Beta-oxidation of 5-hydroxydecanoate, a putative blocker of mitochondrial ATP-sensitive potassium channels.
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 microM and a kcat of 14.1 s-1. For comparison, with decanoyl-CoA (Km approximately 3 microM) as 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.
Hanley
Peter J
PJ
Institut für Normale und Pathologische Physiologie, Universität Marburg, Deutschhausstrasse 2, 35037 Marburg, Germany.
Gopalan
K V
KV
Lareau
Rachel A
RA
Srivastava
D K
DK
von Meltzer
Martin
M
Daut
Jürgen
J
D000214:Acyl Coenzyme A / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D042964:Acyl-CoA Dehydrogenase; D044944:Acyl-CoA Dehydrogenases / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D003652:Decanoic Acids / Q000378:metabolism* / Q000494:pharmacology; D004347:Drug Interactions; D004746:Enoyl-CoA Hydratase / Q000378:metabolism; D006801:Humans; D006880:Hydroxy Acids / Q000378:metabolism* / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D008958:Models, Molecular; D010084:Oxidation-Reduction; D026902:Potassium Channel Blockers / Q000378:metabolism* / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D013379:Substrate Specificity; D013552:Swine
C471070:5-hydroxydecanoyl-coenzyme A; D000214:Acyl Coenzyme A; D003652:Decanoic Acids; D006880:Hydroxy Acids; D026902:Potassium Channel Blockers; D015221:Potassium Channels; C052853:5-hydroxydecanoic acid; D000255:Adenosine Triphosphate; D044944:Acyl-CoA Dehydrogenases; D042964:Acyl-CoA Dehydrogenase; D004746:Enoyl-CoA Hydratase