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Topics: 1. Overview of Lipid Biosynthesis 2. Synthesis of Phospholipids and Triacylglycerols 3. Biosynthesis of Cholesterol 4. Cholesterol Derivatives
1. Overview of Lipid Biosynthesis
Fatty acids are made up of a long hydrocarbon chain having a carboxylic acid at one end. Fatty acids play four major roles in bodily processes roles. Fatty acids are building blocks of phospholipids and glycolipids which are common constituents of cellular membranes. Fatty acids serve as fuel molecules providing energy to the body cells on burning. Triglycerides are the main storage molecules which are uncharged esters of fatty acids with glycerol. Covalent attachment of fatty acids to the proteins helps in the modification of protein conformations so that their target specificity can be maintained in the cell membranes. Derivatives of fatty acids serve as hormones and intracellular messengers. Fatty acid synthesis and degradation are basically the reverse of each other. Degradation: In fatty acid degradation, an aliphatic compound is converted into a set of activated acetyl acetyl CoA units. Step 1: Oxidation of an activated fatty acid in order to introduce a double bond
Step 2: Hydration of double bond in order to introduce oxygen Step 3: Oxidation of the alcohol into a ketone Step 4: The four carbon fragment is finally cleaved by coenzyme A to yield acetyl CoA and a fatty acid chain which is two carbons lesser. Note: If the fatty acid is a saturated one and contains an even number of carbon atoms, the process merely repeats until there is complete conversion of fatty acid into acetyl CoA units. These acetyl CoA molecules can be processed by the Tricarboxylic acid cycle which is the central metabolic pathway in all aerobic organisms. In presence of oxygen, acetyl-CoA molecule is metabolized into citric acid inside the mitochondria and then undergoes a complex series of biological oxidations. This results in the production of free hydrogen ions. At this stage in the Krebs cycle, a net of two ATP molecules is released. Synthesis: Fatty acid synthesis is effectively the reverse of degradation process. Step 1: Synthesis of fatty acids starts with monomers like an activated acyl group (here we take acetyl group) and malonyl units. Step 2: A four-carbon fragment is formed by the condensation of the malonyl unit with the acetyl unit. Step 3: Reduction of carbonyl takes place in order to synthesize the required hydrocarbon chain. Step 4: Repeated reduction and dehydration of the fragment takes place, just exactly the opposite of degradation. This results the carbonyl group to the intensity of a methylene group and butyryl CoA is formed. Step 5: One more activated malonyl group condenses with the butyryl unit and the process is repeated until complete synthesis of a C16 fatty acid takes place.
2. Synthesis of Phospholipids and Triacylglycerols
Biosynthesis of Triacylglycerols: Triacylglycerols are the most common storage and transport form of fatty acids and otherwise known as neutral fats. Fatty acids are synthesized or derived from the diet of an organism. Liver and adipose tissue are the significant locations for synthesis of most triacylglycerols. Adipose tissue also serves as the primary storage site for them.
Synthesized fatty acids or fatty acids derived from the diet can be used in this process. Catabolism of glucose yields the necessary Acetyl CoenzymeA for this synthesis. Initiation: Activation of fatty acid to CoenzymeA thioester by acyl CoenzymeA synthase and ATP Fatty Acid + CoenzymeA -SH → Fatty Acyl CoenzymeA Thioester Glycerol required for the synthesis of triacylglycerols originates from dihydroxyacetone phosphate which is first reduced to glycerol-3-phosphate and then acylated. Acylation of Glycerol occurs at its first hydroxyl position and it is followed by a second acylation, removal of C3-Phosphate by phosphatase and finally a third acylation occurs. Thus a diacylglycerol and finally a triacylglycerol is formed. Lipolysis of Triacylglycerols: Hydrolysis of Triacylglycerol begins in the intestine as soon as it is acted upon by the enzyme pancreatic lipase. Three separate lipases need to catalyze the hydrolysis if the three fatty acids etherified into glycerol. Hormone-sensitive triacylglyceride lipase hydrolyzes the first fatty acids ester which is a rate-limiting step. The enzyme is then phosphorylated into an active form by a cyclicAMP dependent protein kinase. Epinephrine and norepinephrine increase Cyclic AMP production thus results in the stimulation of triacylglycerol hydrolysis. • • Triacylglycerol lipase catalyses the first two hydrolyses. The last hydrolysis is catalyzed by monoacylglycerol lipase.
The resultant glycerol and fatty acids passively diffuse into the intestinal mucosa. These compounds are then reesterified into triacylglycerols. In later stage, chyclomicrons are formed when the triacylglycerols are surrounded by protein phospholipid and cholesterol. The chyclomicrons enter the lymphatics and the blood stream. In the vasculature; the endothelial cells produce lipoprotein lipase which hydrolyzes the triacylglycerols to glycerols and free fatty acids. The free fatty acids are taken up by the cells of muscle and adipose tissue. The compounds are reesterified into triacylglycerols for storage in adipose tissue. In muscles, the free fatty acids are used for energy. After the completion of all these events, chyclomicrons and free glycerol remain in the blood. The chyclomicrons are rich in cholesterol and return to the liver for bile synthesis.
Triacylglycerols which remains stored in adipose tissue can be later hydrolyzed by a hormone sensitive lipase present within the adipose tissue. Biosynthesis of Phospholipids:
3. Biosynthesis of Cholesterol
Cholesterol originates in the diet or is synthesized in the body. It is an integral component of membrane phospholipids, vitamin D, many hormones and bile salts. Cholesterol Biosynthesis: A series of more than twenty reactions are involved in the usual metabolic pathway for cholesterol biosynthesis. Each of these reactions is catalyzed by a specific enzyme. The rate-limiting step in the sequence is the synthesis of a six-carbon molecule, mevalonate, catalyzed by the enzyme 3-hydroxy-3-methylglutaryl CoA reductase (HMG CoA reductase). The liver is the major site of cholesterol biosynthesis. The location of synthesis is cytoplasmic, with acetyl CoA providing all the necessary carbon atoms.
In the first series of reactions, acetyl CoA is used to synthesize β-hydroxyl – β-methylglutarylCoA (HMG-CoA). In the next step, the enzyme HMG-CoA reducatse uses NADPH to reduce HMG-CoA. In the next step, mevalonic acid is actiated into pyrophosphate form, then decarboxylated and dehydrated. The isopentenyl phosphate can then undergo isomeriztion. The isopentenyl and 3, 3-dimethylallypyrophosphate condenses. This compound combines with another isopentyl pyrophosphate Two molecules of farnesyl pyrophosphate then condense to form squalene. Squalene undergoes cyclization to form lanosterol. Lanosterol is subsequently reduced and three methyl units removed (demethylation) to form the end product cholesterol.
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Regulation: Cholesterol biosynthesis is widely regulated. HMG-CoA reducatse is stimulated by the diets rich in fat and carbohydrate and thereby increasing cholesterol synthesis. HMG CoA reducatse is the rate limiting enzyme in the synthesis of cholesterol. The enzyme activity is suppressed by high amounts of dietary cholesterol. On the other hand, ‘fasting’ limits the available acetyl CoA and NADPH required for cholesterol synthesis. HMG-CoA reducatse is also under hormonal control, stimulated by insulin and thyroxine. Constant recycling of cholesterol exists between liver and extra hepatic sites. Down regulation of the membrane receptors also suppresses the de nova synthesis of cholesterol by the cells. It can also be inhibited by drugs of statin class like Lovastatin. Significant Functions of Cholesterol: • • Structural components of membranes Important precursor of bile salts, steroid hormones, and vitamin D.
Degradation of Cholesterol: Metabolization of Cholesterol cannot occur. So elimination of Cholesterol chiefly occurs through the conversion of cholesterol into bile salts and addition of cholesterol to bile which is followed by excretion via gastro intestinal tract.
4. Cholesterol Derivatives
Bile and Bile Salts: Bile acids and salts serve to emulsify fats that are essential for fat digestion and absorption. Before leaving liver, bile salts are conjugated by amide linkage to glycine to become enhanced detergents. Bacteria in intestine and de-conjugated bile acids or modify bile acids which may then be reabsorbed by intestine and circulated back to the liver. Cholelithiasis: It is a condition when more cholesterol enters the bile than can be excreted. This occurs due to intestinal diseases, bile duct obstruction, and hepatic dysfunction leading to decreased bile salts initiating cholesterol stone formation (gallstones).
Cholesterol Derivatives: 1. Bile salts: Bile salts are 24-carbon steroids derived from cholesterol and are synthesized in the liver. The 8 carbon side chain in cholesterol is converted into a 5 carbon side chain in bile. In addition, the double bond at the 5-carbon is reduced and various hydroxyl groups are added to the carbon backbone. An example of bile salt is cholic acid. The liver may also conjugate these bile salts with compounds such as glycine or taurine (tauorcholic acid). 2. Fat soluble vitamins: The soluble vitamins A, D, E and K are relatives of the basic cholesterol structure. 3. Steroid Hormones: Common precursor is Pregnenalone.
Five Classes: • • • • • Glucocorticoids Mineralcorticoids Estrogens Androgens Progestins
Mineralcorticoids are under control of the enzyme rennin. Secretion of hormones from gonads: These hormones bind nuclear receptors to regulate DNA transcription to affect growth and differentiation. The hormones are synthesized by adrenal cortex, testis, ovary, and placenta. These hormones are also structurally related to cholesterol. The best examples are Adrenal cortical steroid, Aldosterone, Cortisol, Gonadal steroids, Progesterone and Testosterone.
Points To Remember:
• • • • • • Fatty acid synthesis and degradation are basically the reverse process of each other. Triacylglycerols are the most common storage and transport form of fatty acids and hence otherwise known as neutral fats. Fatty acids are synthesized or derived from the diet of an organism. Liver and adipose tissue are the significant locations for synthesis of most triacylglycerols. Adipose tissue serves as the primary storage site for triacylglycerols. A series of more than twenty reactions are involved in the usual metabolic pathway for cholesterol biosynthesis and each reaction is catalyzed by a specific enzyme. The rate-limiting step in the sequence is the synthesis of a six-carbon molecule, mevalonate, catalyzed by the enzyme 3-hydroxy-3-methylglutaryl CoA reductase (HMG CoA reductase).
• • • • • • •
The liver is the major site of cholesterol biosynthesis. The location of synthesis is cytoplasmic, with acetyl CoA providing all the necessary carbon atoms. HMG-CoA reducatse can be inhibited by drugs of statin class like Lovastatin. Cholesterol cannot be metabolized in the body. Bile acids and salts serve to emulsify fats that are essential for fat digestion and absorption. Cholelithiasis is a condition when more cholesterol enters the bile than can be excreted. The soluble vitamins A, D, E and K are relatives of the basic cholesterol structure. Hormones are synthesized by adrenal cortex, testis, ovary, and placenta like Adrenal cortical steroid, Aldosterone, Cortisol, Gonadal steroids, Progesterone and Testosterone. These are also structurally related to cholesterol.
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