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  Structural basis for antibiotic action of the B1 antivitamin 2′-methoxy-thiamine

Rabe von Pappenheim, F., Aldeghi, M., Shome, B., Begley, T., de Groot, B. L., & Tittmann, K. (2020). Structural basis for antibiotic action of the B1 antivitamin 2′-methoxy-thiamine. Nature Chemical Biology, 16(11), 1237-1245. doi:10.1038/s41589-020-0628-4.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0007-152D-0 Version Permalink: http://hdl.handle.net/21.11116/0000-0007-706C-2
Genre: Journal Article

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 Creators:
Rabe von Pappenheim, F.1, Author              
Aldeghi, M.2, Author              
Shome, B., Author
Begley, T., Author
de Groot, B. L.2, Author              
Tittmann, K.1, Author              
Affiliations:
1Department of Structural Dynamics, MPI for Biophysical Chemistry, Max Planck Society, ou_2205645              
2Research Group of Computational Biomolecular Dynamics, MPI for biophysical chemistry, Max Planck Society, ou_578573              

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Free keywords: Enzyme mechanisms; Enzymes; Microbiology; Natural products; X-ray crystallography
 Abstract: The natural antivitamin 2′-methoxy-thiamine (MTh) is implicated in the suppression of microbial growth. However, its mode of action and enzyme-selective inhibition mechanism have remained elusive. Intriguingly, MTh inhibits some thiamine diphosphate (ThDP) enzymes, while being coenzymatically active in others. Here we report the strong inhibition of Escherichia coli transketolase activity by MTh and unravel its mode of action and the structural basis thereof. The unique 2′-methoxy group of MTh diphosphate (MThDP) clashes with a canonical glutamate required for cofactor activation in ThDP-dependent enzymes. This glutamate is forced into a stable, anticatalytic low-barrier hydrogen bond with a neighboring glutamate, disrupting cofactor activation. Molecular dynamics simulations of transketolases and other ThDP enzymes identify active-site flexibility and the topology of the cofactor-binding locale as key determinants for enzyme-selective inhibition. Human enzymes either retain enzymatic activity with MThDP or preferentially bind authentic ThDP over MThDP, while core bacterial metabolic enzymes are inhibited, demonstrating therapeutic potential.

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Language(s): eng - English
 Dates: 2020-08-242020-11
 Publication Status: Published in print
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 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s41589-020-0628-4
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Title: Nature Chemical Biology
Source Genre: Journal
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Pages: - Volume / Issue: 16 (11) Sequence Number: - Start / End Page: 1237-1245 Identifier: -