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Biosynthesis of nervonic acid and perspectives for its production by microalgae and other microorganisms

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Nervonic acid (NA) is a major very long-chain monounsaturated fatty acid found in the white matter of mammalian brains, which plays a critical role in the treatment of psychotic disorders and neurological development. In the nature, NA has been synthesized by a handful plants, fungi, and microalgae. Although the metabolism of fatty acid has been studied for decades, the biosynthesis of NA has yet to be illustrated. Generally, the biosynthesis of NA is considered starting from oleic acid through fatty acid elongation, in which malonyl-CoA and long-chain acyl-CoA are firstly condensed by a rate-limiting enzyme 3-ketoacyl-CoA synthase (KCS). Heterologous expression of kcs gene from high NA producing species in plants and yeast has led to synthesis of NA. Nevertheless, it has also been reported that desaturases in a few plants can catalyze very long-chain saturated fatty acid into NA. This review highlights recent advances in the biosynthesis, the sources, and the biotechnological aspects of NA.
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MINI-REVIEW
Biosynthesis of nervonic acid and perspectives for its production
by microalgae and other microorganisms
Yong Fan
1
&Hui-Min Meng
1
&Guang-Rong Hu
1
&Fu-Li Li
1
Received: 2 December 2017 /Revised: 11 February 2018 /Accepted: 12 February 2018 /Published online: 24 February 2018
#Springer-Verlag GmbH Germany, part of Springer Nature 2018
Abstract
Nervonic acid (NA) is a major verylong-chain monounsaturated fatty acid found in the white matter of mammalian brains, which
plays a critical role in the treatment of psychotic disorders and neurological development. In the nature, NA has been synthesized
by a handful plants, fungi, and microalgae. Although the metabolism of fatty acid has been studied for decades, the biosynthesis
of NA has yet to be illustrated. Generally, the biosynthesis of NA is considered starting from oleic acid through fatty acid
elongation, in which malonyl-CoA and long-chain acyl-CoA are firstly condensed by a rate-limiting enzyme 3-ketoacyl-CoA
synthase (KCS). Heterologous expression of kcs gene from high NA producing species in plants and yeast has led to synthesis of
NA. Nevertheless, it has also been reported that desaturases in a few plants can catalyze very long-chain saturated fatty acid into
NA. This review highlights recent advances in the biosynthesis, the sources, and the biotechnological aspects of NA.
Keywords Very long-chain monounsaturated fatty acids .Synthetic biology .Metabolic engineering .Cellular engineering .
3-Ketoacyl-CoA synthesis
Introduction
Nervonic acid (C24:1 Δ15; cis-tetracos-15-enoic acid, ω-9;
NA) is a major very long-chain monounsaturated fatty acid
(VLCMFA), which is bound via an amide bond to a sphingo-
sine base (Jr et al. 1997; Poulos 1995). Nervonyl
sphingolipids are main components of the white matter of
brains and myelin sheath of nerve fibers (Martínez and
Mougan 2010). NA level has been found to be significantly
decreased in individuals with a psychotic disorder (Amminger
et al. 2012), whereas no significant differences have been
observed for other fatty acids, including docosahexaenoic acid
(DHA) or arachidonic acid (AA). As a major component of
the myelin sheath, reduced levels of NA may reflect the sub-
optimal myelin status in individuals at a high risk of develop-
ing psychotic disorders (Coupland and Raoul 2001).
The use of NA supplements has become an established
method for the treatment of symptoms of several neurological
disorders (Vozella et al. 2017). The NA content of
sphingomyelin in the tissues of developing rats can be elevat-
ed by feeding dietary NA (Strandvik et al. 2016). NA has also
been reported to act as an essential long-chain fatty acid in
infants, particularly during nerve cell development in prema-
ture infants (Farquharson et al. 1996).
NA is able to interact with DNA polymerase β(Mizushina
et al. 1999) by spatially binding with four amino acids (Leull,
Lys35, His51, and Thr79). This binding pocket is similar to
that of the human immunodeficiency virustype-1reverse tran-
scriptase (HIV-1 RT), which allowed the researchers to build a
structural model of HIV-1 RT. NA can function as a non-
competitive inhibitor of HIV-RT in a dose-dependent manner
(Kasai et al. 2002). More recently, monounsaturated fatty
acids were demonstrated to be able to extend lifespan in
Caenorhabditis elegans. Since lipid metabolism between
worms and mammal is conserved, suggesting the benefits of
long-chain monounsaturated fatty acids on health might also
be conserved (Han et al. 2017). This provides a new perspec-
tive to understand the physiological functions of VLCMFAs,
especially NA.
Yong Fan and Hui-Min Meng contributed equally to this work
*Fu-Li Li
lifl@qibebt.ac.cn
1
Key Laboratory of Biofuels, Shandong Provincial Key Laboratory of
Synthetic Biology, Qingdao Engineering Laboratory of Single Cell
Oil, Qingdao Institute of Bioenergy and Bioprocess Technology,
Chinese Academy of Sciences, 189 Songling Road,
Qingdao 266101, Peoples Republic of China
Applied Microbiology and Biotechnology (2018) 102:30273035
https://doi.org/10.1007/s00253-018-8859-y
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... Each elongation cycle involves four successive reactions. Malonyl-CoA and a long-chain acyl-CoA are condensed by KCS, which is then reduced by KCR to 3hydroxyacyl-CoA, and then 3-hydroxyacyl-CoA is dehydrated by HCD and subsequently reduced to form elongated acyl-CoA catalyzed by ECR (Harwood, 2005;Haslam and Kunst, 2013;Li-Beisson et al., 2013;Huai et al., 2015;Fan et al., 2018; Figure 2). ...
... After synthesis, EA is assembled and stored as TAGs, and the pathway consists of the sequential acylation and dephosphorylation of glycerol-3-phosphate (G3P). G3P is catalyzed by glycerol-3-phosphate acyltransferase (GPAT) to produce lysophospholipids (LPAs); LPA is catalyzed by lysophosphatidic acid acyltransferase (LPAT/LPAAT) to produce phosphatidic acid (PA); PA is catalyzed by phosphatidic acid phosphorylase (PAP) to produce diacylglycerol (DAG); and DAG is catalyzed by diacylglycerol acyltransferase (DGAT) to produce TAG (Stumpf and Pollard, 1983;Bates et al., 2009;Li-Beisson et al., 2013;Fan et al., 2018; Figure 2). GPAT, LPAAT, and DGAT are the three main enzymes of the Kennedy pathway and play very important regulatory roles in the biosynthesis of lipids and phospholipids. ...
... synthesis in plants. Phospholipid diacylglycerol acyltransferase (PDAT) allows the transfer of FAs from the sn-2 position of phosphatidylcholine (PC) to the sn-3 position of DAG, producing TAG and lysophosphatidylcholine (LPC) products (Bates et al., 2009;Lu et al., 2009;Taylor et al., 2011;Fan et al., 2018; Figure 2). PDCT mediates a symmetrical interconversion between phosphatidylcholine (PC) and DAG by catalyzing the shuffling of acyl groups between them. ...
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... Both of these lipid species are examples of very-long-chain fatty-acyl sphingolipids. While shorter fatty acids (≤C18) are prevalent in the human diet 44 , often serving as preferential substrates for ceramide synthesis by certain gut microbes, longer-chain fatty acids, such as nervonic acid (24:1), are often the product of elongation by host enzymes before incorporation into sphingolipids primarily found in brain tissue 45 . This result was corroborated in Bar et al., where only short-chain sphingolipids were observed to be associated with the microbiome 1 . ...
... Ceramides with a ≤C18 fatty-acyl group showed stronger correspondence with the gut microbiome, consistent with the high prevalence of these fatty acids in the diet 44 and their preferential incorporation into ceramides by certain gut taxa 53 . On the other hand, ceramides with very-long-chain fatty-acyl groups (22:1, 24:1), which are most abundant in brain tissue and often synthesized through elongation by host enzymes 45 , showed a stronger correspondence with host genetics. Importantly, ceramides with different fatty-acyl chain lengths have been implicated in a number of human diseases including Alzheimer's disease, depression and mood disorders 54 . ...
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... First discovered in the brain of sharks, nervonic acid, also known as selacholeic acid, is very abundant in nervous system and brain tissues of vertebrate animals, where it is bound to sphingosine via amide linkage to form nervonyl sphingolipids [370]. These sphingolipids are the principal components of white matter and the myelin sheath of nerve fibers [371][372][373]. ...
... Genetic engineering approaches have been implemented to obtain microorganisms, microalgae, and plants producing oils rich in nervonic acid suitable for nutraceutical and pharmacological applications [196,370,393]. Improvement of existing plant sources, especially in the Brassicaceae family, was considered to generate new elite cultivars. ...
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... It binds to sphingosine to form sphingomyelin, which is an integral component of myelin (Martínez and Mougan, 2010). Some clinical studies and animal disease models suggest that, on the one hand, NA intake can promote brain development (Fan et al., 2018;. The NA level in sphingomyelin of red blood cells from premature infants may reflect NA levels in sphingomyelin of the brain and could thus reflect brain maturity (Babin et al., 1993); On the other hand, NA can relieve the symptoms of some neurodegenerative diseases (Zheng et al., 2017). ...
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... The traditional urea inclusion method and crystallization method have a low efficiency [4]. NA can be chemically synthesized with cis-13-docosenyl methyl ester as a precursor; however, the yield of NA by chemical synthesis is low, and there are many by-products [5,6]. ...
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