Fatty Acid Oxidation and Synthesis PDF

Lippincott’s illustrated reviews Chapter 16 – Page 181 Lecture 27 Fatty Acid Oxidation and Synthesis 1  Specific Objectives By the end of this lecture students can be able to: Differentiate between different types of fatty acids. Understan...

Lippincott’s illustrated reviews Chapter 16 – Page 181 Lecture 27 Fatty Acid Oxidation and Synthesis 1  Specific Objectives By the end of this lecture students can be able to: Differentiate between different types of fatty acids. Understand the metabolic pathways of fatty acids. Explain the importance of carnitine shuttle in fatty acid oxidation. 2  Existence and Function of Fatty acids Fatty acids exist “free” in the body (that is, they are unesterified), and are also found as fatty acyl esters in more complex molecules, such as triacylglycerols. Low levels of free fatty acids occur in all tissues, but substantial amounts can sometimes be found in the plasma, particularly during fasting. 3 Plasma free fatty acids (transported on serum albumin) are in route from their point of origin (triacylglycerol of adipose tissue or circulating lipoproteins) to their site of consumption (most tissues). Free fatty acids can be oxidized by many tissues — particularly liver and muscle—to provide energy. 4  Fatty acids are also structural components of membrane lipids, such as phospholipids and glycolipids. Fatty acids are attached to certain intra - cellular proteins to enhance the ability of those proteins to associate with membranes. Fatty acids are also precursors of the hormone-like prostaglandins. Esterified fatty acids, in the form of triacylglycerols stored in adipose cells, serve as the major energy 5 reserve of the body.  Structure of fatty acids A fatty acid consists of a hydrophobic hydrocarbon chain with a terminal carboxyl group. This anionic group (COO-) has an affinity for water, giving the fatty acid its amphipathic nature (having both a hydrophilic and a hydrophobic region). However, for long-chain fatty acids (LCFAs), the hydrophobic 6 portion is predominant.  Saturation of fatty acids Fatty acid chains may contain no double bonds— that is, be saturated— or contain one or more double bonds—that is, be mono- or polyunsaturated (PUFA). The presence of double bonds in some fatty acids helps maintain the fluid nature of those lipids. 7  Most important PUFA Linoleic acid has 2 double bonds (omega 6) Linolenic acid has 3 double bonds (omega 3) Arachidonic acid has 4 double bonds (omega 6) Pentaenoic acid present in fish oil is of great nutritional importance (ῳ3 unsaturated fatty acid). 8  Chain lengths of fatty acids The carbon atoms of fatty acids are numbered as C1, C2 etc. starting from the COOH group. Or, starting from the methyl end, the carbon atoms may be numbered as omega (ῳ)-1,2,3, etc. 12 11 10 9 8 7 6 5 4 3 2 1 CH3 – CH2 – CH2 – CH2 – CH2 – CH2 – CH2 – CH2 – CH2 – CH2- CH2 - COOH ῳ1 ῳ2 ῳ3 ῳ4 ῳ5 ῳ6 ῳ7 ῳ8 ῳ9 ῳ10 ῳ11 For example, Arachidonic acid, 20:4 (ω-6), linoleic acid, 18:2(ω-6), linolenic acid, 18:3(ω-3). (Number beside ω- detect the first double bond). 9  Essential fatty acids Two fatty acids are dietary essentials in humans because of our inability to synthesize them: Linoleic acid, which is the precursor of ω-6 arachidonic acid, the substrate for prostaglandin synthesis Linolenic acid, the precursor of other ω-3 fatty acids important for growth and development. 10  Plants provide us with the essential fatty acids. Essential fatty acid deficiency can result in a scaly dermatitis (ichthyosis), as well as visual and neurologic abnormalities. Essential fatty acid deficiency, however, is rare. 11  De novo synthesis of fatty acids A large proportion of the fatty acids used by the body is supplied by the diet. Carbohydrates and protein obtained from the diet in excess of the body’s needs for these compounds can be converted to fatty acids, which are stored as triacylglycerols. 12  In adult humans, fatty acid synthesis occurs primarily in the liver and lactating mammary glands and, to a lesser extent, in adipose tissue 13  This cytosolic process incorporates carbons from acetyl coenzyme A (CoA) into the growing fatty acid chain, using adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide phosphate (NADPH). 14  Utilization of fatty acids After hydrolysis of TAG in adipose tissues, the free (unesterified) fatty acids move through the cell membrane of the adipocyte, and bind to plasma albumin. 15  Fatty acids transport to the tissues, enter cells, then activate to their CoA derivatives (fatty acyl CoA) in the cytosol (using 2 ATP), then transport to mitochondria and oxidize to produce energy. 16  Important Note: Regardless of their levels, plasma free fatty acids (FFA) cannot be used for fuel by erythrocytes, which have no mitochondria. Brain, too, does not use fatty acids for energy, but the reasons are less clear. 17  Transport of long-chain fatty acids (LCFA) into the mitochondria (Role of carnitine) Carnitine is a specialized carrier that transport the long-chain acyl group from the cytosol into the mitochondrial matrix. This step is a rate-limiting transport process called the carnitine shuttle. 18 19 Sources of carnitine: Carnitine can be obtained from the diet, where it is found primarily in meat products. Carnitine can also be synthesized from the amino acids lysine and methionine by an enzymatic pathway found in the liver and kidney but not in skeletal or heart muscle. 20 Carnitine deficiencies: Such deficiencies result in a decreased ability of tissues to use LCFA as a metabolic fuel. 21  Secondary carnitine deficiency Occurs in many situations, including: 1) In patients with liver disease causing decreased synthesis of carnitine. 2) In individuals suffering from malnutrition or those on strictly vegetarian diets. 3) In those with an increased requirement for carnitine as a result of, for example, pregnancy, severe infections, burns, or trauma. 4) in those undergoing hemodialysis, which removes carnitine from the blood. 22  Primary carnitine deficiency May resulted from congenital deficiencies in one of the components of the carnitine palmitoyltransferase system (CPT), in renal tubular reabsorption of carnitine, or in carnitine uptake by cells. 1) Genetic CPT-I deficiency This affects the liver, where there is inability to use LCFA for fuel. This can lead to severe hypoglycemia, coma, and death. 23 2) CPT-II deficiency This occurs primarily in cardiac and skeletal muscle, where symptoms of carnitine deficiency range from cardiomyopathy to muscle weakness with myoglobinemia following prolonged exercise. Treatment includes avoidance of prolonged fasts, adopting a diet high in carbohydrate and low in LCFA, but supplemented 24 with medium-chain fatty acids and carnitine.  β-Oxidation of fatty acids β-oxidation occurs in the mitochondrial matrix. It is the major pathway for catabolism of fatty acids. Fatty acyl-CoA rounds many times according to the number of carbons in the chain. In each round two-carbon fragments are successively removed from the carboxyl end of the fatty acyl CoA, producing acetyl CoA, NADH, and FADH2. 25 Steps of -Oxidation of Fatty Acids 26 Energy yield from fatty acid oxidation: The energy yield from the β-oxidation pathway is high. For example, the oxidation of a molecule of palmitoyl CoA (16 carbons) to CO2 and H2O takes 7 rounds. How to calculate energy from β-oxidation 7 NADH = 7x3= 21 ATP 7 FADH2 = 7x2= 14 ATP 8 acetyl CoA= 8x12= 96 ATP Sum = 131 ATP Activation = 2ATP Thus, the net yield from palmitate is 129 ATP. 27 Reference Book: Champe, P. C., Harvey, R. A. and Ferrier, D. R., 2005. Biochemistry “Lippincott’s Illustrated Reviews”, 5th or 6th Edition 28