Active-site probes of carnitine acyltransferases. Inhibition of carnitine acetyltransferase by hemiacetylcarnitinium, a reaction intermediate analogue |
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Authors: | R D Gandour W J Colucci T C Stelly P S Brady L J Brady |
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Affiliation: | 1. Department of Biochemistry, Memorial University of Newfoundland, St. John''s, NL, Canada A1B 3X9;2. Department of Laboratory Medicine, Faculty of Medicine, Memorial University of Newfoundland, St. John''s, NL, Canada A1B 3V6;3. Diabetes & Nutritional Sciences Division, King''s College, London, United Kingdom SE1 9NH |
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Abstract: | Hemiacetylcarnitinium (2S,6R:2R,65)-6-carboxymethyl-2-hydroxy-2,4,4- trimethylmorpholinium) chloride is a relatively potent competitive inhibitor (Ki = 0.89 mM) of pigeon breast carnitine acetyltransferase (CAT) and of the crude rat liver CAT (Ki = 4.72 mM) but is neither an inhibitor nor an effective substrate for purified rat liver carnitine palmitoyltransferase (CPT). It does not inhibit state 3 oxygen consumption in isolated hepatic mitochondria using palmitoyl-CoA or palmitoylcarnitine as substrates. This compound is a reaction intermediate analogue of the proposed tetrahedral intermediate for acetyl transfer between acetylcarnitine and CoASH. Because the hemiketal carbon is chiral, a suggestion is made that one of the enantiomers has the same relative configuration as the proposed tetrahedral intermediate. |
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