChristian Hertweck
Aug 11, 2007·Angewandte Chemie·Angéla SchenkChristian Hertweck
Oct 5, 2007·Journal of the American Chemical Society·Keishi IshidaChristian Hertweck
Apr 17, 2012·Natural Product Reports·Malte GerschStephan A Sieber
Jul 13, 2012·Journal of the American Chemical Society·Leonard KaysserBradley S Moore
Dec 24, 2013·Archives of Biochemistry and Biophysics·Mieke M E HuijbersWillem J H van Berkel
Apr 2, 2015·Proceedings of the National Academy of Sciences of the United States of America·Jeremy G OwenSean F Brady
Oct 21, 2015·Chembiochem : a European Journal of Chemical Biology·Joyce LiuWenjun Zhang

❮ Previous
Next ❯

Citations

Mar 22, 2016·Journal of the American Chemical Society·Daniel ZabalaGregory L Challis
Jun 18, 2017·Archives of Biochemistry and Biophysics·Robin Teufel
Dec 8, 2017·Nature Communications·Franziska LeipoldtLeonard Kaysser
Mar 31, 2018·Chembiochem : a European Journal of Chemical Biology·Felix WolfLeonard Kaysser
Apr 30, 2017·Angewandte Chemie·Felix WolfLeonard Kaysser

❮ Previous
Next ❯

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.