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J. Biol. Chem., Vol. 283, Issue 33, 22352-22362, August 15, 2008

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Metabolic Engineering of 3-Very Long Chain Polyunsaturated Fatty Acid Production by an Exclusively Acyl-CoA-dependent Pathway^*

Mareike Hoffmann, Martin Wagner, Amine Abbadi, Martin Fulda, and Ivo Feussner¹

From the Albrecht-von-Haller-Institut für Pflanzenwissenschaften, Abteilung Biochemie der Pflanze, Justus-von-Liebig-Weg 11, D-37077 Göttingen and Norddeutsche Pflanzenzucht, Hans-Georg Lembke KG, Hohenlieth, 24363 Holtsee, Germany

3-Very long chain polyunsaturated fatty acids (VLCPUFA) are essential for human development and brain function and, thus, are indispensable components of the human diet. The current main source of VLCPUFAs is represented by ocean fish stocks, which are in severe decline, and the development of alternative, sustainable sources of VLCPUFAs is urgently required. Our research aims at exploiting the powerful infrastructure available for the large scale culture of oilseed crops, such as rapeseed, to produce VLCPUFAs such as eicosapentaenoic acid in transgenic plants. VLCPUFA biosynthesis requires repeated desaturation and repeated elongation of long chain fatty acid substrates. In previous experiments the production of eicosapentaenoic acid in transgenic plants was found to be limited by an unexpected bottleneck represented by the acyl exchange between the site of desaturation, endoplasmic reticulum-associated phospholipids, and the site of elongation, the cytosolic acyl-CoA pool. Here we report on the establishment of a coordinated, exclusively acyl-CoA-dependent pathway, which avoids the rate-limiting transesterification steps between the acyl lipids and the acyl-CoA pool during VLCPUFA biosynthesis. The pathway is defined by previously uncharacterized enzymes, encoded by cDNAs isolated from the microalga Mantoniella squamata. The conceptual enzymatic pathway was established and characterized first in yeast to provide proof-of-concept data for its feasibility and subsequently in seeds of Arabidopsis thaliana. The comparison of the acyl-CoA-dependent pathway with the known lipid-linked pathway for VLCPUFA biosynthesis showed that the acyl-CoA-dependent pathway circumvents the bottleneck of switching the 6-desaturated fatty acids between lipids and acyl-CoA in Arabidopsis seeds.

Received for publication, March 26, 2008 , and in revised form, June 12, 2008.

^* This work was supported by grants from Fonds der Chemischen Industrie and the Union zur Förderung von Oelund Proteinpflanzen e. V. (to M. H.) and by the Bundesministerium für Bildung und Forschung 0313637c (Project "OLeRa" (to I. F.)). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AM949596 [GenBank] and AM949597.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ To whom correspondence should be addressed. Tel.: 49-551-39-5743; Fax: 49-551-39-5749; E-mail: ifeussn{at}uni-goettingen.de.

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