Document Detail

Straight-chain acyl-CoA oxidase knockout mouse accumulates extremely long chain fatty acids from alpha-linolenic acid: evidence for runaway carousel-type enzyme kinetics in peroxisomal beta-oxidation diseases.
MedLine Citation:
PMID:  11855929     Owner:  NLM     Status:  MEDLINE    
Extremely long chain polyunsaturated fatty acids (ELCPs) with >24 carbons and four or more double bonds are normally found in excitatory tissues but have no known function, and are greatly increased in brain and other tissues of humans with peroxisomal disorders. Straight-chain acyl-CoA oxidase (AOX) catalyzes the first, rate-limiting step of peroxisomal beta-oxidation of very-long-chain saturated and unsaturated fatty acids. We have studied the polyunsaturated fatty acid metabolism of AOX knockout mice (AOX-/- as a model of human AOX deficiency (pseudo-neonatal adrenoleukodystrophy), and as a genetic tool to test the putative peroxisomal beta-oxidation involvement in polyunsaturated fatty acid synthesis. Liver lipids of 26-day-old weanling AOX-/- mice livers accumulate n-3 and n-6 ELCPs from C24 to C30 with 5 and 6 double bonds, have 356 +/- 66 microg/g docosahexaenoic acid (22:6n-3), similar to congenic (AOX -/* = AOX+/+ and AOX+/-) controls (401 +/- 96 microg/g), but increased 22:5n-6 (22.4 +/- 3.7 vs 6.4 +/- 1.5 microg/g). AOX+/* mice injected intraperitoneally at 23 days with [U-(13)C]-18:3n-3 show strong labeling of 22:6n-3 after 72 h, whereas AOX -/- mice display less labeling of 22:6n-3 but strong tracer incorporation into 24:6n-3, 26:6n-3, and 28:6n-3, after the same period. These data suggest that ELCPs are natural runaway elongation by-products of 22:6n-3 and 22:5n-6 synthesis, which are normally disposed of by peroxisomal beta-oxidation. Under conditions with impaired peroxisomal beta-oxidation, such as Zellweger syndrome and adrenoleukodystrophies, ELCPs accumulate due to increased synthesis and impaired disposal. Two mechanisms for the formation of these runaway elongation by-products and the involvement of secondary carnitine deficiency in this process are proposed: n-3 ELCPs are synthesized by a carnitine-dependent multifunctional mitochondrial docosahexaenoic acid synthase (mtDHAS) which normally synthesizes primarily 22:6n-3, while n-6 ELCPs are synthesized by independent elongation enzymes in the endoplasmic reticulum.
Juan P Infante; Carolyn L Tschanz; Natacha Shaw; Anthony L Michaud; Peter Lawrence; J Thomas Brenna
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Molecular genetics and metabolism     Volume:  75     ISSN:  1096-7192     ISO Abbreviation:  Mol. Genet. Metab.     Publication Date:  2002 Feb 
Date Detail:
Created Date:  2002-03-07     Completed Date:  2002-05-21     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  9805456     Medline TA:  Mol Genet Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  108-19     Citation Subset:  IM    
Institute for Theoretical Biochemistry and Molecular Biology, Ithaca, New York, 14852
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MeSH Terms
Acyl-CoA Oxidase
Adrenoleukodystrophy / genetics,  metabolism*
Disease Models, Animal
Fatty Acids / metabolism*
Mice, Knockout
Oxidoreductases / genetics,  metabolism*
Peroxisomal Disorders / genetics*,  metabolism*
alpha-Linolenic Acid / metabolism*
Grant Support
Reg. No./Substance:
0/Fatty Acids; 463-40-1/alpha-Linolenic Acid; EC 1.-/Oxidoreductases; EC Oxidase

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