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Lipid and Amino Acid Metabolism
Biochemistry/Lab (CHEM 3650)
Nova Southeastern University
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Lipid and Amino Acid Metabolism Lecture notes (Can be used for MCAT review too)
Lipid Digestion and Absorption
Lipids serve many functions: energy storage/source, fat soluble vitamins act as coenzymes, prostaglandins and steroid hormones are necessary for homeostasis
Digestion
Dietary fats consist mainly of triacylglycerols o Remainder consists of cholesterol, cholesteryl esters, phospholipids and free fatty acids. Digestion is minimal in the stomach and mouth. o Upon entry into the duodenum, emulsification occurs, which is the mixing of two normally immiscible liquids o Emulsion formation increases the surface area of the lipid: permits greater enzymatic interaction and procession Emulsification is aided by bile: bile salts, pigments and cholesterol o This is secreted by the liver and stored in the gallbladder The pancreas secretes pancreatic lipase, colipase & cholesterol esterase into the small intestine as well. o Enzymes hydrolyze the lipid components into 2-monoacylglycerol, free fatty acids, and cholesterol
Micelle Formation
Emulsification is followed by absorption of fats by intestinal cells Micelles: consist of free fatty acids, cholesterol, 2-monoacylglycerol, and bile salts o These are clusters of amphipathic lipids that are soluble in aqueous intestinal environment o Water soluble spheres with lipid soluble interior Micelles are present from the duodenum all the way to the end of the ileum o Bile salts are recycled and restored at the end
Absorption
Micelles diffuse into the brush border of the intestinal mucosal cells Digested lipids pass through the brush border and are absorbed into the mucosa and re- esterified to form triacylglycerols and cholesteryl esters Chylomicrons: packages of triacylglycerols, cholesteryl esters, apoproteins, fat-soluble vitamins, and other lipids o Leave the intestine via lacteals (lactic system vessels), and then reenter the bloodstream via the thoracic duct (long lymphatic vessel that empties into the left subclavian vein) Water soluble fatty acid chains can be absorbed by simple diffusion into the bloodstream.
Lipid Mobilization
Hormone-sensitive lipase (HSL): hydrolyzes triacylglycerols which yields fatty acids and glycerol o This is activated by a fall in insulin levels or an increase in cortisol and epinephrine Released glycerol from fat may be transported to the liver for glycolysis or gluconeogenesis o HSL is effective within adipose cells Lipoprotein Lipase (LPL): is necessary for the metabolism of chylomicrons and very-low- density lipoproteins (VLDL) o This is an enzyme that can release free fatty acids from triacylglycerols in these lipoproteins
Lipid Transport
Free fatty acids are transported through the blood in association with an albumin carrier protein Triacylglycerol and cholesterol are transported in the blood as lipoproteins: o Aggregates of apolipoproteins and lipids o These are named after according to their density Density increases in proportion to the percentage of protein in the particle Chylomicrons are the least dense (high fat-to-protein ratio), followed by VLDL, followed by IDL, LDL and HDL
Chylomicrons
Highly soluble in lymphatic fluid and blood Function in the transport of dietary triacylglycerols, cholesterol, and cholesteryl esters Assembly occurs in the intestinal lining. A newly formed chylomicron that contains lipids and apolipoproteins
VLDL (Very-Low-Density Lipoproteins)
Metabolism is similar to chylomicrons o Difference is that VLDL is produced and assembled in the liver cells Main function is the transport of triacylglycerols
Specific Enzymes
Lecithin-cholesterol acyltransferase (LCAT): found in the bloodstream and is activated by HDL apoproteins o Adds a fatty acid to cholesterol. This produces soluble cholesteryl esters such as those in HDL Cholesteryl ester transfer protein (CETP): facilitates the transfer of cholesteryl esters from HDL to other lipoproteins like IDL
Fatty Acid and Triacylglycerols
Fatty Acids: long chain carboxylix acids o Carboxyl carbon is carbon 1 and carbon 2 is known as the alpha-carbon
Nomenclature
Total number of carbons is given along with the number of double bonds o E. – carbons: double bonds o Can be further specified by indicating the position and isomerism of the double bonds Saturated fatty acids: no double bonds while unsaturated fatty acids have one or more double bonds Humans can only synthesize a few fatty acids, the rest come from diet o -Linolenic Acid & Linoleic acid: poly unsaturated fatty acids are important in maintain cell membrane fluidity, Omega (w) numbering system: used for unsaturated fatty acids o w designation describes the position of the last double bond in relation to the end of the chain Also identifies the major precursor fatty acid Double bonds are usually in the cis configuration
Synthesis
Fuel fatty acids are primarily supplied through diet, but excess carbohydrates and proteins can also be converted to fatty acids and stored as energy reserves Lipid and carbohydrate synthesis is termed non-template synthesis o Since they do not rely on the coding of a nucleic acid Fatty Acid Biosynthesis This occurs in the livers, while its products are transferred to adipose tissue Adipose also has the ability to synthesize smaller quantities of fatty acids Synthesis is driven by the reactants: Acetyl-CoA carboxylase & fatty acid synthase o These are stimulated by insulin Palmitic acid (palmitate): primary end product of fatty acid synthesis Acetyl-CoA Shuttling Acetyl-CoA accumulates in the mitochondrial matrix if a large fatty meal is eaten o It needs to be moved to the cytosol for fatty acid biosynthesis since it slows the citric acid cycle Acetyl-CoA is a product of the pyruvate dehydrogenase complex o It combines with oxaloacetate to form citrate, this begins the citric acid cycle
Limited by isocitrate dehydrogenase A buildup of acetyl-CoA causes a buildup of citrate o Citrate is able to diffuse across the mitochondrial membrane and be split up (by citrate lyase) Splits into acetyl-CoA and oxaloacetate Acetyl-CoA Carboxylase This is the rate limiting step of fatty acid synthesis Acetyl-CoA carboxylase requires ATP and biotin to function o Adds a CO 2 to Acetyl-CoA to form malonyl-CoA Enzyme is activated by insulin and citrate CO 2 is never incorporated into the fatty acid since it is removed during fatty acid synthase Fatty Acid Synthase More appropriately called palmitate synthase since palmitate is the only fatty acid that humans can synthesize de novo Large multi-enzyme complex that is found in the cytosol o Induced by the liver after meals eaten that are high in carbohydrates (insulin induces the complex) Complex contains an acyl carrier protein (ACP) o This protein requires pantothenic acid (Vitamin B 5 ) o NADPH is required to reduce acetyl groups that are added to the fatty acid Palminate requires 8 acetyl-CoA groups Fatty acyl-CoA can be elongated and desaturated to a limited extent by the smooth endoplasmic reticulum Steps involved are: attachment to acyl carrier protein, bond formation between activated malonyl-CoA and the growing chain, reduction of a carbonyl group, dehydration and reduction of a double bond o Reaction occurs many times until a 16 carbon palmitate is created. Can usually be reversed by B-oxidation Triacylglycerol Synthesis Formed by attaching three fatty acids (as fatty Acyl-CoA) to glycerol Storage form of fatty acids Occurs primarily in the liver and a little in the Adipose tissue Small amount also comes directly from the diet In the liver, triglycerides are packaged and sent to adipose tissue as VLDL
o Succinyl-CoA is used in the citric acid cycle as an intermediate, but can also be converted to malate to enter the gluconeogenic pathway in cytosol.
Unsaturated fatty acids require two additional enzymes to account for the double bonds o Enzyme must have at most one double bond in their active site Bond must be located between carbons 2 & 3 o Enoyl-CoA isomerase rearranges cis double bonds at the 3,4 position to trans double bonds at the 2,3 positions This is the only extra step required so that monounsaturated fatty acids can undergo beta-oxidation o Poly unsaturated fatty acids require further reduction by using 2,4-dienoyl-CoA reductase This convertes two conjugated double bonds to just one double bond at the 3,4 position Will then undergo same rearrangement as above
Ketone Bodies
When fasting, the liver converts excess acetyl-CoA (from beta oxidation) into ketone bodies acetoacetate and 3-hydroxybutyrate (-hydroxybutyrate) o This can be used for energy in various tissues o Cardiac and skeletal muscle, and the renal cortex are able to metabolize above two products back into acetyl-CoA o If fasting lasts for longer than a week, concentration of ketones in blood becomes high enough to allow the brain to begin metabolizing them
Ketogenesis
Occurs in the mitochondria of liver cells when excess acetyl-CoA accumulates in the fasting state HMG-CoA synthase forms HMG-CoA HMG-CoA lyase breaks down HMG-CoA into acetoacetate Acetoacetate can be reduced to 3-hydroxybutyrate and acetone (is not used for energy)
Ketolysis
Acetoacetate is picked up from the blood and is activated in the mitochondria by succinyl-CoA acetoacetyl-CoA transferase (thiophorase) o Thiophorase is an enzyme that is only present in tissues outside of the liver o Liver lacks the enzyme so that it does not consume the ketones it produces 3-hydroxybutyrate is oxidized to acetoacetate Ketolysis in the Brain After one week of fasting, brain derives two-thirds of its energy from ketone bodies When ketones are metabolized to acetyl-CoA, pyruvate dehydrogenase is inhibited This switch spares essential proteins which would ordinarily be used in gluconeogenesis to produce glucose.
Lipid and Amino Acid Metabolism
Course: Biochemistry/Lab (CHEM 3650)
University: Nova Southeastern University
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