Chapter 22, Fatty Acid Metabolism CH 3 (CH 2 ) 14 CO 2 R C C O2 CH 2 OH O R. Lipase + 3 H 2 O

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1 hapter 22, Fatty Acid Metabolism Pages: I. Introduction - Fatty acids have 4 major physiological roles: - omponents of phospholipids and glycolipids (membranes) - Attachment to Proteins targets the proteins to membrane locations (anchors them in the membrane).c - Fuel molecules which are much more efficient than glycogen (100,000 kcal in a 70 kg male, vs only 600 kcal of glycogen). Fatty acids are more highly reduced than carbohydrates, and require much less water of hydration. They are stored as fats, or triglycerides, in adipose tissue. - Intracellular messengers (recall c-amp story) - Nomenclature - 12:0 means 12 carbons, 0 double bonds, 16:0 means 16 carbons, 0 double bonds, 18:1) 9 means 18 carbons, 1 double bond beginning at the # 9 position counting from the carboxyl carbon. - ommon names are lauric acid (laurate, 12:0), stearic acid (stearate, 18:0, oleic acid (oleate, 18:1 ) 9 ) - Initial stages of metabolism ; - Dietary fat is emulsified with bile salts (derivatives of cholesterol), and taken up by chylomicrons in the lymph. The chylomicrons deliver the triglycerides to adipose where they are stored. - As glucose is stored as glycogen in the liver and muscle, fatty acids are stored as triglycerides in adipose tissue. Mobilization of fatty acids is initiated by hormones (epinephrine, norepinephrine, glucagon, adrenocorticotropic hormone), the intercellular messengers, and mediated intra cellularly by c-amp in a manner similar to mobilization of glycogen. Hydrolysis of triglycerides is catalyzed by a cellular lipase. 16:0 H 3 (H 2 ) 14 2 R R H 2 R 2 H H 2 R H 2 Lipase H H 2 H H H 2 H + R1 R2 R 3 The fatty acids are carried to a target muscle cell through the blood bound to albumin. II. ellular (intermediary) metabolism of fatty acids - glycerol enters glycolysis via a minipathway at DHAP:

2 H H 2 H H H 2 H H H 2 H H H 2 H H 2 P 3 H ATP ADP NAD + 2 NADH P 3 Glycerol Glycerol 3-phosphate Dihydroxyacetone Phosphate - Fatty acids are catabolized in the mitochondria, but are initially converted to a fatty acyl oa in the cytoplasm R + ATP R S oa HSoA + AMP + PPi Pyrophosphatase 2 Pi, whereupon they enter the mitochondria via a 3-step process, involving carnitine. R SoA + H H 3 N H 3 Transferase I H 3 R 2 H 3 N H 3 H 3 2 Acylcarnitine R H 3 N H 3 H 3 2 Translocase R H 3 N H 3 H 3 2 ytoplasm Matrix R H 3 N H 3 H 3 2 Transferase II R SoA + H H 3 N H 3 H 3 2 See Figure Fatty acids enter the metabolic mainstream as acetyl oa:

3 Glucose Pyruvate Beta oxidation Acetyl oa Fatty acids Fats A - $-oxidation is a mini-pathway that enzymatically cleaves carbons off the fatty acyl oa 2 at a time as acetyl oa. For a 16-carbon fatty acid the process is repeated for a total of 7 times to yield 8 acetyl oa: 16:0 oa H 2 H 2 S oa Beta oxidation H 2 S oa Thiolase H 2 H 2 S oa + H 3 SoA 14:0 oa -Recall the sequence of reactions in the A which are very similar to those of $-oxidation: succinate 6 fumarate 6 malate 6 oxaloacetate

4 H 2 H 2 H H H H H 2 FAD FADH 2 NAD + NADH H 2 - Unsaturated fatty acids, such as oleic acid (18:0 ) 9 ) require either one or two auxiliary enzymes to deal with the points of unsaturation. 18:1 (9) SoA (9,12) 18:2 SoA - Total ATP output: # ATP = rounds of $-oxidation X 5 ATP/round + 8 acetyl oa X 12 ATP/oA = 129 (note difference here with respect to text) - dd-chain fatty acids, such as 15:0, must yield a final product with an odd number of carbons (i.e., not acetyl oa). This 3-carbon product, propionyl oa, enters the A as succinyl oa via another mini-pathway requiring coenzymes derived from biotin and B 12 : S oa Biotin, B 12 SoA H 2 H 2 H 3 H 2 - During periods of starvation (Atkins diet) or uncontrolled diabetes, the acetyl oa from fat metabolism cannot enter the A because oxaloacetate is consumed to produce glucose via gluconeogenesis (hence the phrase fats burn in the flame of carbohydrate). In such cases ketone bodies can be formed, the initial step of the process involving a reversal of the last stage of $-oxidation:

5 2 acetyl oa Acetoacetate oa SoA NADH NAD + oa S oa H 2 H H 2 H 2 2 H H 3 H H H 2 Acetyl oa H H 3 H 3 3 Acetyl oa Acetoacetyl oa 3-H 3-Methyl 3-H butyrate Glutaryl oa 2 H 3 H 3 holesterol Acetone Notes: 1. This pathway has features common with cholesterol biosynthesis, which branches off at 3- H methyl glutaryl oa (lovastatin) 2. 3-H butyrate is exported to other tissues (heart and renal cortex) where it serves as a major fuel: NAD + NADH H 2 H 2 H H H 3 H 3 Succinyl oa Succinate oa SoA H 2 2 Acetyl oa A H 3 Thioase III. Fatty acid biosynthesis - As in the case of glycolysis/gluconeogenesis and glycogen breakdown/synthesis, fatty acid breakdown/biosynthesis have different features: - breakdown occurs in the mitochondria, synthesis occurs in the cytoplasm - Acetyl oa must be activated to malonyl oa H 3 Biotin H 3 SoA H 2 ATP ADP S Malonyl oa - Note that fatty acid breakdown is regulated at the level of entry of fatty acyl oa into the mitochondria by transferase I. This step, which commits the fatty acyl oa to $-oxidation, is inhibited by malonyl oa. Problems: 1 oa

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