Identification of the peroxisomal beta-oxidation enzymes involved in the biosynthesis of docosahexaenoic acid.
DHA (C22:6n-3) is an important PUFA implicated in a number of (patho)physiological processes. For a long time, the exact mechanism of DHA formation has remained unclear, but now it is known that it involves the production of tetracosahexaenoic acid (C24:6n-3) from dietary linolenic acid (C18:3n-3) via a series of elongation and desaturation reactions, followed by beta-oxidation of C24:6n-3 to C22:6n-3. Although DHA is deficient in patients lacking peroxisomes, the intracellular site of retroconversion of C24:6n-3 has remained controversial. By making use of fibroblasts from patients with defined mitochondrial and peroxisomal fatty acid oxidation defects, we show in this article that peroxisomes, and not mitochondria, are involved in DHA formation by catalyzing the beta-oxidation of C24:6n-3 to C22:6n-3. Additional studies of fibroblasts from patients with X-linked adrenoleukodystrophy, straight-chain acyl-CoA oxidase (SCOX) deficiency, d-bifunctional protein (DBP) deficiency, and rhizomelic chondrodysplasia punctata type 1, and of fibroblasts from l-bifunctional protein and sterol carrier protein X (SCPx) knockout mice, show that the main enzymes involved in beta-oxidation of C24:6n-3 to C22:6n-3 are SCOX, DBP, and both 3-ketoacyl-CoA thiolase and SCPx. These findings are of importance for the treatment of patients with a defect in peroxisomal beta-oxidation.
Ferdinandusse
S
S
Department of Clinical Chemistry, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Denis
S
S
Mooijer
P A
PA
Zhang
Z
Z
Reddy
J K
JK
Spector
A A
AA
Wanders
R J
RJ
D000101:Acetyl-CoA C-Acetyltransferase / Q000172:deficiency / Q000235:genetics; D000102:Acetyl-CoA C-Acyltransferase / Q000235:genetics / Q000378:metabolism; D042962:Acyl-CoA Oxidase; D000818:Animals; D002333:Carnitine Acyltransferases / Q000172:deficiency / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D005347:Fibroblasts; D006801:Humans; D008052:Lipid Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000172:deficiency / Q000235:genetics; D020675:Peroxisomes / Q000201:enzymology*; D011868:Radioisotopes; D015211:Zellweger Syndrome / Q000378:metabolism
D002352:Carrier Proteins; D011868:Radioisotopes; C072087:sterol carrier proteins; D004281:Docosahexaenoic Acids; D010088:Oxidoreductases; D042962:Acyl-CoA Oxidase; D002333:Carnitine Acyltransferases; D000102:Acetyl-CoA C-Acyltransferase; D000101:Acetyl-CoA C-Acetyltransferase