8R1R

Structure of the Diels Alderase TedJ, in complex with cofactor FAD

Summary for 8R1R

• Entry DOI: 10.2210/pdb8r1r/pdb
• Descriptor: Short-chain dehydrogenase/reductase, FLAVIN-ADENINE DINUCLEOTIDE (3 entities in total)
• Functional Keywords: diels alderase, decalin cyclase, tetradecamycin, class ii spirotetronate, oxidoreductase
• Biological source: Streptomyces
• Total number of polymer chains: 1
• Total formula weight: 53798.18

Authors

Back, C.R.,Race, P.R. (deposition date: 2023-11-02, release date: 2024-11-13, Last modification date: 2026-06-17)

Primary citation

Russell, S.J.,Back, C.R.,Perry, C.,Cheung, K.A.,Maschio, L.,Charlton, S.N.,Lees, N.R.,Manzo-Ruiz, M.,Hayes, M.A.,van der Kamp, M.W.,Race, P.R.,Willis, C.L.
Chemoenzymatic total synthesis of the antibiotic (-)-13-deoxytetrodecamycin using the Diels-Alderase TedJ.
Chem Sci, 16:16993-16999, 2025

PubMed Abstract: The tetrodecamycins are tetracyclic natural products that exhibit potent antimicrobial activity against a multitude of drug-resistant pathogens. These compounds are structurally distinguished by the presence of a tetronate ring and -decalin with six contiguous asymmetric centres united by a seven-membered oxygen heterocycle. Herein we describe the first total synthesis of the antibiotic (-)-13-deoxytetrodecamycin. Our strategy is predicated on an enantioselective [4 + 2]-cycloaddition catalysed by the FAD-dependent Diels-Alderase TedJ, forming the -decalin with concomitant creation of two rings and four contiguous stereocenters with exquisite selectivity under mild conditions. In complementary studies, enzyme assays, X-ray crystallography and computational modelling are used to provide molecular insights into the TedJ catalysed reaction. These studies illustrate the power of adopting a chemoenzymatic approach for the enantioselective synthesis of a target compound which would be difficult to achieve using non-biological methods and provide a practical demonstration of the use of Diels-Alder biocatalysts in total synthesis. This approach has potentially widespread value in the global challenge of discovery and development of new antibiotics.

PubMed: 40880792
DOI: 10.1039/d5sc05480j

Experimental method

X-RAY DIFFRACTION (1.59 Å)