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Issue 12, 2004
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Inhibition of thiamin diphosphate dependent enzymes by 3-deazathiamin diphosphate

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Abstract

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 α-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).

Graphical abstract: Inhibition of thiamin diphosphate dependent enzymes by 3-deazathiamin diphosphate

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Publication details

The article was received on 17 Mar 2004, accepted on 22 Apr 2004 and first published on 25 May 2004


Article type: Paper
DOI: 10.1039/B403619K
Citation: Org. Biomol. Chem., 2004,2, 1732-1741
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    Inhibition of thiamin diphosphate dependent enzymes by 3-deazathiamin diphosphate

    S. Mann, C. Perez Melero, D. Hawksley and F. J. Leeper, Org. Biomol. Chem., 2004, 2, 1732
    DOI: 10.1039/B403619K

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