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Fatty acid oxidation- Subjective questions (Set-1)
Answer– A fatty acid contains a long hydrocarbon chain and a terminal carboxylate group. The fatty acids can be obtained from diet, by adipolysis or can be synthesized de novo from precursor molecules.
Functions-Fatty acids have four major physiological roles.
1) Fatty acids are building blocks of phospholipids and glycolipids. These amphipathic molecules are important components of biological membranes,
2) Many proteins are modified by the covalent attachment of fatty acids, which target them to membrane locations
3) Fatty acids are fuel molecules. They are stored as triacylglycerols (also called neutral fats or triglycerides), which are uncharged esters of fatty acids with glycerol. Fatty acids mobilized from triacylglycerols are oxidized to meet the energy needs of a cell or organism.
4) Fatty acid derivatives serve as hormones and intracellular messengers e.g. steroids, sex hormones and prostaglandins.
Q.2- “The processes of fatty acid synthesis and fatty acid degradation are, in many ways, the reverse of each other”, justify the statement giving an overview of the two processes.
Answer- Although fatty acids are both oxidized to acetyl-CoA and synthesized from acetyl-CoA, fatty acid oxidation is not the simple reverse of fatty acid biosynthesis but an entirely different process taking place in a separate compartment of the cell.
Fatty acid degradation – The separation of fatty acid oxidation in mitochondria from biosynthesis in the cytosol allows each process to be individually controlled and integrated with tissue requirements. Each step in fatty acid oxidation involves acyl-CoA derivatives catalyzed by separate enzyme, utilizes NAD+ and FAD as coenzymes, and generates ATP. It is an aerobic process, requiring the presence of oxygen.
The process of degradation converts an aliphatic compound into a set of activated acetyl units (acetyl CoA) that can be processed by the citric acid cycle (Figure-1). An activated fatty acid is oxidized to introduce a double bond; the double bond is hydrated to introduce oxygen; the alcohol is oxidized to a ketone; and, finally, the four carbon fragment is cleaved by coenzyme A to yield acetyl CoA and a fatty acid chain two carbons shorter. If the fatty acid has an even number of carbon atoms and is saturated, the process is simply repeated until the fatty acid is completely converted into acetyl CoA units.
Fatty acid synthesis – is essentially the reverse of this process. Because the result is a polymer, the process starts with monomers in this case with activated acyl group (most simply, an acetyl unit) and malonyl units (Figure1). The malonyl unit is condensed with the acetyl unit to form a four-carbon fragment. To produce the required hydrocarbon chain, the carbonyl must be reduced. The fragment is reduced, dehydrated, and reduced again, exactly the opposite of degradation, to bring the carbonyl group to the level of a methylene group with the formation of butyryl CoA. Another activated malonyl group condenses with the butyryl unit and the process is repeated until a C16 fatty acid is synthesized.
Figure-1- showing the differentiation between fatty acid synthesis and fatty acid degradation
Q.-3- What is likely the reason that triacylglycerols rather than glycogen were selected in evolution as the major energy reservoir?
Answer- Triacylglycerols are highly concentrated stores of metabolic energy because they are reduced and anhydrous.
1) The yield from the complete oxidation of fatty acids is about 9 kcal g-1 (38 kJ g-1), in contrast with about 4 kcal g-1 (17 kJ g-1) for carbohydrates and proteins. The basis of this large difference in caloric yield is that fatty acids are much more reduced.
2) Furthermore, triacylglycerols are nonpolar, and so they are stored in a nearly anhydrous form, whereas much more polar proteins and carbohydrates are more highly hydrated. In fact, 1 g of dry glycogen binds about 2 g of water. Consequently, a gram of nearly anhydrous fat stores more than six times as much energy as a gram of hydrated glycogen, which is likely the reason that triacylglycerols rather than glycogen were selected in evolution as the major energy reservoir.
3) In a 70-kg man, who has fuel reserves of 100,000 kcal (420,000 kJ) in triacylglycerols, 25,000 kcal (100,000 kJ) in protein (mostly in muscle), 600 kcal (2500 kJ) in glycogen, and 40 kcal (170 kJ) in glucose.
Triacylglycerols constitute about 11 kg of his total body weight. If this amount of energy were stored in glycogen, his total body weight would be 55 kg greater. The glycogen and glucose stores provide enough energy to sustain biological function for about 24 hours, whereas the Triacylglycerol stores allow survival for several weeks.
Q.4- Give an overview of provision of fatty acids from different sources for utilization as fuel molecules.
Dietary lipids-Most lipids are ingested in the form of triacylglycerols but must be degraded to fatty acids for absorption across the intestinal epithelium.These are hydrophobic molecules, and have to be hydrolyzed and emulsified to very small droplets (micelles) before they can be absorbed.
Triacylglycerols in the intestinal lumen are incorporated into micelles formed with the aid of bile salts, amphipathic molecules synthesized from cholesterol in the liver and secreted from the gall bladder.
Incorporation of lipids into micelles (Figure-2) orients the ester bonds of the lipid toward the surface of the micelle, rendering the bonds more susceptible to digestion by pancreatic lipases that are in aqueous solution.
Figure-2 -showing micelle formation.
The lipases digest the triacylglycerols into free fatty acids and monoacylglycerol (Figure-3). These digestion products are carried in micelles to the intestinal epithelium where they are absorbed across the plasma membrane.
Figure-3- showing the action of Pancreatic Lipases. Lipases secreted by the pancreas convert triacylglycerols into fatty acids and monoacylglycerol for absorption into the intestine.
In the intestinal mucosal cells, the triacylglycerols are resynthesized from fatty acids and monoacylglycerols and then packaged into lipoprotein transport particles called chylomicrons, stable particles ranging from approximately 180 to 500 nm in diameter (Figure-4)
Figure-4- showing the structure of chylomicron
These particles are composed mainly of triacylglycerols, with apoprotein B-48 as the main protein component. Protein constituents of lipoprotein particles are called apolipoproteins. Chylomicrons also function in the transport of fat-soluble vitamins and cholesterol. The chylomicrons are released into the lymph system and then into the blood (Figure-5). These particles bind to membrane-bound lipoprotein lipases, primarily at adipose tissue and muscle, where the triacylglycerols are once again degraded into free fatty acids and monoacylglycerol for transport into the tissue. The triacylglycerols are then resynthesized inside the cell and stored.
Figure-5- showing the Chylomicron Formation. Free fatty acids and monoacylglycerols are absorbed by intestinal epithelial cells. Triacylglycerols are resynthesized and packaged with other lipids and apoprotein B-48 to form chylomicrons, which are then released into the lymph system.
Peripheral tissues gain access to the lipid energy reserves stored in adipose tissue through three stages of processing.
1) First, the lipids must be mobilized. In this process, triacylglycerols are degraded to fatty acids and glycerol, (Figure-6) which are released from the adipose tissue and transported to the energy-requiring tissues.
Figure-6- showing the degradation of triglyceride by hormone sensitive lipase in the adipose tissue
The lipase of adipose tissue are activated on treatment of these cells with the hormones epinephrine, nor epinephrine, glucagon and adrenocorticotropic hormone. Thus, these hormones induce lipolysis.
2) Transportation of free fatty acids
Free fatty acids—also called unesterified (UFA) or nonesterified (NEFA) fatty acids—are fatty acids that are in the unesterified state. In plasma, longer-chain FFA are combined with albumin, and in the cell they are attached to a fatty acid-binding protein, so that in fact they are never really “free.” Shorter-chain fatty acids are more water-soluble and exist as the un-ionized acid or as a fatty acid anion. By these means, free fatty acids are made accessible as a fuel in other tissues.
Glycerol formed by lipolysis is absorbed by the liver and phosphorylated, oxidized to dihydroxyacetone phosphate, and then isomerized to glyceraldehyde 3-phosphate (Figure-7).This molecule is an intermediate in both the glycolytic and the gluconeogenic pathways.
Figure-7- showing the phosphorylation and subsequent utilization of glycerol as intermediates of glycolysis
3) In tissues, the fatty acids must be activated and transported into mitochondria for degradation. The fatty acids are then broken down in a step-by step fashion into acetyl CoA, which is then processed in the citric acid cycle.
Q.4- Enlist the other different ways by which fatty acids can be oxidised in different cells? Explain the mechanism of activation of fatty acids prior to catabolism,
Answer– Fatty acids can be oxidized by-
1) Beta oxidation- Major mechanism ,occurs in the mitochondria matrix . It is the process by which fatty acids are degraded by removal of 2-C units . The process begins with oxidation of the carbon that is “beta” to the carboxyl carbon, so the process is called “beta oxidation” The 2-C units are released as acetyl CoA, not free acetate .
2) Alpha oxidation– Predominantly takes place in brain and liver, one carbon is lost in the form of CO2 per cycle.
3) Omega oxidation- Minor mechanism, but becomes important in conditions of impaired beta oxidation
4) Peroxisomal oxidation- Mainly for the trimming of the very long chain fatty acids.
Activation of fatty acids-Fatty acids must first be converted to an active intermediate before they can be catabolized. This is the only step in the complete degradation of a fatty acid that requires energy from ATP. In the presence of ATP and coenzyme A, the enzyme acyl-CoA synthetase (thiokinase) catalyzes the conversion of a fatty acid (or free fatty acid) to an “active fatty acid” or acyl-CoA, which uses one high-energy phosphate with the formation of AMP and PPi (Figure-8 ). The PPi is hydrolyzed by inorganic pyrophosphatase with the loss of a further high-energy phosphate, ensuring that the overall reaction goes to completion. Acyl-CoA synthetases are found in the endoplasmic reticulum, peroxisomes, and inside and on the outer membrane of mitochondria.
Figure-8- Showing the activation of fatty acids to form Acyl co A and AMP
The activation of a fatty acid is accomplished in two steps-
1) First, the fatty acid reacts with ATP to form an acyl adenylate. In this mixed anhydride, the carboxyl group of a fatty acid is bonded to the phosphoryl group of AMP. The other two phosphoryl groups of the ATP substrate are released as pyrophosphate. The sulfhydryl group of CoA then attacks the acyl adenylate, which is tightly bound to the enzyme, to form acyl CoA and AMP (Figure-9)
Figure-9-showing the 2 steps of Acyl co A formation
These partial reactions are freely reversible. Pyrophosphate is rapidly hydrolyzed by a pyrophosphatase, hence the overall reaction is driven forward.This reaction is quite favorable because the equivalent of two molecules of ATP is hydrolyzed, whereas only one high transfer-potential compound is formed.
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