Matches in SemOpenAlex for { <https://semopenalex.org/work/W3080454854> ?p ?o ?g. }
- W3080454854 endingPage "1245" @default.
- W3080454854 startingPage "1237" @default.
- W3080454854 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. Structural and biochemical analysis of E. coli transketolase with 2′-methoxy-thiamine shows that this antivitamin selectively inhibits the bacterial enzyme via a steric clash with a critical glutamate residue, preventing cofactor activation." @default.
- W3080454854 created "2020-09-01" @default.
- W3080454854 creator A5006762102 @default.
- W3080454854 creator A5021967400 @default.
- W3080454854 creator A5044839728 @default.
- W3080454854 creator A5056535696 @default.
- W3080454854 creator A5056823974 @default.
- W3080454854 creator A5064237607 @default.
- W3080454854 date "2020-08-24" @default.
- W3080454854 modified "2023-09-27" @default.
- W3080454854 title "Structural basis for antibiotic action of the B1 antivitamin 2′-methoxy-thiamine" @default.
- W3080454854 cites W1031578623 @default.
- W3080454854 cites W1970690135 @default.
- W3080454854 cites W1972992743 @default.
- W3080454854 cites W1973836176 @default.
- W3080454854 cites W1976499671 @default.
- W3080454854 cites W1979155909 @default.
- W3080454854 cites W1987083186 @default.
- W3080454854 cites W1996448836 @default.
- W3080454854 cites W1997268606 @default.
- W3080454854 cites W1999608828 @default.
- W3080454854 cites W2000024111 @default.
- W3080454854 cites W2017052832 @default.
- W3080454854 cites W2018779619 @default.
- W3080454854 cites W2023454927 @default.
- W3080454854 cites W2025636837 @default.
- W3080454854 cites W2027173246 @default.
- W3080454854 cites W202818787 @default.
- W3080454854 cites W2032696229 @default.
- W3080454854 cites W2034371095 @default.
- W3080454854 cites W2035266068 @default.
- W3080454854 cites W2037789407 @default.
- W3080454854 cites W2038408520 @default.
- W3080454854 cites W2040008731 @default.
- W3080454854 cites W2045683699 @default.
- W3080454854 cites W2049884529 @default.
- W3080454854 cites W2058817784 @default.
- W3080454854 cites W2065247258 @default.
- W3080454854 cites W2065781312 @default.
- W3080454854 cites W2069310822 @default.
- W3080454854 cites W2071613506 @default.
- W3080454854 cites W2072484658 @default.
- W3080454854 cites W2077970385 @default.
- W3080454854 cites W2081350198 @default.
- W3080454854 cites W2081693079 @default.
- W3080454854 cites W2084953881 @default.
- W3080454854 cites W2092963470 @default.
- W3080454854 cites W2097245475 @default.
- W3080454854 cites W2125084048 @default.
- W3080454854 cites W2128912763 @default.
- W3080454854 cites W2132911648 @default.
- W3080454854 cites W2139447954 @default.
- W3080454854 cites W2144288821 @default.
- W3080454854 cites W2147993766 @default.
- W3080454854 cites W2154714625 @default.
- W3080454854 cites W2165565773 @default.
- W3080454854 cites W2180229411 @default.
- W3080454854 cites W2271347306 @default.
- W3080454854 cites W2296686360 @default.
- W3080454854 cites W2330799739 @default.
- W3080454854 cites W2331053199 @default.
- W3080454854 cites W2335008302 @default.
- W3080454854 cites W2601824148 @default.
- W3080454854 cites W2903836900 @default.
- W3080454854 cites W2972356650 @default.
- W3080454854 cites W2973922700 @default.
- W3080454854 cites W3176495066 @default.
- W3080454854 cites W4233025621 @default.
- W3080454854 cites W4248872320 @default.
- W3080454854 doi "https://doi.org/10.1038/s41589-020-0628-4" @default.
- W3080454854 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/32839604" @default.
- W3080454854 hasPublicationYear "2020" @default.
- W3080454854 type Work @default.
- W3080454854 sameAs 3080454854 @default.
- W3080454854 citedByCount "11" @default.
- W3080454854 countsByYear W30804548542020 @default.
- W3080454854 countsByYear W30804548542021 @default.
- W3080454854 countsByYear W30804548542022 @default.
- W3080454854 countsByYear W30804548542023 @default.
- W3080454854 crossrefType "journal-article" @default.
- W3080454854 hasAuthorship W3080454854A5006762102 @default.
- W3080454854 hasAuthorship W3080454854A5021967400 @default.
- W3080454854 hasAuthorship W3080454854A5044839728 @default.
- W3080454854 hasAuthorship W3080454854A5056535696 @default.
- W3080454854 hasAuthorship W3080454854A5056823974 @default.
- W3080454854 hasAuthorship W3080454854A5064237607 @default.
- W3080454854 hasBestOaLocation W30804548542 @default.
- W3080454854 hasConcept C103432212 @default.
- W3080454854 hasConcept C181199279 @default.
- W3080454854 hasConcept C185592680 @default.
- W3080454854 hasConcept C197957613 @default.
- W3080454854 hasConcept C2776203871 @default.
- W3080454854 hasConcept C41183919 @default.
- W3080454854 hasConcept C55493867 @default.
- W3080454854 hasConcept C71240020 @default.
- W3080454854 hasConceptScore W3080454854C103432212 @default.
- W3080454854 hasConceptScore W3080454854C181199279 @default.
- W3080454854 hasConceptScore W3080454854C185592680 @default.