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Publikācija: Inhibition of Carnitine Acetyltransferase by Mildronate

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Nosaukums oriģinālvalodā Inhibition of Carnitine Acetyltransferase by Mildronate, a Regulator of Energy Metabolism
Pētniecības nozare 1. Dabaszinātnes
Pētniecības apakšnozare 1.4. Ķīmija
Autori Kristaps Jaudzems
J. Kuka
A. Gutsaits
K. Zinovjevs
I. Kalviņš
Edvards Liepiņš
M. Dambrova
Atslēgas vārdi Carnitine acetyltransferase, acetyl-CoA, mildronate, STD NMR, inhibition
Anotācija Carnitine acetyltransferase (CrAT; EC 2.3.1.7) catalyzes the reversible transfer of acetyl groups between acetyl-coenzyme A (acetyl-CoA) and L-carnitine; it also regulates the cellular pool of CoA and the availability of activated acetyl groups. In this study, biochemical measurements, saturation transfer difference (STD) nuclear magnetic resonance (NMR) spectroscopy, and molecular docking were applied to give insights into the CrAT binding of a synthetic inhibitor, the cardioprotective drug mildronate (3-(2,2,2-trimethylhydrazinium)-propionate). The obtained results show that mildronate inhibits CrAT in a competitive manner through binding to the carnitine binding site, not the acetyl-CoA binding site. The bound conformation of mildronate closely resembles that of carnitine except for the orientation of the trimethylammonium group, which in the mildronate molecule is exposed to the solvent. The dissociation constant of the mildronate CrAT complex is approximately 0.1 mM, and the K(i) is 1.6 mM. The results suggest that the cardioprotective effect of mildronate might be partially mediated by CrAT inhibition and concomitant regulation of cellular energy metabolism pathways.
DOI: 10.3109/14756360902829527
Hipersaite: http://informahealthcare.com/doi/abs/10.3109/14756360902829527 
Atsauce Jaudzems, K., Kuka, J., Gutsaits, A., Zinovjevs, K., Kalviņš, I., Liepiņš, E., Dambrova, M. Inhibition of Carnitine Acetyltransferase by Mildronate, a Regulator of Energy Metabolism. Journal of Enzyme Inhibition and Medicinal Chemistry, 2009, Vol.24, No.6, 1269.-1275.lpp. ISSN 1475-6366. e-ISSN 1475-6374. Pieejams: doi:10.3109/14756360902829527
ID 7165