The 3-deaza analogue of thiamine diphosphate (TPP), a close mimic of the ylid intermediate, has been synthesised and is an extremely potent inhibitor of a variety of TPP-dependent enzymes, binding much more tightly than TPP itself. Results using deazaTPP complexed to the E1 subunit of pyruvate dehydrogenase have led to a novel proposal about the mechanism of this enzyme. 2-Substituted forms of deazaTPP, which mimic other intermediates in the catalytic mechanism, can also be synthesised and 2-(1-hydroxyethyl)deazaTPP is also an extremely potent inhibitor of pyruvate decarboxylase. Attachment of such 2-substituents is expected to be a way to introduce selectivity in the inhibition of the various different TPP-dependent enzymes.
Department of Chemistry
University of Cambridge