Leeper Group



Issue cover 106
S. Mann, C. Perez Melero, D. Hawksley and F. J. Leeper
"Inhibition of thiamin diphosphate dependent enzymes by 3-deazathiamin diphosphate."
Org. Biomolec. Chem.,, 2004, 2 (12), 1732-1741. Full Text

3-Deazathiamin diphosphate (deazaTPP) and a second thiamin diphosphate (TPP) analogue having a benzene ring in place of the thiazolium ring have been synthesised. These compounds are both extremely potent inhibitors of pyruvate decarboxylase from Zymomonas mobilis; binding is competitive with TPP and is essentially irreversible even though no covalent linkage is formed. DeazaTPP binds approximately seven-fold faster than TPP and at least 25,000-fold more tightly (Ki less than 14 pM). DeazaTPP is also a potent inhibitor of the E1 subunit of 2-ketoglutarate dehydrogenase from E. coli and binds more than 70-fold faster than TPP. In this case slow reversal of the inhibition could be observed and a Ki value of about 5 nM was calculated (ca. 500-fold tighter binding than TPP).

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Department of Chemistry
University of Cambridge