Regulation of the biosynthesis of 4,7,10,13,16,19-docosahexaenoic acid.
The synthesis of 4,7,10,13,16,19-docosahexaenoic acid (22:6(n-3)) requires that when 6,9,12,15,18,21-tetracosahexaenoic acid (24:6(n-3)) is produced in the endoplasmic reticulum, it preferentially moves to peroxisomes for one cycle of beta-oxidation rather than serving as a substrate for membrane lipid synthesis. Both 24:6(n-3) and its precursor, 9,12,15,18,21-tetracosapentaenoic acid (24:5(n-3)), were poor substrates for acylation into 1-acyl-sn-glycero-3-phosphocholine (1-acyl-GPC) by rat liver microsomes. When peroxisomes were incubated with 1-14C- or 3-14C-labeled 7,10,13,16,19-docosapentaenoic acid (22:5(n-3)), [1-14C]22:6(n-3), [3-14C]24:5(n-3), or [3-14C]24:6(n-3), only small amounts of acid-soluble radioactivity were produced when double bond removal at positions 4 and 5 was required. When microsomes and 1-acyl-GPC were included in incubations, the preferred metabolic fate of acids, with their first double bond at either positions 4 or 5, was to move out of peroxisomes for esterification into the acceptor rather than serving as substrates for continued beta-oxidation. When [1-14C]22:6(n-3) or [3-14C]24:6(n-3) was incubated with peroxisomes, 2-trans-4,7,10,13,16,19-22:7 accumulated. The first cycle of 20:5(n-3) beta-oxidation proceeds through 2-trans-4,8,11,14,17-20:6 and thus requires both Delta3,5,Delta2, 4-dienoyl-CoA isomerase and 2,4-dienoyl-CoA reductase. The accumulation of the substrate for 2,4-dienoyl-CoA reductase, as generated from 22:6(n-3), but not from 20:5(n-3), suggests that this enzyme distinguishes between subtle structural differences. When 22:6(n-3) is produced from 24:6(n-3), its continued degradation is impaired because of low 2,4-dienoyl-CoA reductase activity. This slow reaction rate likely contributes to the transport of 22:6(n-3) out of peroxisomes for rapid acylation into 1-acyl-GPC by microsomes.
Luthria
D L
DL
Department of Medical Biochemistry, The Ohio State University, Columbus, Ohio 43210, USA.
Mohammed
B S
BS
Sprecher
H
H
D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D002994:Clofibrate / Q000494:pharmacology*; D004032:Diet; D004281:Docosahexaenoic Acids / Q000302:isolation & purification / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008563:Membrane Lipids / Q000302:isolation & purification / Q000378:metabolism; D008830:Microbodies / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D008954:Models, Biological; D010084:Oxidation-Reduction; D011865:Radioisotope Dilution Technique; D051381:Rats; D017207:Rats, Sprague-Dawley
C100600:6,9,12,15,18,21-tetracosahexaenoic acid; D000214:Acyl Coenzyme A; D002250:Carbon Radioisotopes; D008563:Membrane Lipids; D004281:Docosahexaenoic Acids; D002994:Clofibrate