title: The Δ4-desaturation pathway for DHA biosynthesis is operative in the human species: differences between normal controls and children with the Zellweger syndrome.
abstract: BACKGROUND
  Docosahexaenoic acid (DHA, 22:6ω3) is a fundamental component of cell membranes, especially in the brain and retina. In the experimental animal, DHA deficiency leads to suboptimal neurological performance and visual deficiencies. Children with the Zellweger syndrome (ZS) have a profound DHA deficiency and symptoms that can be attributed to their extremely low DHA levels. These children seem to have a metabolic defect in DHA biosynthesis, which has never been totally elucidated. Treatment with DHA ethyl ester greatly improves these patients, but if we could normalize their endogenous DHA production we could get additional benefits. We examined whether DHA biosynthesis by Δ4-desaturation could be enhanced in the human species by transfecting the enzyme, and if this could normalize the DHA levels in cells from ZS patients.
  
  
  RESULTS
  We showed that the Δ4-desaturase gene (Fad4) from Thraustochytrium sp, which can be expressed by heterologous transfection in other plant and yeast cells, can also be transfected into human lymphocytes, and that it expresses the enzyme (FAD4, Δ4-desaturase) by producing DHA from direct Δ4-desaturation of 22:5ω3. We also found that the other substrate for Δ4-desaturase, 22:4ω6, was parallely desaturated to 22:5ω6.
  
  
  CONCLUSIONS
  The present "in vitro" study demonstrates that Δ4-desaturase can be transfected into human cells and synthesize DHA (as well as 22:5ω6, DPA) from 22:5ω3 and 22:4ω6, respectively, by putative Δ4-desaturation. Even if this pathway may not be the physiological route for DHA biosynthesis "in vivo", the present study opens new perspectives for the treatment of patients within the ZS spectrum.
authors.affiliation: Manuela Martinez Foundation for Children with Metabolic Diseases, Research Laboratory, Plaza Karl Marx 1, Barcelona 08042, Spain. 3572mmr@comb.cat
authors.forename: Manuela
authors.initials: M
authors.lastname: Martinez
authors.forename: Natalia
authors.initials: N
authors.lastname: Ichaso
authors.forename: Fernando
authors.initials: F
authors.lastname: Setien
authors.forename: Nuria
authors.initials: N
authors.lastname: Durany
authors.forename: Xiao
authors.initials: X
authors.lastname: Qiu
authors.forename: William
authors.initials: W
authors.lastname: Roesler
mesh_terms: D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D044943:Fatty Acid Desaturases / Q000235:genetics* / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D005228:Fatty Acids, Essential / Q000172:deficiency / Q000378:metabolism; D043371:Fatty Acids, Omega-6 / Q000378:metabolism; D005658:Fungi / Q000235:genetics; D015723:Gene Library; D005800:Genes, Fungal; D015316:Genetic Therapy; D006801:Humans; D007223:Infant; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism; D018901:Peroxisomal Disorders / Q000628:therapy; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D052919:Refsum Disease, Infantile / Q000628:therapy; D013379:Substrate Specificity; D014162:Transfection; D015211:Zellweger Syndrome / Q000235:genetics / Q000378:metabolism* / Q000628:therapy
chemical_list: D005227:Fatty Acids; D005228:Fatty Acids, Essential; D043371:Fatty Acids, Omega-6; D011993:Recombinant Fusion Proteins; D004281:Docosahexaenoic Acids; D044943:Fatty Acid Desaturases; C434953:delta-4 fatty acid desaturase