Review
Metabolism of highly unsaturated n-3 and n-6 fatty acids

https://doi.org/10.1016/S1388-1981(00)00077-9Get rights and content

Introduction

It is generally accepted that dietary linoleate and linolenate are metabolized, respectively, to 5,8,11,14–20:4 and 5,8,11,14,17–20:5 via the use of position-specific Δ6 and Δ5 desaturases and a malonyl-CoA-dependent chain elongation step as follows:

  • •

    the n-6 pathway starting from dietary linoleate, 9,12–18:2→6,9,12–18:3→8,11,14–20:3→5,8,11,14–20:4;

  • •

    the n-3 pathway starting from dietary linolenate, 9,12,15–18:3→6,9,12,15–18:4→8,11,14,17–20:4→5,8,11,14,17–20:5.

The first objective of this review is to summarize some of the more important contributions that have been made to establish the validity of these pathways.

For many years, it was assumed, but not proven, that the synthesis of 22-carbon acids with their first double bond at position 4 requires an acyl-CoA-dependent Δ4 desaturase. It has now been established that the synthesis of these compounds requires a degradative step and proceeds as follows:

  • •

    the n-6 pathway, 5,8,11,14–20:4→7,10,13,16–22:4→9,12,15,18–24:4→6,9,12,15,18–24:5→4,7,10,13,16–22:5;

  • •

    the n-3 pathway, 5,8,11,14,17–20:5→7,10,13,16,19–22:5→9,12,15,18,21–24:5→6,9,12,15,18,21–24:6→4,7,10,13,16,19–22:6.

The second objective of this review is to summarize evidence that led to the elucidation of these pathways and controls that are operative for regulating the synthesis of polyunsaturated fatty acids (PUFA) with their first double bond at position 4.

The revised pathways for the biosynthesis of PUFA require the participation of both microsomes and peroxisomes as they relate to the synthesis of 22-carbon acids with their first double bond at position 4. The last objective of the review is to summarize results of studies to determine what regulates biosynthesis of 20-versus 22-carbon n-3 and n-6 PUFA.

Section snippets

Synthesis of 20-carbon PUFA

The metabolic pathways of PUFA biosynthesis were elucidated primarily in the laboratories of Klenk [1] and Mead [2] more than 40 years ago. Both groups of investigators developed techniques to synthesize labeled PUFA which were administered to animals. Tissue lipid PUFA were isolated and degraded. The labeling profiles of these compounds were used to propose pathways for PUFA biosynthesis. These studies also established that there was no direct interconversion between metabolites in the two

Synthesis of 22-carbon PUFA with their first double bond at position 4

For years it was assumed that 4,7,10,13,16–22:5 and 4,7,10,13,16,19–22:6 were synthesized, respectively, from 7,10,13,16–22:4 and 7,10,13,16,19–22:5 by a microsomal acyl-CoA-dependent Δ4 desaturase. The first paper questioning this hypothesis was published in 1973 when Ayala et al. [37] reported that testes and liver microsomes did not desaturate 7,10,13,16–22:4. In essence, we repeated this experiment and observed that liver microsomes did not desaturate 7,10,13,16,19–22:5. When malonyl-CoA

Control of the biosynthesis of PUFA with their first double bond at position 4

The synthesis and esterification of 22-carbon acids, with their first double bond at position 4, is a more complex process than is the synthesis of 20-carbon acids with their first double bond at position 5. Enzymes in both peroxisomes and microsomes are used. In addition, fatty acids move between these two subcellular compartments. The diagram in Fig. 1 depicts a simplified overview of some of these processes. When 24-carbon PUFA are produced from precursors in hepatocytes, or used directly as

Revised pathways for the biosynthesis of PUFA

The diagram in Fig. 2 depicts revised pathways for the biosynthesis of n-3 and n-6 PUFA. These pathways raise several new questions about the regulation of PUFA biosynthesis. Both 9,12–18:2 and 9,12,15–18:3 are metabolized via identical reaction sequences. The pathways show that there is recycling of 22- and 24-carbon PUFA. These pathways show that fatty acids are partially degraded without the loss of any double bonds. These conversions use only the enzymes of saturated fatty acid degradation.

Conclusions

Recent progress in the cloning and expression of Δ6 and Δ5 desaturases has conclusively established that position-specific desaturases are required to synthesize 20-carbon acids with their first double bond at position 5. It remains to be determined if there are 18- and 24-carbon chain-length-specific Δ6 desaturases. There has been relatively little recent progress in determining how many enzymes are required to chain elongate PUFA. The number of proteins expressed in tissue-specific ways is

Acknowledgments

The authors studies cited in this review were partially supported by NIH Grants DK20387 and DK48744.

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