TY - JOUR
T1 - Inhibition of carnitine acetyltransferase by mildronate, a regulator of energy metabolism
AU - Jaudzems, Kristaps
AU - Kuka, Janis
AU - Gutsaits, Aleksandrs
AU - Zinovjevs, Kirils
AU - Kalvinsh, Ivars
AU - Liepinsh, Edgars
AU - Liepinsh, Edvards
AU - Dambrova, Maija
N1 - Funding Information:
Declaration of interest: This study was supported by a grant from the Latvian Science Council (05.1461) and Latvian State Research Program “New medicines and biocorrection tools: design, transport forms and mechanisms of action.”
PY - 2009/12
Y1 - 2009/12
N2 - 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 0.1mM, and the Ki is 1.6mM. The results suggest that the cardioprotective effect of mildronate might be partially mediated by CrAT inhibition and concomitant regulation of cellular energy metabolism pathways.
AB - 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 0.1mM, and the Ki is 1.6mM. The results suggest that the cardioprotective effect of mildronate might be partially mediated by CrAT inhibition and concomitant regulation of cellular energy metabolism pathways.
KW - Acetyl-CoA
KW - Carnitine acetyltransferase
KW - Inhibition
KW - Mildronate
KW - STD NMR
UR - http://www.scopus.com/inward/record.url?scp=73949103710&partnerID=8YFLogxK
U2 - 10.3109/14756360902829527
DO - 10.3109/14756360902829527
M3 - Article
C2 - 19912061
AN - SCOPUS:73949103710
SN - 1475-6366
VL - 24
SP - 1269
EP - 1275
JO - Journal of Enzyme Inhibition and Medicinal Chemistry
JF - Journal of Enzyme Inhibition and Medicinal Chemistry
IS - 6
ER -