Studies on thiamine diphosphate-dependent enzymes.
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.
Leeper
F J
FJ
University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, UK. fjl1@cam.ac.uk
Hawksley
D
D
Mann
S
S
Perez Melero
C
C
Wood
M D H
MD
D011494:Protein Kinases / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D013835:Thiamine Pyrophosphate / Q000031:analogs & derivatives* / Q000378:metabolism*
D011768:Pyruvate Dehydrogenase Complex; D011494:Protein Kinases; C035627:(3-methyl-2-oxobutanoate dehydrogenase (lipoamide)) kinase; D013835:Thiamine Pyrophosphate