Beta Oxidation Fatty Acids Pdf
Fatty acid metabolism consists of processes that generate energy, and processes that create biologically important molecules (triglycerides, phospholipids, second messengers, local hormones and ). Are a family of molecules classified within the class. One role of fatty acids in metabolism is energy production, captured in the form of (ATP).
When compared to other macronutrient classes (carbohydrates and protein), fatty acids yield the most ATP on an energy per gram basis, when they are completely oxidized to CO 2 and water by and the. Fatty acids (mainly in the form of ) are therefore the foremost storage form of fuel in most animals, and to a lesser extent in plants.
Beta Oxidation of Fatty Acids An Overview Beta oxidation of fatty acids takes place in the mitochondrial matrix forthe most part. However, fatty.
In addition, fatty acids are important components of the that form the out of which all the membranes of the cell are constructed (the, and the membranes that enclose all the within the cells, such as the, the, and the ). Fatty acids can also be cleaved, or partially cleaved, from their chemical attachments in the cell membrane to form within the cell, and in the immediate vicinity of the cell. The made from stored in the cell membrane, are probably the most well known group of these local hormones. A diagrammatic illustration of the process of lipolysis (in a fat cell) induced by high and low levels in the blood. Epinephrine binds to a in the cell membrane of the adipocyte, which causes to be generated inside the cell. The cAMP activates a, which phosphorylates and thus, in turn, activates a in the fat cell. This lipase cleaves free fatty acids from their attachment to glycerol in the fat stored in the fat droplet of the adipocyte.
The free fatty acids and glycerol are then released into the blood. However more recent studies have shown that has to first convert triacylglycerides to diacylglycerides, and that converts the diacylglycerides to monoglycerides and free fatty acids. Monoglycerides are hydrolyzed by monoglyceride lipase. The activity of hormone sensitive lipase is regulated by the circulation hormones, and, as shown in the diagram. A diagrammatic illustration of the process of the of an acyl-CoA molecule in the mitochodrial matrix. During this process an acyl-CoA molecule which is 2 carbons shorter than it was at the beginning of the process is formed.
Acetyl-CoA, water and 5 molecules are the other products of each beta-oxidative event, until the entire acyl-CoA molecule has been reduced to a set of molecules. Fatty acids are released, between meals, from the fat depots in, where they are stored as, as follows:., the removal of the fatty acid chains from the glycerol to which they are bound in their storage form as triglycerides (or fats), is carried out. These lipases are activated by high and levels in the blood (or secreted by in adipose tissue), caused by declining blood levels after meals, which simultaneously lowers the level in the blood. Once freed from, the free fatty acids enter the blood, which transports them, attached to plasma, throughout the body. Long chain free fatty acids enter the metabolizing cells (i.e. Most living cells in the body except and in the ) through specific, such as the family fatty acid transport protein.
Red blood cells do not contain and are therefore incapable of metabolizing fatty acids; the tissues of the central nervous system cannot use fatty acids, despite containing mitochondria, because long chain fatty acids (as opposed to medium chain fatty acids ) cannot cross the into the that bathe these cells. Once inside the cell catalyzes the reaction between a fatty acid molecule with (which is broken down to and inorganic pyrophosphate) to give a fatty acyl-adenylate, which then reacts with free to give a fatty molecule. In order for the acyl-CoA to enter the mitochondrion the carnitine shuttle is used:. Acyl-CoA is transferred to the hydroxyl group of carnitine by, located on the cytosolic faces of the and. Acyl-carnitine is shuttled inside by a, as a carnitine is shuttled outside.
Acyl-carnitine is converted back to acyl-CoA by, located on the interior face of the. The liberated carnitine is shuttled back to the cytosol, as an acyl-CoA is shuttled into the matrix., in the mitochondrial matrix, then cuts the long carbon chains of the fatty acids (in the form of acyl-CoA molecules) into a series of two-carbon units, which, combined with, form molecules of, which condense with to form at the 'beginning' of the.
It is convenient to think of this reaction as marking the 'starting point' of the cycle, as this is when fuel - acetyl-CoA - is added to the cycle, which will be dissipated as CO 2 and H 2O with the release of a substantial quantity of energy captured in the form of, during the course of each turn of the cycle. Briefly, the steps in beta oxidation (the initial breakdown of free fatty acids into acetyl-CoA) are as follows:. Dehydrogenation by, yielding 1. Hydration by. Dehydrogenation by, yielding 1. Cleavage by, yielding 1 and a fatty acid that has now been shortened by 2 carbons (forming a new, shortened ) This beta oxidation reaction is repeated until the fatty acid has been completely reduced to or, in, the case of fatty acids with odd numbers of carbon atoms, and 1 molecule of per molecule of fatty acid.
Each beta oxidative cut of the acyl-CoA molecule yields 5 molecules. The acetyl-CoA produced by beta oxidation enters the in the mitochondrion by combining with to form.
This results in the complete combustion of the acetyl-CoA to CO 2 and water. The energy released in this process is captured in the form of 1 and 11 molecules per acetyl-CoA molecule oxidized. This is the fate of acetyl-CoA wherever beta oxidation of fatty acids occurs, except under certain circumstances in the. In the liver oxaloacetate can be wholly or partially diverted into the during fasting, starvation, a low carbohydrate diet, prolonged strenuous exercise, and in uncontrolled. Under these circumstances oxaloacetate is hydrogenated to which is then removed from the mitochondrion to be converted into in the cytoplasm of the liver cells, from where it is released into the blood. In the liver, therefore, oxaloacetate is unavailable for condensation with acetyl-CoA when significant gluconeogenesis has been stimulated by low (or absent) and high concentrations in the blood.
Under these circumstances acetyl-CoA is diverted to the formation of and. Acetoacetate, beta-hydroxybutyrate, and their spontaneous breakdown product, are frequently, but confusingly, known as (as they are not 'bodies' at all, but water-soluble chemical substances). The ketone bodies are released by the liver into the blood. All cells with mitochondria can take ketone bodies up from the blood and reconvert them into acetyl-CoA, which can then be used as fuel in their citric acid cycles, as no other tissue can divert its oxaloacetate into the gluconeogenic pathway in the way that this can occur in the liver. Unlike free fatty acids, ketone bodies can cross the and are therefore available as fuel for the cells of the, acting as a substitute for glucose, on which these cells normally survive. The occurrence of high levels of ketone bodies in the blood during starvation, a low carbohydrate diet, prolonged heavy exercise and uncontrolled type 1 diabetes mellitus is known as, and, in its extreme form, in out-of-control type 1 diabetes mellitus, as.
The glycerol released by lipase action is by in the liver (the only tissue in which this reaction can occur), and the resulting is oxidized to. The glycolytic enzyme converts this compound to, which is oxidized via, or converted to glucose via. Fatty acids as an energy source. Example of an unsaturated fat triglyceride. Left part:, right part from top to bottom:,.
Chemical formula: C 55H 98O 6 Fatty acids, stored as triglycerides in an organism, are an important source of energy because they are both and. The energy yield from a of fatty acids is approximately 9 (37 kJ), compared to 4 kcal (17 kJ) for carbohydrates. Since the portion of fatty acids is, these can be stored in a relatively (water-free) environment. Carbohydrates, on the other hand, are more highly hydrated. For example, 1 g of can bind approximately 2 g of, which translates to 1.33 kcal/g (4 kcal/3 g).
This means that fatty acids can hold more than six times the amount of energy per unit of storage mass. Put another way, if the human body relied on carbohydrates to store energy, then a person would need to carry 31 kg (67.5 ) of hydrated glycogen to have the energy equivalent to 4.6 kg (10 lb) of. Animals provide a good example for utilizing fat reserves as fuel. For example, bears hibernate for about 7 months, and, during this entire period, the energy is derived from degradation of fat stores. Migrating birds similarly build up large fat reserves before embarking on their intercontinental journeys.
Thus the young adult human’s fat stores average between about 10–20 kg, but varies greatly depending on age, gender, and individual disposition. By contrast the human body stores only about 400 g of, of which 300 g is locked inside the skeletal muscles and is unavailable to the body as a whole. The 100 g or so of glycogen stored in the liver is depleted within one day of starvation. Thereafter the glucose that is released into the blood by the liver for general use by the body tissues, has to be synthesized from and a few other, which do not include fatty acids. Please note however that lipolysis releases glycerol which can enter the pathway of gluconeogenesis. Animals and plants synthesize carbohydrates from both glycerol and fatty acids Fatty acids are broken down to by means of inside the mitochondria, whereas from acetyl-CoA outside the mitochondria, in the cytosol.
The two pathways are distinct, not only in where they occur, but also in the reactions that occur, and the substrates that are used. The two pathways are mutually inhibitory, preventing the acetyl-CoA produced by beta-oxidation from entering the synthetic pathway via the reaction. It can also not be converted to as the reaction is irreversible. Instead the acetyl-CoA produced by the beta-oxidation of fatty acids condenses with, to enter the. During each turn of the cycle, two carbon atoms leave the cycle as CO 2 in the decarboxylation reactions catalyzed by and.
Thus each turn of the citric acid cycle oxidizes an acetyl-CoA unit while regenerating the oxaloacetate molecule with which the acetyl-CoA had originally combined to form. The decarboxylation reactions occur before is formed in the cycle. Only plants possess the enzymes to convert acetyl-CoA into oxaloacetate from which malate can be formed to ultimately be converted to glucose. However acetyl-CoA can be converted to acetoacetate, which can decarboxylate to (either spontaneously, or by ).
It can then be further metabolized to isopropanol which is excreted in breath/urine, or by into (acetol). Acetol can be converted to. This converts to and (the latter converting to glucose), or (by two alternative enzymes), or, or to then (the common lactate isomer). Another pathway turns acetol to, then to, or to (via S-D-lactoyl-glutathione or otherwise) then. D-lactate metabolism (to glucose) is slow or impaired in humans, so most of the D-lactate is excreted in the urine; thus D-lactate derived from acetone can contribute significantly to the metabolic acidosis associated with ketosis or isopropanol intoxication. L-Lactate can complete the net conversion of fatty acids into glucose.
Fatty Acids List
The first experiment to show conversion of acetone to glucose was carried out in 1951. This, and further experiments used carbon. Up to 11% of the glucose can be derived from acetone during starvation in humans.
The glycerol released into the blood during the of triglycerides in adipose tissue can only be taken up by the liver. Here it is converted into by the action of which hydrolyzes one molecule of per glycerol molecule which is phosphorylated.
Glycerol 3-phosphate is then oxidized to, which is, in turn, converted into by the enzyme. From here the three carbon atoms of the original glycerol can be oxidized via, or converted to glucose via. Other functions and uses of fatty acids Intracellular signaling.
Chemical structure of the diglyceride 1-palmitoyl-2-oleoyl-glycerol Fatty acids are an integral part of the phospholipids that make up the bulk of the, or cell membranes, of cells. These phospholipids can be cleaved into (DAG) and (IP 3) through of the phospholipid, (PIP 2), by the cell membrane bound enzyme (PLC). An example of a diacyl-glycerol shown on the right. This DAG is 1-palmitoyl-2-oleoyl-glycerol, which contains side-chains derived from and. Diacylglycerols can also have many other combinations of fatty acids attached at either the C-1 and C-2 positions or the C-1 and C-3 positions of the glycerol molecule. 1,2 disubstituted glycerols are always chiral, 1,3 disubstituted glycerols are chiral if the substituents are different from each other. PIP 2 cleavage to IP 3 and DAG.
IP 3 initiates intracellular calcium release, while DAG activates PKC (protein kinase C). Note: PLC (phospholipase C) is not an intermediate, as possibly suggested by the diagram, but is the enzyme that catalyzes the IP3/DAG separation. (IP 3) functions as an intracellular, which initiates the (which activates intracellular enzymes, causes the release of hormones and neurotransmitters from the cells in which they are stored, and causes contraction when released by IP 3), and the activation of (PKC), which is then translocated from the cell cytoplasm to the cell membrane. Although inositol trisphosphate, (IP 3), diffuses into the, (DAG) remains within the, due to its properties.
IP 3 stimulates the release of calcium ions from the smooth endoplasmic reticulum, whereas DAG is a physiological activator of (PKC), promoting its translocation from the cytosol to the. PKC is a multifunctional protein kinase which phosphorylates and residues in many target proteins.
However PKC is only active in the presence of calcium ions, and it is DAG that increases the affinity of PKC for Ca 2+ and thereby renders it active at the physiological intracellular levels of this ion. Diacylglycerol and IP 3 act transiently because both are rapidly metabolized. This is important as their message function should not linger after the message has been” received” by their target molecules. DAG can be phosphorylated to or it can be it can be hydrolysed to glycerol and its constituent fatty acids. IP 3 is rapidly converted to into derivatives that that do not open calcium ion channels.
Eicosanoid paracrine hormones. The are a group of active compounds having diverse -like effects in animals. Prostaglandins have been found in almost every in humans and other animals. They are derived from a 20-carbon polyunsaturated fatty acid. Every prostaglandin therefore contains 20 atoms, including a.
They are a subclass of and form the class of fatty acid derivatives. The prostaglandins are synthesized in the cell membrane by the cleavage of arachidonate from the phospholipids that make up the membrane. This is catalyzed either by acting directly on a membrane phospholipid, or by a lipase acting on DAG (diacyl-glycerol). The arachidonate is then acted upon by the component of. This forms a ring in roughly the middle of the fatty acid chain. The reaction also adds 4 oxygen atoms derived from two molecules of O 2. The resulting molecule is prostaglandin G 2 which is converted by the hydroperoxidase component of the enzyme complex into prostaglandin H 2.
This highly unstable compound is rapidly transformed into other prostaglandins, prostacyclin and thromboxanes. These are then released into the interstitial fluids surrounding the cells that have manufactured the eicosanoid hormone. If arachidonate is acted upon by a instead of cyclooxygenase, and are formed. They also act as local hormones. Prostaglandins were originally believed to leave the cells via passive diffusion because of their high lipophilicity. The discovery of the (PGT, SLCO2A1), which mediates the cellular uptake of prostaglandin, demonstrated that diffusion alone cannot explain the penetration of prostaglandin through the cellular membrane. The release of prostaglandin has now also been shown to be mediated by a specific transporter, namely the (MRP4, ABCC4), a member of the superfamily.
Whether MRP4 is the only transporter releasing prostaglandins from the cells is still unclear. The structural differences between prostaglandins account for their different biological activities. A given prostaglandin may have different and even opposite effects in different tissues. The ability of the same prostaglandin to stimulate a reaction in one tissue and inhibit the same reaction in another tissue is determined by the type of to which the prostaglandin binds.
They act as or factors with their target cells present in the immediate vicinity of the site of their. Prostaglandins differ from in that they are not produced at a specific site but in many places throughout the human body.
Prostaglandins have two derivatives: and. The eagle 2011 soundtrack. Prostacyclins are powerful locally acting and inhibit the aggregation of blood.
Through their role in vasodilation, prostacyclins are also involved in. They are synthesized in the walls of blood vessels and serve the physiological function of preventing needless clot formation, as well as regulating the contraction of tissue.
Conversely, thromboxanes (produced by platelet cells) are and facilitate platelet aggregation. Their name comes from their role in clot formation. Dietary sources of fatty acids, their digestion, absorption, transport in the blood and storage.
Diagrammatic illustration of mixed micelles formed in the duodenum in the presence of bile acids (e.g. Cholic acid) and the digestion products of fats, the fat soluble vitamins and cholesterol. A significant proportion of the fatty acids in the body are obtained from the diet, in the form of triglycerides of either animal or plant origin. The fatty acids in the fats obtained from land animals tend to be saturated, whereas the fatty acids in the triglycerides of fish and plants are often polyunsaturated and therefore present as oils.
These, cannot be absorbed by the. They are broken down into and plus free fatty acids (but no free glycerol) by, which forms a 1:1 complex with a protein called (also a constituent of pancreatic juice), which is necessary for its activity. The activated complex can work only at a water-fat interface.
Therefore, it is essential that fats are first by for optimal activity of these enzymes. The digestion products consisting of a mixture of tri-, di- and monoglycerides and free fatty acids, which, together with the other fat soluble contents of the diet (e.g. The fat soluble vitamins and cholesterol) and bile salts form mixed, in the watery duodenal contents (see diagrams on the right). The contents of these micelles (but not the bile salts) enter the (epithelial cells lining the small intestine) where they are resynthesized into triglycerides, and packaged into which are released into the (the capillaries of the of the intestines). These lacteals drain into the which empties into the venous blood at the junction of the left jugular and left subclavian veins on the lower left hand side of the neck.
This means that the fat soluble products of digestion are discharged directly into the general circulation, without first passing through the liver, as all other digestion products do. The reason for this peculiarity is unknown. A schematic diagram of a chylomicron.
The chylomicrons circulate throughout the body, giving the a milky, or creamy appearance after a fatty meal. on the of the capillaries, especially in, but to a lesser extent also in other tissues, partially digests the chylomicrons into free fatty acids, glycerol and chylomicron remnants. The fatty acids are absorbed by the adipocytes , but the glycerol and remain in the blood plasma, ultimately to be removed from the circulation by the liver. The free fatty acids released by the digestion of the chylomicrons are absorbed by the adipocytes , where they are resynthesized into triglycerides using glycerol derived from glucose in the. These triglycerides are stored, until needed for the fuel requirements of other tissues, in the fat droplet of the. The absorbs a proportion of the glucose from the blood in the coming from the intestines.
After the liver has replenished its stores (which amount to only about 100 g of glycogen when full) much of the rest of the glucose is converted into fatty acids as described below. These fatty acids are combined with glycerol to form triglycerides which are packaged into droplets very similar to chylomicrons, but known as (VLDL). These VLDL droplets are handled in exactly the same manner as chylomicrons, except that the VLDL remnant is known as an (IDL), which is capable of scavenging cholesterol from the blood. This converts IDL into (LDL), which is taken up by cells that require cholesterol for incorporation into their cell membranes or for synthetic purposes (e.g. The formation of the ). The remainder of the LDLs is removed by the liver. And lactating also take up glucose from the blood for conversion into triglycerides.
This occurs in the same way as it does in the liver, except that these tissues do not release the triglycerides thus produced as VLDL into the blood. Adipose tissue cells store the triglycerides in their fat droplets, ultimately to release them again as free fatty acids and glycerol into the blood (as described ), when the plasma concentration of insulin is low, and that of glucagon and/or epinephrine is high.
Mammary glands discharge the fat (as cream fat droplets) into the milk that they produce under the influence of the hormone. All cells in the body need to manufacture and maintain their membranes and the membranes of their organelles. Whether they rely for this entirely on free fatty acids absorbed from the blood, or are able to synthesize their own fatty acids from the blood glucose, is not known. The cells of the central nervous system will almost certainly have the capability of manufacturing their own fatty acids, as these molecules cannot reach them through the, while, on the other hand, no cell in the body can manufacture the required which have to be obtained from the diet and delivered to each cell via the blood.
Fatty acid synthesis. Synthesis of saturated fatty acids via Fatty Acid Synthase II in E. Coli Much like, straight-chain fatty acid synthesis occurs via the six recurring reactions shown below, until the 16-carbon is produced. The diagrams presented show how fatty acids are synthesized in microorganisms and list the enzymes found in. These reactions are performed by II (FASII), which in general contain multiple enzymes that act as one complex. FASII is present in, plants, fungi, and parasites, as well as in.
In animals, as well as some fungi such as yeast, these same reactions occur on fatty acid synthase I (FASI), a large dimeric protein that has all of the enzymatic activities required to create a fatty acid. FASI is less efficient than FASII; however, it allows for the formation of more molecules, including 'medium-chain' fatty acids via early chain termination. Once a 16:0 carbon fatty acid has been formed, it can undergo a number of modifications, resulting in desaturation and/or elongation.
Elongation, starting with stearate (18:0), is performed mainly in the ER by several membrane-bound enzymes. The enzymatic steps involved in the elongation process are principally the same as those carried out by FAS, but the four principal successive steps of the elongation are performed by individual proteins, which may be physically associated. Step Enzyme Reaction Description (a).
Reduces the C2-C3 double bond. Abbreviations: ACP –, CoA –, NADP –.
Note that during fatty synthesis the reducing agent is, whereas is the oxidizing agent in (the breakdown of fatty acids to acetyl-CoA). This difference exemplifies a general principle that NADPH is consumed during biosynthetic reactions, whereas NADH is generated in energy-yielding reactions. (Thus NADPH is also required for the synthesis of from acetyl-CoA; while NADH is generated during.) The source of the NADPH is two-fold. When is oxidatively decarboxylated by “NADP +-linked malic enzyme', CO 2 and NADPH are formed. NADPH is also formed by the which converts glucose into ribose, which can be used in synthesis of and, or it can be catabolized to pyruvate. Glycolytic end products are used in the conversion of carbohydrates into fatty acids. Main article: In humans, fatty acids are formed from carbohydrates predominantly in the and, as well as in the during lactation.
The cells of the probably also make most of the fatty acids needed for the phospholipids of their extensive membranes from glucose, as blood-born fatty acids cannot cross the to reach these cells. However, how the, which mammals cannot synthesize themselves, but are nevertheless important components of cell membranes (and described above) reach them is unknown. The produced by is an important intermediary in the conversion of carbohydrates into fatty acids and cholesterol. This occurs via the conversion of pyruvate into acetyl-CoA in the mitochondrion. However, this acetyl CoA needs to be transported into cytosol where the synthesis of fatty acids and cholesterol occurs.
This cannot occur directly. To obtain cytosolic acetyl-CoA, (produced by the condensation of acetyl CoA with oxaloacetate) is removed from the and carried across the inner mitochondrial membrane into the cytosol.
There it is cleaved by into acetyl-CoA and oxaloacetate. The oxaloacetate is returned to mitochondrion as malate (and then converted back into oxaloacetate to transfer more acetyl-CoA out of the mitochondrion). The cytosolic acetyl-CoA is carboxylated by into, the first committed step in the synthesis of fatty acids. Regulation of fatty acid synthesis Acetyl-CoA is formed into malonyl-CoA by, at which point malonyl-CoA is destined to feed into the fatty acid synthesis pathway. Acetyl-CoA carboxylase is the point of regulation in saturated straight-chain fatty acid synthesis, and is subject to both and.
Regulation by phosphorylation occurs mostly in mammals, while allosteric regulation occurs in most organisms. Allosteric control occurs as feedback inhibition by palmitoyl-CoA and activation by citrate. When there are high levels of palmitoyl-CoA, the final product of saturated fatty acid synthesis, it allosterically inactivates acetyl-CoA carboxylase to prevent a build-up of fatty acids in cells. Citrate acts to activate acetyl-CoA carboxylase under high levels, because high levels indicate that there is enough acetyl-CoA to feed into the and produce energy.
High plasma levels of in the blood plasma (e.g. After meals) cause the dephosphorylation of acetyl-CoA carboxylase, thus promoting the formation of malonyl-CoA from acetyl-CoA, and consequently the conversion of carbohydrates into fatty acids, while and (released into the blood during starvation and exercise) cause the phosphorylation of this enzyme, inhibiting in favor of fatty acid oxidation via. Disorders Disorders of fatty acid metabolism can be described in terms of, for example, (too high level of ), or other types of. These may be familial or acquired. Familial types of disorders of fatty acid metabolism are generally classified as. These disorders may be described as or as a, and are any one of several that result from enzyme defects affecting the ability of the body to in order to produce energy within muscles, liver, and other types. References.
A revised pathway (the reductase-dependent pathway) by which polyunsaturated fatty acids are β-oxidized is presented. This pathway requires the involvement of a NADPH-dependent 2,4-dienoyl-CoA reductase in addition to Δ 3-cis- Δ 2-trans- enoyl- CoA isomerase and the enzymes necessary for the oxidation of saturated fatty acids.
The original pathway (the epimerase-dependent pathway) with 3-hydroxyacyl-CoA epimerase as an auxillary enzyme is inoperative in mitochondria but may play a minor role in non-mitochondrial β-oxidation systems.