Binding of thyroxine analogs to human liver aldehyde dehydrogenases.
A fragment of a cytosolic thyroid-hormone-binding protein from Xenopus liver was reported to be 92-100% identical to residues 236-258 in several cytosolic aldehyde dehydrogenases [Yamauchi, K. & Tata, J. R. (1994) Eur. J. Biochem. 225, 1105-1112], which have been proposed to form part of the hinge region necessary to bind the adenosine moiety of NAD. Here we investigated the effects of two thyroxine analogs, 3,3',5-triiodo-L-thyronine and 3,3',5-triiodothyroacetic acid, on purified human liver mitochondrial and cytosolic aldehyde dehydrogenases. The compounds were found to be competitive inhibitors against NAD and uncompetitive inhibitors with respect to aldehyde. At pH 7.4, the apparent Ki values were in the micromolar range when the concentration of NAD was varied. The inhibition against recombinantly expressed mutant forms of aldehyde dehydrogenase, which possessed diminished NAD binding, was determined. Essentially no differences were found between the native enzyme and the mutants, showing that the analog binding was not affected by altering the NAD-binding site. Furthermore, the analogs could displace NAD but not NADH from the enzyme. These findings indicated that the binding of NAD differed from that of NADH, and that aldehyde dehydrogenases, like other dehydrogenases, can be inhibited by thyroxine analogs.
Zhou
J
J
Department of Biochemistry, Purdue University, West Lafayette, USA.
Weiner
H
H
D000098:Acetophenones / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D001667:Binding, Competitive; D002846:Chromatography, Affinity; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D009243:NAD; D013050:Spectrometry, Fluorescence; D013974:Thyroxine / Q000031:analogs & derivatives* / Q000378:metabolism; D014284:Triiodothyronine / Q000031:analogs & derivatives / Q000378:metabolism
D000098:Acetophenones; D014284:Triiodothyronine; D009243:NAD; C010642:3,3',5-triiodothyroacetic acid; D000249:Adenosine Monophosphate; D000444:Aldehyde Dehydrogenase; C031335:4-hydroxyacetophenone; D013974:Thyroxine