Synthesis and metabolism of straight chain fatty acids

From LipidomicsWiki

Ninety percent of all fatty acids in mammalian cells are obtained from de novo synthesis and most fatty acids of biological importance have a chain length between 14 and 20 C-atoms. In mammalian organisms fatty acids are composed of carbon hydrates, which constitute the majority, and partially of some amino acids. The highest rate of de novo synthesis occurs in liver, where excess glucose is converted to pyruvate and then to citrate, which is used by ATP citrate lyase to produce acetyl CoA.

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The first step in the synthesis involves acetyl CoA from mitochondria, which is transported from mitochondria to the cytosol via the citrate/pyruvate shuttle (Fig.5). The multicomplex of acetyl CoA carboxylase (ACC) mediates the carboxylation to malonyl CoA. Malonyl-CoA serves dual functions as an intermediate in fatty acid synthesis and as a regulatory effector, that means: malonyl-CoA controls fatty acid oxidation both in liver and muscle by regulating the entry of fatty acids into mitochondria (Dowell et al. 2005). There are two isoforms of ACC, ACC1 and ACC2, both of which catalyse formation of malonyl-CoA and exhibit different tissue expression patterns (Munday, 2002; Brownsey et al. 2006). ACC1 is expressed primarily in lipogenic tissues, e.g., liver and adipose, whereas ACC2 is expressed primarily in heart and skeletal muscle. ACC1 carries out the first and key regulatory step in fatty acid biosynthesis. Malonyl-CoA formed in this step serves as substrate for FAS, which catalyzes chain reductive elongation, leading to the formation of long-chain (C16 and C18) fatty acids. Certain tissues, i.e., skeletal and heart muscle, do not carry out fatty acid synthesis because they lack FAS. However, these tissues express ACC2 and another enzyme, i.e., MCD, which removes malonyl-CoA. The ACC-catalyzed reaction is regulated in several ways, including regulation by allosteric effectors and phosphorylation by the 5AMPdependent protein kinase.
Malonyl CoA, acetyl CoA and NADPH are substrates for fatty acid synthase (FAS) in the elongation of fatty acids. Mammalian FAS is a complexed multifunctional enzyme that consists of two identical monomers and one monomer contains six catalytic activities needed for fatty acid synthesis, however only the dimeric form is functionally active (Chirala et al. 2004). FAS has been found in various epithelial tumor cells, including breast cancer and recent studies showed that inhibition of FAS causes accumulation of malonyl-CoA, which leads to inhibition of carnitine palmitoyltransferase (CPT-1) and up-regulation of ceramide and induction of the proapoptotic genes BNIP3, TRAIL, and DAPK2, resulting in apoptosis (Bandyopadhyaa et al. 2006).
FAS catalyses series of progressive reactions of elongation of the acetyl group by C2 units derived from malonyl-CoA tethered to the enzyme by the pantotheine arm. The ß-ketoacylsynthase- condensing enzyme is responsible for the condensation of the three-carbon malonyl-CoA with the two carbon acetyl-CoA, releasing CO2, and elongating the fatty-acid carbon chain. After the reductase and dehydratase steps, the entire process is repeated seven times to generate palmitate (C16:0), which is cleaved from FAS by its thioesterase activity to release the free fatty acid.
The synthesis of fatty acids longer than 16 carbons occurs in microsomes and utilizes malonyl CoA as the source of carbon (Fig.6).

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Nutritional availability of essential n-3 polyunsaturated fatty acids (n-3 PUFAs) is critical for many physiological processes (Jeffrey et al. 2001, Salem et al. 2001, Uauy et al. 2001). PUFAs can serve as intermediates in signal transduction (Brash et al. 2001), as a source of eicosanoids or docosanoids (Fitzpatrick et al. 2001, Zhou et al. 2001), as proinflammatory factors (Toborek et al. 2002) and as neuroprotective agents (Lauritzen et al. 2000). They also modulate immune and inflammatory responses (Kelley et al. 2001), and influence human cardiovascular (Dewailly et al. 2001) and brain diseases (Martinez et al. 2001). Western diets are rich in n-6 PUFAs, and an increasing consumption of n-3 PUFAs may counteract some of the effects produced by n-6 PUFAs.
The action of n–6 and n–3 fatty acids on metabolic and physiologic pathways may involve 3 general mechanisms: membrane phospholipid fatty acids influence the properties of the microenvironment of membrane bilayers and this in turn can affect the activity of membrane-associated proteins, receptors, transport systems, and ion channels; membrane phospholipids and their n–6 and n–3 fatty acids function as signal molecules and as precursors for eicosanoids; and finally, the n–6 and n–3 fatty acids have rapid and direct effects on gene expression through peroxisome proliferator activated receptor (PPAR)-dependent and PPAR-independent mechanisms.
Arachidonic acid (ARA, 20:4n–6) and docosahexaenoic acid (DHA, 22:6n–3) are formed from linoleic acid (LA, 18:2n–6) and α-linolenic acid, (LNA, 18:3n–3), respectively, in the liver by a series of alternating desaturation (addition of a double bond) and elongation (addition of a 2-carbon unit) reactions (Ferdinandusse et al. 2001, Sprecher et al. 1999).
Although LA and LNA are formed in plants, they cannot be formed in mammalian cells because of the absence of the Δ12 and 15 enzymes necessary to insert a double bond at the n (or ω) 6 or 3 position of a fatty acid carbon chain. LA and LNA are, therefore, considered essential dietary nutrients. Once obtained from the diet, LA and LNA are further metabolized by Δ6 desaturation, elongation, and Δ5 desaturation to form ARA and eicosapentaenoic acid (EPA, 20:5n–3), respectively. The Δ5 desaturase and subsequent steps in the pathway are found in animal but not in plant cells. Preformed ARA and DHA are present in the diet in meat, fish, and eggs but not in fruits, vegetables, nuts, grains, or their products. For many years, it was assumed that fatty acid desaturation occurred in the endoplasmic reticulum and that the final steps in the synthesis of DHA and the n–6 DPA (22:5n–6) involved a Δ4 desaturation of 22:5n–3 to 22:6n–3 and 22:4n–6 to 22:5n–6. However, it is now known that the pathway involves synthesis of 24:5n–3 and 24:4n–6 by elongation of the 22 carbon chain products of Δ5 desaturase (Ferdinandusse et al. 2001, Sprecher et al. 1999) The 24:5n–3 and 24:4n–6 are desaturated at position 6 to yield 24:6n–3 and 24:6n–3, which are translocated to the peroxisomes where partial oxidation generates DHA (22:6n–3) and DPA (22:5n–6) (Ferdinandusse et al. 2001).
Endogenous synthesis of DHA and ARA is believed to use the same Δ6 and Δ5 desaturase enzymes. This can result in competition between LA and LNA as well as inhibition of the enzyme pathway by products of the same and the opposing series of fatty acids. For example, high dietary intakes of EPA or DHA result in decreased tissue ARA and decreased formation of ARA derived eicosanoids in favor of n–3 fatty acid derived eicosanoids (Broughton et al. 2002, Fischer et al. 1989).