title: Studies on thiamine diphosphate-dependent enzymes.
abstract: The 3-deaza analogue of TPP (thiamine diphosphate), a close mimic of the ylid intermediate, has been synthesized and is an extremely potent inhibitor of a variety of TPP-dependent enzymes, binding much more tightly than TPP itself. Results using deazaTPP complexed with the E1 subunit of PDH (pyruvate dehydrogenase) have led to a novel proposal about the mechanism of this enzyme. The 2-substituted forms of deazaTPP, which mimic other intermediates in the catalytic mechanism, can also be synthesized and 2-(1-hydroxyethyl)deazaTPP is also an extremely potent inhibitor of PDC (pyruvate decarboxylase). Attachment of such 2-substituents is expected to be a way to introduce selectivity in the inhibition of various TPP-dependent enzymes.
authors.affiliation: University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, UK. fjl1@cam.ac.uk
authors.forename: F J
authors.initials: FJ
authors.lastname: Leeper
authors.forename: D
authors.initials: D
authors.lastname: Hawksley
authors.forename: S
authors.initials: S
authors.lastname: Mann
authors.forename: C
authors.initials: C
authors.lastname: Perez Melero
authors.forename: M D H
authors.initials: MD
authors.lastname: Wood
mesh_terms: D011494:Protein Kinases / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D013835:Thiamine Pyrophosphate / Q000031:analogs & derivatives* / Q000378:metabolism*
chemical_list: D011768:Pyruvate Dehydrogenase Complex; D011494:Protein Kinases; C035627:(3-methyl-2-oxobutanoate dehydrogenase (lipoamide)) kinase; D013835:Thiamine Pyrophosphate