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First published online on January 31, 2003.
 Copyright © 2003 by The Physiological Society
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Received December 4, 2002
Accepted after revision January 27, 2003

{beta}-Oxidation of 5-hydroxydecanoate, a putative blocker of mitochondrial ATP-sensitive potassium channels

Peter J. Hanley1, K.V. Gopalan2, Rachel A. Lareau2, D.K. Srivastava2, Martin von Meltzer3, and J. Daut1*

1 Institut für Normale und Pathologische Physiologie, Universität Marburg, Deutschhausstrasse 2, 35037 Marburg, Germany
2 Department of Biochemistry and Molecular Biology, North Dakota State University, Fargo, ND 58105, USA
3 Fachbereich Chemie, Universität Marburg, Hans-Meerwein-Strasse, 35032 Marburg, Germany

* To whom correspondence should be addressed. E-mail: daut{at}mailer.uni-marburg.de.

5-Hydroxydecanoate (5-HD) inhibits ischaemic and pharmacological preconditioning of the heart. Since 5-HD is thought to inhibit specifically the putative mitochondrial ATP-sensitive K+ (KATP) channel, this channel has been inferred to be a mediator of preconditioning. However, it has recently been shown that 5-HD is a substrate for acyl-CoA synthetase, the mitochondrial enzyme which 'activates' fatty acids. Here, we tested whether activated 5-HD, 5-hydroxydecanoyl-CoA (5-HD-CoA), is a substrate for medium-chain acyl-CoA dehydrogenase (MCAD), the committed step of the mitochondrial {beta}-oxidation pathway. Using a molecular model, we predicted that the hydroxyl group on the acyl tail of 5-HD-CoA would not sterically hinder the active site of MCAD. Indeed, we found that 5-HD-CoA was a substrate for purified human liver MCAD with a Km of 12.8 ± 0.6 µM and a kcat of 14.1 s-1. For comparison, with decanoyl-CoA (Km ~3 µM) as a substrate, kcat was 6.4 s-1. 5-HD-CoA was also a substrate for purified pig kidney MCAD. We next tested whether the reaction product, 5-hydroxydecenoyl-CoA (5-HD-enoyl-CoA), was a substrate for enoyl-CoA hydratase, the second enzyme of the {beta}-oxidation pathway. Similar to decenoyl-CoA, purified 5-HD-enoyl-CoA was also a substrate for the hydratase reaction. In conclusion, we have shown that 5-HD is metabolised at least as far as the third enzyme of the {beta}-oxidation pathway. Our results open the possibility that {beta}-oxidation of 5-HD or metabolic intermediates of 5-HD may be responsible for the inhibitory effects of 5-HD on preconditioning of the heart.




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