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. 2000 Sep 15;350(Pt 3):765–770.

Cloning of a human cDNA encoding a novel enzyme involved in the elongation of long-chain polyunsaturated fatty acids.

A E Leonard 1, E G Bobik 1, J Dorado 1, P E Kroeger 1, L T Chuang 1, J M Thurmond 1, J M Parker-Barnes 1, T Das 1, Y S Huang 1, P Mukerji 1
PMCID: PMC1221308  PMID: 10970790

Abstract

The Saccharomyces cerevisiae protein ELO2p is involved in the elongation of saturated and monounsaturated fatty acids. Among several sequences with limited identity with the S. cerevisiae ELO2 gene, a consensus cDNA sequence was identified from the LifeSeq(R) database of Incyte Pharmaceuticals, Inc. Human liver cDNA was amplified by PCR using oligonucleotides complementary to the 5' and 3' ends of the putative human cDNA sequence. The resulting full-length sequence, termed HELO1, consisted of 897 bp, which encoded 299 amino acids. However, in contrast with the ELO2 gene, expression of this open reading frame in S. cerevisiae demonstrated that the encoded protein was involved in the elongation of long-chain polyunsaturated fatty acids, as determined by the conversion of gamma-linolenic acid (C(18:3, n-6)) into dihomo-gamma-linolenic acid (C(20:3, n-6)), arachidonic acid (C(20:4, n-6)) into adrenic acid (C(22:4, n-6)), stearidonic acid (C(18:4, n-3)) into eicosatetraenoic acid (C(20:4, n-3)), eicosapentaenoic acid (C(20:5, n-3)) into omega3-docosapentaenoic acid (C(22:5, n-3)) and alpha-linolenic acid (C(18:3, n-3)) into omega3-eicosatrienoic acid (C(20:3, n-3)). The predicted amino acid sequence of the open reading frame had only 29% identity with the yeast ELO2 sequence, contained a single histidine-rich domain and had six transmembrane-spanning regions, as suggested by hydropathy analysis. The tissue expression profile revealed that the HELO1 gene is highly expressed in the adrenal gland and testis. Furthermore, the HELO1 gene is located on chromosome 6, best known for encoding the major histocompatibility complex, which is essential to the human immune response.

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Selected References

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  1. Albert D. H., Rhamy R. K., Coniglio J. G. Desaturation of eicosa-11,14-dienoic acid in human testes. Lipids. 1979 May;14(5):498–500. doi: 10.1007/BF02533468. [DOI] [PubMed] [Google Scholar]
  2. Balendran N., Clough R. L., Arguello J. R., Barber R., Veal C., Jones A. B., Rosbotham J. L., Little A. M., Madrigal A., Barker J. N. Characterization of the major susceptibility region for psoriasis at chromosome 6p21.3. J Invest Dermatol. 1999 Sep;113(3):322–328. doi: 10.1046/j.1523-1747.1999.00710.x. [DOI] [PubMed] [Google Scholar]
  3. Carlson S. E., Werkman S. H., Peeples J. M., Cooke R. J., Tolley E. A. Arachidonic acid status correlates with first year growth in preterm infants. Proc Natl Acad Sci U S A. 1993 Feb 1;90(3):1073–1077. doi: 10.1073/pnas.90.3.1073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cinti D. L., Cook L., Nagi M. N., Suneja S. K. The fatty acid chain elongation system of mammalian endoplasmic reticulum. Prog Lipid Res. 1992;31(1):1–51. doi: 10.1016/0163-7827(92)90014-a. [DOI] [PubMed] [Google Scholar]
  5. Cook H. W., Byers D. M., Palmer F. B., Spence M. W., Rakoff H., Duval S. M., Emken E. A. Alternate pathways in the desaturation and chain elongation of linolenic acid, 18:3(n-3), in cultured glioma cells. J Lipid Res. 1991 Aug;32(8):1265–1273. [PubMed] [Google Scholar]
  6. Cox A., Camp N. J., Cannings C., di Giovine F. S., Dale M., Worthington J., John S., Ollier W. E., Silman A. J., Duff G. W. Combined sib-TDT and TDT provide evidence for linkage of the interleukin-1 gene cluster to erosive rheumatoid arthritis. Hum Mol Genet. 1999 Sep;8(9):1707–1713. doi: 10.1093/hmg/8.9.1707. [DOI] [PubMed] [Google Scholar]
  7. Crawford M. A., Costeloe K., Ghebremeskel K., Phylactos A., Skirvin L., Stacey F. Are deficits of arachidonic and docosahexaenoic acids responsible for the neural and vascular complications of preterm babies? Am J Clin Nutr. 1997 Oct;66(4 Suppl):1032S–1041S. doi: 10.1093/ajcn/66.4.1032S. [DOI] [PubMed] [Google Scholar]
  8. Davies A. F., Mirza G., Flinter F., Ragoussis J. An interstitial deletion of 6p24-p25 proximal to the FKHL7 locus and including AP-2alpha that affects anterior eye chamber development. J Med Genet. 1999 Sep;36(9):708–710. [PMC free article] [PubMed] [Google Scholar]
  9. Delgado-Escueta A. V., Medina M. T., Serratosa J. M., Castroviejo I. P., Gee M. N., Weissbecker K., Westling B. W., Fong C. Y., Alonso M. E., Cordova S. Mapping and positional cloning of common idiopathic generalized epilepsies: juvenile myoclonus epilepsy and childhood absence epilepsy. Adv Neurol. 1999;79:351–374. [PubMed] [Google Scholar]
  10. Dhopeshwarkar G. A., Subramanian C. Intracranial conversion of linoleic acid to arachidonic acid: evidence for lack of delta8 desaturase in the brain. J Neurochem. 1976 Jun;26(6):1175–1179. doi: 10.1111/j.1471-4159.1976.tb07003.x. [DOI] [PubMed] [Google Scholar]
  11. Dittrich F., Zajonc D., Hühne K., Hoja U., Ekici A., Greiner E., Klein H., Hofmann J., Bessoule J. J., Sperling P. Fatty acid elongation in yeast--biochemical characteristics of the enzyme system and isolation of elongation-defective mutants. Eur J Biochem. 1998 Mar 15;252(3):477–485. doi: 10.1046/j.1432-1327.1998.2520477.x. [DOI] [PubMed] [Google Scholar]
  12. Garcia P. T., Holman R. T. Competitive inhibitions in the metabolism of polyunsaturated fatty acids studied via the composition of phospholipids, triglycerides and cholesteryl esters of rat tissues. J Am Oil Chem Soc. 1965 Dec;42(12):1137–1141. doi: 10.1007/BF02636930. [DOI] [PubMed] [Google Scholar]
  13. Gardner R. J., Mungall A. J., Dunham I., Barber J. C., Shield J. P., Temple I. K., Robinson D. O. Localisation of a gene for transient neonatal diabetes mellitus to an 18.72 cR3000 (approximately 5.4 Mb) interval on chromosome 6q. J Med Genet. 1999 Mar;36(3):192–196. [PMC free article] [PubMed] [Google Scholar]
  14. Grammatikos S. I., Subbaiah P. V., Victor T. A., Miller W. M. n-3 and n-6 fatty acid processing and growth effects in neoplastic and non-cancerous human mammary epithelial cell lines. Br J Cancer. 1994 Aug;70(2):219–227. doi: 10.1038/bjc.1994.283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hampe J., Shaw S. H., Saiz R., Leysens N., Lantermann A., Mascheretti S., Lynch N. J., MacPherson A. J., Bridger S., van Deventer S. Linkage of inflammatory bowel disease to human chromosome 6p. Am J Hum Genet. 1999 Dec;65(6):1647–1655. doi: 10.1086/302677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Horrocks L. A., Yeo Y. K. Health benefits of docosahexaenoic acid (DHA) Pharmacol Res. 1999 Sep;40(3):211–225. doi: 10.1006/phrs.1999.0495. [DOI] [PubMed] [Google Scholar]
  17. Hsu M. H., Chirala S. S., Wakil S. J. Human fatty-acid synthase gene. Evidence for the presence of two promoters and their functional interaction. J Biol Chem. 1996 Jun 7;271(23):13584–13592. doi: 10.1074/jbc.271.23.13584. [DOI] [PubMed] [Google Scholar]
  18. Knutzon D. S., Thurmond J. M., Huang Y. S., Chaudhary S., Bobik E. G., Jr, Chan G. M., Kirchner S. J., Mukerji P. Identification of Delta5-desaturase from Mortierella alpina by heterologous expression in Bakers' yeast and canola. J Biol Chem. 1998 Nov 6;273(45):29360–29366. doi: 10.1074/jbc.273.45.29360. [DOI] [PubMed] [Google Scholar]
  19. Kösel S., Hofhaus G., Maassen A., Vieregge P., Graeber M. B. Role of mitochondria in Parkinson disease. Biol Chem. 1999 Jul-Aug;380(7-8):865–870. doi: 10.1515/BC.1999.106. [DOI] [PubMed] [Google Scholar]
  20. Leonard A. E., Kelder B., Bobik E. G., Chuang L. T., Parker-Barnes J. M., Thurmond J. M., Kroeger P. E., Kopchick J. J., Huang Y. S., Mukerji P. cDNA cloning and characterization of human Delta5-desaturase involved in the biosynthesis of arachidonic acid. Biochem J. 2000 May 1;347(Pt 3):719–724. [PMC free article] [PubMed] [Google Scholar]
  21. Lindholm E., Ekholm B., Balciuniene J., Johansson G., Castensson A., Koisti M., Nylander P. O., Pettersson U., Adolfsson R., Jazin E. Linkage analysis of a large Swedish kindred provides further support for a susceptibility locus for schizophrenia on chromosome 6p23. Am J Med Genet. 1999 Aug 20;88(4):369–377. [PubMed] [Google Scholar]
  22. Luthria D. L., Sprecher H. Studies to determine if rat liver contains multiple chain elongating enzymes. Biochim Biophys Acta. 1997 Jun 23;1346(3):221–230. doi: 10.1016/s0005-2760(97)00037-4. [DOI] [PubMed] [Google Scholar]
  23. Oh C. S., Toke D. A., Mandala S., Martin C. E. ELO2 and ELO3, homologues of the Saccharomyces cerevisiae ELO1 gene, function in fatty acid elongation and are required for sphingolipid formation. J Biol Chem. 1997 Jul 11;272(28):17376–17384. doi: 10.1074/jbc.272.28.17376. [DOI] [PubMed] [Google Scholar]
  24. Olynyk J. K., Cullen D. J., Aquilia S., Rossi E., Summerville L., Powell L. W. A population-based study of the clinical expression of the hemochromatosis gene. N Engl J Med. 1999 Sep 2;341(10):718–724. doi: 10.1056/NEJM199909023411002. [DOI] [PubMed] [Google Scholar]
  25. Oturai A., Larsen F., Ryder L. P., Madsen H. O., Hillert J., Fredrikson S., Sandberg-Wollheim M., Laaksonen M., Koch-Henriksen N., Sawcer S. Linkage and association analysis of susceptibility regions on chromosomes 5 and 6 in 106 Scandinavian sibling pair families with multiple sclerosis. Ann Neurol. 1999 Oct;46(4):612–616. [PubMed] [Google Scholar]
  26. Shanklin J., Whittle E., Fox B. G. Eight histidine residues are catalytically essential in a membrane-associated iron enzyme, stearoyl-CoA desaturase, and are conserved in alkane hydroxylase and xylene monooxygenase. Biochemistry. 1994 Nov 1;33(43):12787–12794. doi: 10.1021/bi00209a009. [DOI] [PubMed] [Google Scholar]
  27. Simopoulos A. P. Essential fatty acids in health and chronic disease. Am J Clin Nutr. 1999 Sep;70(3 Suppl):560S–569S. doi: 10.1093/ajcn/70.3.560s. [DOI] [PubMed] [Google Scholar]
  28. Smith S. The animal fatty acid synthase: one gene, one polypeptide, seven enzymes. FASEB J. 1994 Dec;8(15):1248–1259. [PubMed] [Google Scholar]
  29. Spector A. A. Essentiality of fatty acids. Lipids. 1999;34 (Suppl):S1–S3. doi: 10.1007/BF02562220. [DOI] [PubMed] [Google Scholar]
  30. Sprecher H. An update on the pathways of polyunsaturated fatty acid metabolism. Curr Opin Clin Nutr Metab Care. 1999 Mar;2(2):135–138. doi: 10.1097/00075197-199903000-00007. [DOI] [PubMed] [Google Scholar]
  31. Steinberg S. J., Wang S. J., McGuinness M. C., Watkins P. A. Human liver-specific very-long-chain acyl-coenzyme A synthetase: cDNA cloning and characterization of a second enzymatically active protein. Mol Genet Metab. 1999 Sep;68(1):32–42. doi: 10.1006/mgme.1999.2883. [DOI] [PubMed] [Google Scholar]
  32. Suneja S. K., Nagi M. N., Cook L., Cinti D. L. Decreased long-chain fatty acyl CoA elongation activity in quaking and jimpy mouse brain: deficiency in one enzyme or multiple enzyme activities? J Neurochem. 1991 Jul;57(1):140–146. doi: 10.1111/j.1471-4159.1991.tb02108.x. [DOI] [PubMed] [Google Scholar]
  33. Takayasu K., Okuda K., Yoshikawa I. Fatty acid composition of human and rat adrenal lipids: occurrence of omega 6 docosatrienoic acid in human adrenal cholesterol ester. Lipids. 1970 Sep;5(9):743–750. doi: 10.1007/BF02531386. [DOI] [PubMed] [Google Scholar]
  34. Toke D. A., Martin C. E. Isolation and characterization of a gene affecting fatty acid elongation in Saccharomyces cerevisiae. J Biol Chem. 1996 Aug 2;271(31):18413–18422. doi: 10.1074/jbc.271.31.18413. [DOI] [PubMed] [Google Scholar]
  35. Uauy R., Birch E., Birch D., Peirano P. Visual and brain function measurements in studies of n-3 fatty acid requirements of infants. J Pediatr. 1992 Apr;120(4 Pt 2):S168–S180. doi: 10.1016/s0022-3476(05)81252-1. [DOI] [PubMed] [Google Scholar]
  36. Uauy R., Peirano P., Hoffman D., Mena P., Birch D., Birch E. Role of essential fatty acids in the function of the developing nervous system. Lipids. 1996 Mar;31 (Suppl):S167–S176. doi: 10.1007/BF02637071. [DOI] [PubMed] [Google Scholar]
  37. Wallis J. G., Browse J. The Delta8-desaturase of Euglena gracilis: an alternate pathway for synthesis of 20-carbon polyunsaturated fatty acids. Arch Biochem Biophys. 1999 May 15;365(2):307–316. doi: 10.1006/abbi.1999.1167. [DOI] [PubMed] [Google Scholar]

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