Biology:FADS2
Fatty acid desaturase 2 (FADS2) is an enzyme that in humans is encoded by the FADS2 gene.[1][2]
Function
Desaturation
The protein encoded by the FADS2 gene is a member of the fatty acid desaturase (FADS) gene family. It has three catalytic activities acting on fatty-acid-CoA:[3]
- As a Delta 6 desaturase, it desaturates omega-3 and omega-6 polyunsaturated fatty acids at the delta-6 position, catalyzing the first and rate-limiting step in the formation of tetracosapentaenoic acid and tetracosahexaenoic acid.
- As a Delta 8 desaturase, desaturation at the delta-8 position.
- As a Delta 4 desaturase, desaturation at the delta-4 position.[4]
Desaturase enzymes (such as those encoded by FADS2) cause desaturation of fatty acids through the introduction of double bonds between defined carbons of the fatty acyl chain. FADS family members are considered fusion products composed of an N-terminal cytochrome b5-like domain and a C-terminal multiple membrane-spanning desaturase portion, both of which are characterized by conserved histidine motifs. This gene is clustered with family members FADS1 and FADS2 at 11q12-q13.1; this cluster is thought to have arisen evolutionarily from gene duplication based on its similar exon/intron organization.[1]
Re-esterification
Separately from its function in synthesizing EPA and DHA, D6D plays a contributory role in fatty acid re-esterification,[5] required for the return of unoxidized free fatty acids into white adipose tissue as triglycerides.
Agonists and inhibiting factors
D6D is upregulated by estrogen,[6] low levels of omega-3s, and moderate food restriction (up to 300%) .
D6D activity slows with age, suggested by reductions in GLA and subsequent metabolites.[7][8] Other inhibiting factors include alcohol, radiation, and diabetes .
The conversion rate of ALA into DHA is vulnerable to suppression by dietary fatty acids. ALA intake greater than 1% and total polyunsaturated intake above 3% were found to drastically limit synthesis of EPA and DHA.[9]
Clinical significance
D6D deficiency can result in deficiencies in DHA, and in GLA and its metabolites dihomo-gamma-linolenic acid (DGLA) and prostaglandin E1 (PGE1).
Sperm quality
It is implicated in abnormal sperm production due to deficiency in DHA[10] and atopic dermatitis due to deficiencies in GLA and PGE1.[11]
Intelligence in brease-fed children
It was reported the FADS2 interacts with breastfeeding such that breast-fed children with the rs174575 "C" version of the gene appear about 7 intelligence quotient (IQ) points higher than those with the less common rs174575 "G" version (less than this when adjusted for maternal IQ).[12][13]
An attempt to replicate this study in 5934 8-year-old children failed: No relationship of the common rs174575 C allele to negative effects of formula feeding was apparent, and contra to the original report, the rare rs174575 GG homozygote children performed worse when formula fed than other children on formula milk.[14] A study of over 700 families recently found no evidence for either main or moderating effects of the original SNP (rs174575), nor of two additional FADS2 polymorphisms (rs1535 and rs174583), nor any effect of maternal FADS2 status on offspring IQ.[15]
References
- ↑ 1.0 1.1 "Entrez Gene: FADS1 fatty acid desaturase 1". https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=3992.
- ↑ "cDNA cloning, genomic structure, and chromosomal localization of three members of the human fatty acid desaturase family". Genomics 66 (2): 175–83. June 2000. doi:10.1006/geno.2000.6196. PMID 10860662.
- ↑ Brenna, J Thomas (June 2009). "An alternate pathway to long-chain polyunsaturates: the FADS2 gene product Δ8-desaturates 20:2n-6 and 20:3n-3". Journal of Lipid Research 50 (6): 1195–202. doi:10.1194/jlr.M800630-JLR200. PMID 19202133.
- ↑ Park, HG; Park, WJ; Kothapalli, KS; Brenna, JT (September 2015). "The fatty acid desaturase 2 (FADS2) gene product catalyzes Δ4 desaturation to yield n-3 docosahexaenoic acid and n-6 docosapentaenoic acid in human cells.". FASEB Journal 29 (9): 3911–9. doi:10.1096/fj.15-271783. PMID 26065859.
- ↑ Wang, C.; Hucik, B.; Sarr, O.; Brown, L. H.; Wells, K. R. D.; Brunt, K. R.; Nakamura, M. T.; Harasim-Symbor, E. et al. (2023). "Delta-6 desaturase (Fads2) deficiency alters triacylglycerol/fatty acid cycling in murine white adipose tissue" (in en). Journal of Lipid Research 64 (6). doi:10.1016/j.jlr.2023.100376. PMID 37085033.
- ↑ Giltay, E. J.; Gooren, L. J.; Toorians, A. W.; Katan, M. B.; Zock, P. L. (2004). "Docosahexaenoic acid concentrations are higher in women than in men because of estrogenic effects" (in en). The American Journal of Clinical Nutrition 80 (5): 1167–1174. doi:10.1093/ajcn/80.5.1167. ISSN 0002-9165. PMID 15531662.
- ↑ Horrobin, D. F. (1981). "Loss of delta-6-desaturase activity as a key factor in aging" (in en). Medical Hypotheses 7 (9): 1211–1220. doi:10.1016/0306-9877(81)90064-5. ISSN 0306-9877. PMID 6270521.
- ↑ Biagi, P. L.; Bordoni, A.; Hrelia, S.; Celadon, M.; Horrobin, D. F. (1991). "Gamma-linolenic acid dietary supplementation can reverse the aging influence on rat liver microsome delta 6-desaturase activity" (in en). Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism 1083 (2): 187–192. doi:10.1016/0005-2760(91)90041-F. ISSN 0005-2760. PMID 1674661.
- ↑ Gibson, R. A.; Neumann, M. A.; Lien, E. L.; Boyd, K. A.; Tu, W. C. (2012). "Docosahexaenoic acid synthesis from alpha-linolenic acid is inhibited by diets high in polyunsaturated fatty acids" (in en). Prostaglandins, Leukotrienes, and Essential Fatty Acids 88 (1): 139–146. doi:10.1016/j.plefa.2012.04.003. ISSN 0952-3278. PMID 22515943.
- ↑ "Docosahexaenoic acid supplementation fully restores fertility and spermatogenesis in male delta-6 desaturase-null mice". Journal of Lipid Research 51 (2): 360–367. February 2010. doi:10.1194/jlr.M001180. PMID 19690334.
- ↑ Chung, B. Y.; Park, S. Y.; Jung, M. J.; Kim, H. O.; Park, C. W. (2018). "Effect of Evening Primrose Oil on Korean Patients With Mild Atopic Dermatitis: A Randomized, Double-Blinded, Placebo-Controlled Clinical Study" (in en). Annals of Dermatology 30 (4): 409–416. doi:10.5021/ad.2018.30.4.409. PMID 30065580.
- ↑ Gene governs IQ boost from breastfeeding.
- ↑ "Moderation of breastfeeding effects on the IQ by genetic variation in fatty acid metabolism". Proc. Natl. Acad. Sci. U.S.A. 104 (47): 18860–5. November 2007. doi:10.1073/pnas.0704292104. PMID 17984066. Bibcode: 2007PNAS..10418860C.
- ↑ "FADS2 polymorphisms modify the effect of breastfeeding on child IQ". PLOS ONE 5 (7). 2010. doi:10.1371/journal.pone.0011570. PMID 20644632. Bibcode: 2010PLoSO...511570S.
- ↑ "Cognitive function in adolescence: testing for interactions between breast-feeding and FADS2 polymorphisms". J Am Acad Child Adolesc Psychiatry 50 (1): 55–62.e4. January 2011. doi:10.1016/j.jaac.2010.10.010. PMID 21156270.
Further reading
- "A genome-wide association study of the metabolic syndrome in Indian Asian men.". PLOS ONE 5 (8). 2010. doi:10.1371/journal.pone.0011961. PMID 20694148. Bibcode: 2010PLoSO...511961Z.
- "Genetic variants of the FADS1 FADS2 gene cluster as related to essential fatty acid metabolism.". Curr. Opin. Lipidol. 21 (1): 64–9. 2010. doi:10.1097/MOL.0b013e3283327ca8. PMID 19809313.
- "Association of fatty acid desaturase gene polymorphisms with blood lipid essential fatty acids and perinatal depression among Canadian women: a pilot study.". J. Nutr. Nutr. 2 (4–5): 243–50. 2009. doi:10.1159/000255636. PMID 20395685.
- "FADS gene polymorphisms in Koreans: association with ω6 polyunsaturated fatty acids in serum phospholipids, lipid peroxides, and coronary artery disease.". Atherosclerosis 214 (1): 94–100. 2011. doi:10.1016/j.atherosclerosis.2010.10.004. PMID 21040914.
- "Variants of the FADS1 FADS2 gene cluster, blood levels of polyunsaturated fatty acids and eczema in children within the first 2 years of life.". PLOS ONE 5 (10). 2010. doi:10.1371/journal.pone.0013261. PMID 20948998. Bibcode: 2010PLoSO...513261R.
- "FADS gene cluster polymorphisms: important modulators of fatty acid levels and their impact on atopic diseases.". J. Nutr. Nutr. 2 (3): 119–28. 2009. doi:10.1159/000235559. PMID 19776639. https://epub.ub.uni-muenchen.de/16661/1/10_1159_000235559.pdf.
- "Do FADS genotypes enhance our knowledge about fatty acid related phenotypes?". Clin Nutr 29 (3): 277–87. 2010. doi:10.1016/j.clnu.2009.11.005. PMID 19948371.
- "FADS genetic variants and omega-6 polyunsaturated fatty acid metabolism in a homogeneous island population.". J. Lipid Res. 51 (9): 2766–74. 2010. doi:10.1194/jlr.M008359. PMID 20562440.
- "Genetic variants of the fatty acid desaturase gene cluster predict amounts of red blood cell docosahexaenoic and other polyunsaturated fatty acids in pregnant women: findings from the Avon Longitudinal Study of Parents and Children.". Am. J. Clin. Nutr. 93 (1): 211–9. 2011. doi:10.3945/ajcn.110.006189. PMID 21106917.
- "Single nucleotide polymorphisms in the FADS gene cluster are associated with delta-5 and delta-6 desaturase activities estimated by serum fatty acid ratios.". J. Lipid Res. 51 (8): 2325–33. 2010. doi:10.1194/jlr.M006205. PMID 20427696.
- "Role of FADS1 and FADS2 polymorphisms in polyunsaturated fatty acid metabolism.". Metab. Clin. Exp. 59 (7): 993–9. 2010. doi:10.1016/j.metabol.2009.10.022. PMID 20045144.
- "FADS2 polymorphisms modify the effect of breastfeeding on child IQ.". PLOS ONE 5 (7). 2010. doi:10.1371/journal.pone.0011570. PMID 20644632. Bibcode: 2010PLoSO...511570S.
- "Genetic variation in lipid desaturases and its impact on the development of human disease.". Lipids Health Dis 9. 2010. doi:10.1186/1476-511X-9-63. PMID 20565855.
- "Erythrocyte membrane phospholipid fatty acids, desaturase activity, and dietary fatty acids in relation to risk of type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study.". Am. J. Clin. Nutr. 93 (1): 127–42. 2011. doi:10.3945/ajcn.110.005447. PMID 20980488.
- Genetically determined variation in polyunsaturated fatty acid metabolism may result in different dietary requirements.. Nestlé Nutrition Workshop Series: Pediatric Program. 62. 2008. 35–44; discussion 44–49. doi:10.1159/000146246. ISBN 978-3-8055-8553-8. http://nbn-resolving.de/urn:nbn:de:bvb:19-epub-35257-7.
- Segrè AV (2010). "Common inherited variation in mitochondrial genes is not enriched for associations with type 2 diabetes or related glycemic traits.". PLOS Genet. 6 (8). doi:10.1371/journal.pgen.1001058. PMID 20714348.
- "Genetic variation of the FADS1 FADS2 gene cluster and n-6 PUFA composition in erythrocyte membranes in the European Prospective Investigation into Cancer and Nutrition-Potsdam study". Br. J. Nutr. 104 (12): 1748–59. December 2010. doi:10.1017/S0007114510002916. PMID 20691134.
- "Genetic loci associated with lipid concentrations and cardiovascular risk factors in the Korean population.". J. Med. Genet. 48 (1): 10–5. 2011. doi:10.1136/jmg.2010.081000. PMID 20972250.
- "Dietary n-3 and n-6 polyunsaturated fatty acid intake interacts with FADS1 genetic variation to affect total and HDL-cholesterol concentrations in the Doetinchem Cohort Study". Am. J. Clin. Nutr. 92 (1): 258–65. July 2010. doi:10.3945/ajcn.2009.29130. PMID 20484448.
- "Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study.". Diabetes Care 33 (10): 2250–3. 2010. doi:10.2337/dc10-0452. PMID 20628086.
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