File Name: biosynthesis and oxidation of fatty acids .zip
Fatty acid synthesis is known to occur exclusively in plastids, since it has been shown that the enzymes essential for fatty acid biosynthesis are found only in this organelle Ohlrogge et al. Hence, in leaves fatty acids are made in chloroplasts and in seeds they are formed in modified plastids leucoplasts that are specialized for fatty acid biosynthesis.
Fatty Acid Synthesis and Breakdown
Harwood; Oxidation of polyunsaturated fatty acids to produce lipid mediators. Essays Biochem 23 September ; 64 3 : — The chemistry, biochemistry, pharmacology and molecular biology of oxylipins defined as a family of oxygenated natural products that are formed from unsaturated fatty acids by pathways involving at least one step of dioxygen-dependent oxidation are complex and occasionally contradictory subjects that continue to develop at an extraordinarily rapid rate.
The term includes docosanoids e. For example, the term eicosanoid is used to embrace those biologically active lipid mediators that are derived from C 20 fatty acids, and include prostaglandins, thromboxanes, leukotrienes, hydroxyeicosatetraenoic acids and related oxygenated derivatives.
The key enzymes for the production of prostanoids are prostaglandin endoperoxide H synthases cyclo-oxygenases , while lipoxygenases and oxidases of the cytochrome P family produce numerous other metabolites. In plants, the lipoxygenase pathway from C 18 polyunsaturated fatty acids yields a variety of important products, especially the jasmonates, which have some comparable structural features and functions.
Related oxylipins are produced by non-enzymic means isoprostanes , while fatty acid esters of hydroxy fatty acids FAHFA are now being considered together with the oxylipins from a functional perspective. In all kingdoms of life, oxylipins usually act as lipid mediators through specific receptors, have short half-lives and have functions in innumerable biological contexts. Since the pioneering work of George and Mildred Burr reviewed in [ 1 ] some 90 years ago, it has been known that certain fatty acids are essential in human and most other animal diets.
There are two types of essential fatty acids EFAs , which belong to the n -3 omega-3 and n -6 omega-6 polyunsaturated fatty acid PUFA families i.
They are produced almost entirely in photosynthetic organisms that evolve oxygen—such as cyanobacteria, algae, mosses and higher plants. While LA and ALA can be regarded as the key EFAs of the n -6 and n -3 families, respectively, there may be a need for longer chain PUFAs, produced from these precursors by sequential elongation and desaturation reactions, for specific functions.
Such acids e. Polyunsaturated fatty acids are important components of phospholipids in membranes to which they impart desirable physical properties. However, a major reason why we need EFA and why they produce so many diverse effects is because they are metabolised to give rise to lipid signalling molecules [ 5 ]. Although linoleic acid is an important constituent of skin lipids [ 6 ], where it has vital functions, much of the dietary need for EFAs is to make longer-chain lipid signalling molecules.
In this article, we briefly describe the conversion of n -3 and n -6 PUFAs into various classes of lipid mediators. More details of the metabolism and function of these lipid mediators will be found in subsequent chapters that cover eicosanoids, isoprostanes, specialised pro-resolving mediators SPMs , endocannabinoids and jasmonates. A simplified picture of the generation of classic eicosanoids derived from the Greek for 20 is shown in Figure 1.
Three different types of oxidation reactions utilise a carbon unesterified fatty acid precursor, such as arachidonic acid ARA, the main n -6 precursor or eicosapentaenoic acid EPA, the main n -3 precursor.
These involve lipoxygenase, cyclooxygenase and cytochrome P oxidase or epoxygenase enzymes [ 8 ]. A considerable number of PLA 2 enzymes have been characterised and shown to occur in several unrelated protein families [ 9 ]. The concentration of non-esterified PUFAs, such as arachidonic acid, in cells is normally far below the K m of enzymes such as cyclooxygenase prostaglandin H 2 synthase so activation of hydrolytic enzymes, especially cPLA 2 , is a key regulatory reaction.
Other potential sources of ARA or EPA are the plasmalogens but because these lipids are poor substrates for PLA 2 , they are usually hydrolysed by plasmalogenase alkylglycerol monooxygenase first [ 10 , 11 ].
Release of non-esterified PUFAs from membrane lipids can be enhanced by specific physiological stimulae e. Its activity is increased by phosphorylation. Two specific lipids—ceramide 1-phosphate and phosphatidylinositol 4,5- bis phosphate—bind to the enzyme and modify both its activity and its translocation within cells [ 12 ].
The enzyme is rather non-specific towards different phosphoglycerides and towards the fatty acid present at the sn -2 position. There are suggestions that cPLA 2 is involved in the rapid response in prostaglandin synthesis while sPLA 2 is involved at later stages of prostaglandin stimulation after tissues have been activated further by cytokines, growth factors or inflammatory factors. Once the precursor fatty acid ARA or EPA usually has been released from membrane lipids, it can be oxidised by cyclooxygenases more correctly termed prostaglandin endoperoxide H synthases [ 8 , 13 ].
Two reactions are catalysed by a single enzyme—a cyclooxygenase reaction where two molecules of oxygen are added to the substrate and a second peroxidation Figure 2. There are two major human cyclooxygenase isoforms, COX-1 and COX-2, which are haemoproteins and act as homodimers of and amino acids, respectively.
COX-1 is constitutively expressed in many mammalian tissues. It is thought to be responsible for the formation of prostaglandins involved in the general regulation of physiological events. COX-2, on the other hand, is present at low levels until induced by inflammatory stimuli such as cytokines, endotoxins, tumour promoters and some lipids. Both isoforms have similar V max and K m values for ARA, undergo suicide inactivation and their reactions can be initiated by hydroperoxide.
For example, COX-2 needs lower concentrations of hydroperoxide for activation and has a wider substrate specificity including those relevant to endocannabinoid metabolism than COX-1 [ 14 ]. Furthermore, the products of COX reactions will also relate to the balance of substrates available.
Some examples of prostaglandin precursors and their products are shown in Figure 3. The endoperoxide products, in turn, can form a host of different products see Figure 4. An alternative prostaglandin, PGI 2 also known as prostacyclin [ 18 , 19 ] has a distinct function in promoting vasodilation and inhibiting platelet aggregation. Together with its action in inhibiting smooth muscle proliferation, PGI 2 contributes to myocardial protection.
TxA 2 is extremely labile and rearranges spontaneously with a half-life of approximately 30 s to a stable but physiologically inert TxB 2 Figure 4. Because TxA 2 causes platelet aggregation [ 20 ], there have been considerable efforts in searching for inhibitors of its synthesis.
Since TxA 2 and PGI 2 have antagonistic effects on thrombosis and atherogenesis, it is obvious that their balance is essential for good cardiovascular health and maintenance of vascular homeostasis [ 21 ]. Thus, TxA 2 is synthesised mainly in platelets and its production is enhanced during platelet activation to promote aggregation and vasoconstriction. On the other hand, prostacyclin PGI 2 is the main prostanoid produced by vascular endothelial cells.
It will inhibit platelet aggregation and contributes substantially to cardiovascular protection see [ 2 , 22 ]. In the last two decades, several prostanoid receptors have been identified and partly characterised [ 23—25 ]. For prostaglandins, ten receptors have been characterised. In the case of PGE 2 , four receptors EP1—4 have been identified and each has a different mechanism of action.
The receptors have seven transmembrane segments and belong to the G protein-coupled receptor GPCR family which constitute the largest family of receptors in humans approximately coded in the human genome. Apart from prostanoids [ 26 ], receptors have been identified for other lipid mediators [ 27 ]. Lipoxin [ 28 ] and SPMs [ 29 ] also have identified receptors. By using knockout mice, precise functional roles for the individual receptors are being elucidated.
They are produced within tissues and have their main actions in that locality. In general, prostanoids have very short half-lives in vivo. The lung plays a major role in the catabolism with oxidation of the hydroxyl group at C15 being the usual target. This is followed by attack of the double bond and then beta- and omega-oxidation.
Moreover, unlike conventional hormones, they are produced in almost every cell in the body. The prostanoids are transported out of cells via carrier-mediated mechanisms and, once in the circulation, are deactivated rapidly [ 2 , 8 ]. Aspirin acetylsalicylic acid was originally utilised as a substitute for salicylate medicines which had been used for their health properties for 3, years [ 30 , 31 ].
In contrast, the simultaneous inhibition of COX-1 causes most of the unwanted side-effects, such as gastric ulceration [ 32 ]. Once bound to the COX-1 active site, aspirin will cause irreversible inactivation through acetylation of serine For COX-2, the acetylation reaction still allows oxygenation of ARA, in a similar manner to that of a lipoxygenase, but prostaglandin PGH 2 is not formed see section on resolvins.
Some success was achieved initially [ 34 ], but such compounds caused unwanted cardiovascular effects [ 35 ], which led to the clinical withdrawal of the initial products. Lipoxygenases can catalyse three different types of reactions dioxygenation of lipids to give hydroperoxides; hydroperoxidation of the latter into keto lipids; formation of epoxy leukotrienes via leukotriene synthase reaction due to their multifunctional nature.
There are seven LOXs in mice. Orthologues of the same gene have different reaction selectivities in different species. This can often compromise extrapolation of data from animal experiments to human conditions.
Each of the lipoxygenase proteins in animals has a single polypeptide chain of 75—80 kDa mass. The iron is active in the ferric state. While the PUFA substrate is held in a tight channel, smaller channels direct molecular oxygen towards the selected carbon to allow formation of specific hydroperoxy-eicosatetraenes HPETEs , which are subsequently reduced to hydroxy-eicosatetraenes HETEs. Each lipoxygenase acts with high regio- and stereo-specificity to produce HETE with distinctive biological functions in particular tissues.
For formation of leukotrienes, 5-LOX is the key enzyme [ 37 , 38 ]. As for prostanoids, a non-esterified free fatty acid is the substrate. A two-step concerted reaction begins leukotriene formation Figure 5 [ 8 ]. For the second step, two accessory proteins are needed. The unstable LTA 4 appears to have little biological function on its own but can be metabolised in two ways to yield physiologically important leukotrienes.
The leukotrienes have a variety of important biological effects [ 40 ]. LTB 4 is a potent chemotactic agent and is one of the first signals that attract innate immune cells such as leukocytes to the site of insult. These lipid mediators exert a range of pro-inflammatory actions including constriction of airways and vascular smooth muscles.
These are considered one of a group of specialised pro-resolving mediators SPMs which include resolvins, protectins and maresins see later. Oxidation of ARA needs two different types of lipoxygenase in this case see an example in Figure 6 , and as few cell types have both of the necessary lipoxygenases, the synthesis of lipoxins needs trans-cellular pathways [ 42 ].
In such pathways, because a single cell lacks all of the enzymes necessary for a metabolic sequence, it has to combine with another cell type to complete a particular conversion. Of course, such cellular interactions need appropriate transport mechanism s associated with the pathway. Two other minor classes of lipoxygenase products are the eoxins and the hepoxilins. They are potent pro-inflammatory agents [ 43 ]. Hepoxilins are especially important in human epidermis [ 44 , 45 ] and are made in one of two pathways involving LOX.
In addition to cyclooxygenase or lipoxygenase activity, a third oxygenation of relevant PUFAs involves cytochrome P oxidases Figure 1 [ 8 , 47 , 48 ]. These enzymes are membrane-bound hemoproteins that transfer a single oxygen to the substrate carbon i.
The balance of HETEs generated depends on the tissue, cell type and the catalytic efficiency of the individual cytochrome P oxidase isoforms [ 49 ]. In addition to their function in generating HETE isomers, the cytochrome P oxidases have other important roles in lipid metabolism [ 50 ].
For ARA, three types of reaction can occur. First, a series of HETE products can be formed with cis-trans conjugated diols containing a hydroxyl group at one of six positions 5, 8, 9, 11, 12 or Second, omega or omega-1 hydroxylases introduce a hydroxyl group at carbons 20 or 19, respectively, although minor activities with other oxidases can produce 16, 17 or 18 hydroxyl products.
It regulates vascular smooth muscle and endothelial cells by influencing their proliferation, migration, survival, and tube formation, acting via a specific G protein receptor GPR Depending on the cytochrome oxidase isoform, different EETs may predominate although most enzymes can produce all four isomers.
Fatty acid degradation
In order to participate in any metabolic process, fatty acids must first be activated. The thioester bond is a high energy bond. This is apparently because resonance structures which can occur in esters with alcohols, and which stabilizes them, cannot occur in thioesters. The greater size of the sulfur atom compared to the carboxyl oxygen diminishes the stability of the resonance forms. If the structure has less resonance stability, the energy released upon their hydrolysis will be greater.
Harwood; Oxidation of polyunsaturated fatty acids to produce lipid mediators. Essays Biochem 23 September ; 64 3 : — The chemistry, biochemistry, pharmacology and molecular biology of oxylipins defined as a family of oxygenated natural products that are formed from unsaturated fatty acids by pathways involving at least one step of dioxygen-dependent oxidation are complex and occasionally contradictory subjects that continue to develop at an extraordinarily rapid rate. The term includes docosanoids e. For example, the term eicosanoid is used to embrace those biologically active lipid mediators that are derived from C 20 fatty acids, and include prostaglandins, thromboxanes, leukotrienes, hydroxyeicosatetraenoic acids and related oxygenated derivatives.
Frequently Asked Questions (FAQ)
Fatty acids primarily enter a cell via fatty acid protein transporters on the cell surface . Carnitine palmitoyltransferase 1 CPT1 conversion of the long-chain acyl-CoA to long-chain acylcarnitine allows the fatty acid moiety to be transported across the inner mitochondrial membrane via carnitine translocase CAT , which exchanges long-chain acylcarnitines for carnitine. An inner mitochondrial membrane CPT2 then converts the long-chain acylcarnitine back to long-chain acyl-CoA. An overview of fatty acid oxidation is provided in Figure 1. Fatty acids primarily enter a cell via fatty acid protein transporters on the cell surface.
Fatty acid degradation is the process in which fatty acids are broken down into their metabolites, in the end generating acetyl-CoA , the entry molecule for the citric acid cycle , the main energy supply of animals. It includes three major steps:. Initially in the process of degradation, fatty acids are stored in fat cells adipocytes. The breakdown of this fat is known as lipolysis. The products of lipolysis, free fatty acids , are released into the bloodstream and circulate throughout the body.
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