Inhibition of thiamin diphosphate dependent enzymes by 3-deazathiamin diphosphate.
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 (K(i) less than 14 pM). DeazaTPP is also a potent inhibitor of the E1 subunit of alpha-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 K(i) value of about 5 nM was calculated (ca. 500-fold tighter binding than TPP).
Mann
Stéphane
S
University Chemical Laboratory, Lensfield Road, Cambridge, UKCB2 1EW.
Perez Melero
Concepcion
C
Hawksley
Dan
D
Leeper
Finian J
FJ
D001555:Benzene Derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology; D007655:Ketoglutarate Dehydrogenase Complex / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007700:Kinetics; D008958:Models, Molecular; D011767:Pyruvate Decarboxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013835:Thiamine Pyrophosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D017355:Zymomonas / Q000201:enzymology
D001555:Benzene Derivatives; D004791:Enzyme Inhibitors; D007655:Ketoglutarate Dehydrogenase Complex; D011767:Pyruvate Decarboxylase; D013835:Thiamine Pyrophosphate