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Elongase reactions as control points in long-chain polyunsaturated fatty acid synthesis.
PLoS One. 2011; 6(12):e29662.Plos

Abstract

BACKGROUND

Δ6-Desaturase (Fads2) is widely regarded as rate-limiting in the conversion of dietary α-linolenic acid (18:3n-3; ALA) to the long-chain omega-3 polyunsaturated fatty acid docosahexaenoic acid (22:6n-3; DHA). However, increasing dietary ALA or the direct Fads2 product, stearidonic acid (18:4n-3; SDA), increases tissue levels of eicosapentaenoic acid (20:5n-3; EPA) and docosapentaenoic acid (22:5n-3; DPA), but not DHA. These observations suggest that one or more control points must exist beyond ALA metabolism by Fads2. One possible control point is a second reaction involving Fads2 itself, since this enzyme catalyses desaturation of 24:5n-3 to 24:6n-3, as well as ALA to SDA. However, metabolism of EPA and DPA both require elongation reactions. This study examined the activities of two elongase enzymes as well as the second reaction of Fads2 in order to concentrate on the metabolism of EPA to DHA.

METHODOLOGY/PRINCIPAL FINDINGS

The substrate selectivities, competitive substrate interactions and dose response curves of the rat elongases, Elovl2 and Elovl5 were determined after expression of the enzymes in yeast. The competitive substrate interactions for rat Fads2 were also examined. Rat Elovl2 was active with C(20) and C(22) polyunsaturated fatty acids and this single enzyme catalysed the sequential elongation reactions of EPA→DPA→24:5n-3. The second reaction DPA→24:5n-3 appeared to be saturated at substrate concentrations not saturating for the first reaction EPA→DPA. ALA dose-dependently inhibited Fads2 conversion of 24:5n-3 to 24:6n-3.

CONCLUSIONS

The competition between ALA and 24:5n-3 for Fads2 may explain the decrease in DHA levels observed after certain intakes of dietary ALA have been exceeded. In addition, the apparent saturation of the second Elovl2 reaction, DPA→24:5n-3, provides further explanations for the accumulation of DPA when ALA, SDA or EPA is provided in the diet. This study suggests that Elovl2 will be critical in understanding if DHA synthesis can be increased by dietary means.

Authors+Show Affiliations

Rheumatology Unit, Royal Adelaide Hospital, Adelaide, Australia. melissa.gregory@health.sa.gov.auNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22216341

Citation

Gregory, Melissa K., et al. "Elongase Reactions as Control Points in Long-chain Polyunsaturated Fatty Acid Synthesis." PloS One, vol. 6, no. 12, 2011, pp. e29662.
Gregory MK, Gibson RA, Cook-Johnson RJ, et al. Elongase reactions as control points in long-chain polyunsaturated fatty acid synthesis. PLoS ONE. 2011;6(12):e29662.
Gregory, M. K., Gibson, R. A., Cook-Johnson, R. J., Cleland, L. G., & James, M. J. (2011). Elongase reactions as control points in long-chain polyunsaturated fatty acid synthesis. PloS One, 6(12), e29662. https://doi.org/10.1371/journal.pone.0029662
Gregory MK, et al. Elongase Reactions as Control Points in Long-chain Polyunsaturated Fatty Acid Synthesis. PLoS ONE. 2011;6(12):e29662. PubMed PMID: 22216341.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Elongase reactions as control points in long-chain polyunsaturated fatty acid synthesis. AU - Gregory,Melissa K, AU - Gibson,Robert A, AU - Cook-Johnson,Rebecca J, AU - Cleland,Leslie G, AU - James,Michael J, Y1 - 2011/12/22/ PY - 2011/07/26/received PY - 2011/12/02/accepted PY - 2012/1/5/entrez PY - 2012/1/5/pubmed PY - 2012/5/23/medline SP - e29662 EP - e29662 JF - PloS one JO - PLoS ONE VL - 6 IS - 12 N2 - BACKGROUND: Δ6-Desaturase (Fads2) is widely regarded as rate-limiting in the conversion of dietary α-linolenic acid (18:3n-3; ALA) to the long-chain omega-3 polyunsaturated fatty acid docosahexaenoic acid (22:6n-3; DHA). However, increasing dietary ALA or the direct Fads2 product, stearidonic acid (18:4n-3; SDA), increases tissue levels of eicosapentaenoic acid (20:5n-3; EPA) and docosapentaenoic acid (22:5n-3; DPA), but not DHA. These observations suggest that one or more control points must exist beyond ALA metabolism by Fads2. One possible control point is a second reaction involving Fads2 itself, since this enzyme catalyses desaturation of 24:5n-3 to 24:6n-3, as well as ALA to SDA. However, metabolism of EPA and DPA both require elongation reactions. This study examined the activities of two elongase enzymes as well as the second reaction of Fads2 in order to concentrate on the metabolism of EPA to DHA. METHODOLOGY/PRINCIPAL FINDINGS: The substrate selectivities, competitive substrate interactions and dose response curves of the rat elongases, Elovl2 and Elovl5 were determined after expression of the enzymes in yeast. The competitive substrate interactions for rat Fads2 were also examined. Rat Elovl2 was active with C(20) and C(22) polyunsaturated fatty acids and this single enzyme catalysed the sequential elongation reactions of EPA→DPA→24:5n-3. The second reaction DPA→24:5n-3 appeared to be saturated at substrate concentrations not saturating for the first reaction EPA→DPA. ALA dose-dependently inhibited Fads2 conversion of 24:5n-3 to 24:6n-3. CONCLUSIONS: The competition between ALA and 24:5n-3 for Fads2 may explain the decrease in DHA levels observed after certain intakes of dietary ALA have been exceeded. In addition, the apparent saturation of the second Elovl2 reaction, DPA→24:5n-3, provides further explanations for the accumulation of DPA when ALA, SDA or EPA is provided in the diet. This study suggests that Elovl2 will be critical in understanding if DHA synthesis can be increased by dietary means. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/22216341/Elongase_reactions_as_control_points_in_long_chain_polyunsaturated_fatty_acid_synthesis_ L2 - http://dx.plos.org/10.1371/journal.pone.0029662 DB - PRIME DP - Unbound Medicine ER -