The metabolism of 7,10,13,16,19-docosapentaenoic acid to 4,7,10,13,16,19-docosahexaenoic acid in rat liver is independent of a 4-desaturase.
The hypothesis that the last step in the biosynthesis of 4,7,10,13,16,19-22:6 from linolenate is catalyzed by an acyl-CoA-dependent 4-desaturase has never been evaluated by direct experimentation. When rat liver microsomes were incubated with [1-14C]7,10,13,16,19-22:5, under conditions where linoleate was readily desaturated to 6,9,12-18:3, it was never possible to detect the product of the putative 4-desaturase. In the presence of malonyl-CoA, 7,10,13,16,19-22:5 was sequentially chain-elongated to 9,12,15,18,21-24:5, followed by its desaturation at position 6 to give 6,9,12,15,18,21-24:6. Microsomes desaturated 9,12,15,18,21-24:5 at rates similar to those observed for metabolizing linoleate to 6,9,12-18:3. Rat hepatocytes metabolize [1-14C]7,10,13,16,19-22:5 to 22:6(n-3), but in addition, it was possible to detect small amounts of esterified 24:5(n-3) and 24:6(n-3) in phospholipids, which is a finding consistent with their role as obligatory intermediates in 22:6(n-3) biosynthesis. When 3-14C-labeled 24:5(n-3) or 24:6(n-3) were incubated with hepatocytes, only a small amount of either substrate was esterified. [3-14C] 24:5(n-3) was metabolized both by beta-oxidation to 22:5(n-3) and by serving as a precursor for the biosynthesis of 24:6(n-3) and 22:6(n-3). The primary metabolic fate of [3-14C]24:6(n-3) was beta-oxidation to 22:6(n-3), followed by its acylation into membrane lipids. Our results thus document that 22:5(n-3) is the precursor for 22:6(n-3) but via a pathway that is independent of a 4-desaturase. This pathway involves the microsomal chain elongation of 22:5(n-3) to 24:5(n-3), followed by its desaturation to 24:6(n-3). This microsomal product is then metabolized, via beta-oxidation, to 22:6(n-3).
Voss
A
A
Department of Medical Biochemistry, Ohio State University, Columbus 43210.
Reinhart
M
M
Sankarappa
S
S
Sprecher
H
H
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D044943:Fatty Acid Desaturases / Q000378:metabolism*; D015525:Fatty Acids, Omega-3; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D011874:Radiometry; D051381:Rats; D013379:Substrate Specificity
D015525:Fatty Acids, Omega-3; D005231:Fatty Acids, Unsaturated; D004281:Docosahexaenoic Acids; D044943:Fatty Acid Desaturases; C026219:docosapentaenoic acid