On the molecular etiology of decreased arachidonic (20:4n-6), docosapentaenoic (22:5n-6) and docosahexaenoic (22:6n-3) acids in Zellweger syndrome and other peroxisomal disorders.
Alterations in the metabolism of arachidonic (20:4n-6), docosapentaenoic (22:5n-6), and docosahexaenoic (22:6n-3) acids and other polyunsaturated fatty acids in Zellweger syndrome and other peroxisomal disorders are reviewed. Previous proposals that peroxisomes are necessary for the synthesis of 22:6n-3 and 22:5n-6 are critically examined. The data suggest that 22:6n-3 is biosynthesized in mitochondria via a channelled carnitine-dependent pathway involving an n-3-specific delta-4 desaturase, while 20:4n-6, 20:5n-3 and 22:5n-6 are synthesized by both mitochondrial and microsomal systems; these pathways are postulated to be interregulated as compensatory-redundant systems. Present evidence suggests that 22:6n-3-containing phospholipids may be required for the biochemical events involved in successful neuronal migration and developmental morphogenesis, and as structural cofactors for the functional assembly and integration of a variety of membrane enzymes, receptors, and other proteins in peroxisomes and other subcellular organelles. A defect in the mitochondrial desaturation pathway is proposed to be a primary etiologic factor in the clinicopathology of Zellweger syndrome and other related disorders. Several implications of this proposal are examined relating to effects of pharmacological agents which appear to inhibit steps in this pathway, such as some hypolipidemics (fibrates), neuroleptics (phenothiazines and phenytoin) and prenatal alcohol exposure.
Infante
J P
JP
Institute for Theoretical Biochemistry and Molecular Biology, Ithaca, New York 14852-4512, USA.
Huszagh
V A
VA
D016718:Arachidonic Acid / Q000378:metabolism*; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D018901:Peroxisomal Disorders / Q000378:metabolism*; D015211:Zellweger Syndrome / Q000378:metabolism*
D005231:Fatty Acids, Unsaturated; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; C026219:docosapentaenoic acid