Chapter 27: Lipid Degradation
triacylglycerol
A glycerol that has fatty acyl chains esterified to each of its hydroxyl groups; storage form of fats. Also called neutral fat or triglyceride.
acyl adenylate
A mixed anhydride in which the carboxyl group of a molecule is linked to the phosphoryl group of AMP; the formation of acyl adenylates is a means of activating carboxyl groups in biochemical reactions, such as the formation of fatty acyl CoA molecules from a free fatty acid and coenzyme A.
carnitine
A zwitterionic alcohol formed from lysine that acts as a carrier of long-chain fatty acids from the cytoplasm to the mitochondrial matrix.
Metabolism in Context: Fatty Acid Metabolism Is a Source of Insight into Various Physiological States
Diabetes is characterized by the inability of cells to take up glucose. The lack of glucose as a fuel results in a greater demand for fats as a fuel. Ketone bodies may be produced in such excess as to acidify the blood, a potentially lethal condition called diabetic ketosis. Ketone bodies are also an especially important source of fuel for the brain when glucose is limited, as in prolonged fasting.
Explain why people with a hereditary deficiency of carnitine acyltransferase II have muscle weakness. Why are the symptoms more severe during fasting?
Fatty acids cannot be transported into mitochondria for oxidation. The muscles could not use fats as a fuel. Muscles could use glucose derived from glycogen. However, when glycogen stores are depleted, as after a fast, the effect of the deficiency is especially apparent.
The Degradation of Unsaturated and Odd-Chain Fatty Acids Requires Additional Steps
Fatty acids that contain double bonds or odd numbers of carbon atoms require ancillary steps to be degraded. An isomerase and a reductase are required for the oxidation of unsaturated fatty acids, whereas propionyl CoA derived from chains with odd numbers of carbon atoms requires a vitamin B12-dependent enzyme to be converted into succinyl CoA.
Outline the control of triacylglycerol mobilization.
Glucagon and epinephrine trigger 7TM receptors in adipose tissue that activate adenylate cyclase (p. 228). The increased level of cyclic AMP then stimulates protein kinase A, which phosphorylates two key proteins: perilipin, a fat-droplet-associated protein, and hormone-sensitive lipase. The phosphorylation of perilipin restructures the fat droplet so that the triacylglycerols are more readily mobilized, and it triggers the release of a coactivator for the adipose triglyceride lipase (ATGL). Activated ATGL then initiates the mobilization of triacylglycerols by releasing a fatty acid from triacylglycerol, forming diacylglycerol. Diacylglycerol is converted into a free fatty acid and monoacylglycerol by the hormone-sensitive lipase. Monoacylglycerol lipase completes the mobilization of fatty acids with the production of a free fatty acid and glycerol.
What are the three stages of triacylglycerol utilization?
In stage 1, triacylglycerols are degraded to fatty acids and glycerol, which are released from the adipose tissue and transported to the energy-requiring tissues. In stage 2, the fatty acids are activated and transported into mitochondria for degradation. In stage 3, the fatty acids are broken down in a step-by-step fashion into acetyl CoA, which is then processed in the citric acid cycle.
B-oxidation pathway
In the degradation of a fatty acyl CoA molecule, the sequence of oxidation, hydration, and oxidation reactions that converts a methylene group at the C-3 carbon atom (also called the b-carbon atom) into a b-keto group, which is subsequently cleaved to yield acetyl CoA.
Compare the ATP yield from the complete oxidation of glucose, a six-carbon carbohydrate, and hexanoic acid, a six-carbon fatty acid. Hexanoic acid is also called caproic acid and is responsible for the "aroma" of goats. Why are fats better fuels than carbohydrates?
Keep in mind that, in the citric acid cycle, 1 molecule of FADH2 yields 1.5 molecules of ATP, 1 molecule of NADH yields 2.5 molecules of ATP, and 1 molecule of acetyl CoA yields 10 molecules of ATP. Two molecules of ATP are produced when glucose is degraded to 2 molecules of pyruvate. Two molecules of NADH also are produced, but the electrons are transferred to FADH2 to enter mitochondria. Each molecule of FADH2 can generate 1.5 molecules of ATP. Each molecule of pyruvate will produce 1 molecule of NADH. Each molecule of acetyl CoA generates 3 molecules of NADH, 1 molecule of FADH2, and 1 molecule of ATP. So, we have a total of 10 molecules of ATP per molecule of acetyl CoA, or 20 for the 2 molecules of acetyl CoA. The total for glucose is 30 ATP. Now, what about hexanoic acid? Caproic acid is activated to caproic CoA at the expense of 2 ATP, and so we are 2 ATP in the hole. The first cycle of b oxidation generates 1 FADH2, 1 NADH, and 1 acetyl CoA. After the acetyl CoA has been run through the citric acid cycle, this step will have generated a total of 14 ATP. The second cycle of b oxidation generates 1 FADH2 and 1 NADH but 2 acetyl CoA. After the acetyl CoA has been run through the citric acid cycle, this step will have generated a total of 24 ATP. The total is 36 ATP. Thus, the foul-smelling caproic acid has a net yield of 36 ATP. So on a per carbon basis, this fat yields 20% more ATP than does glucose, a manifestation of the fact that fats are more reduced than carbohydrates.
What are the recurring reactions of the oxidation of saturated fatty acids?
Oxidation by flavin adenine dinucleotide (FAD), hydration, oxidation by nicotinamide adenine dinucleotide (NAD+), and thiolysis by coenzyme A.
ketone body
Refers to acetoacetate, b-hydroxybutyrate, and acetone, produced when acetyl CoA is diverted from the citric acid cycle to the formation of acetoacetyl CoA in the liver; subsequent reactions generate the three compounds, known as ketone bodies.
Ketone Bodies Are Another Fuel Source Derived from Fats
The primary ketone bodies—acetoacetate and d-3-hydroxybutyrate—are formed in the liver by the condensation of acetyl CoA units. Ketone bodies are released into the blood and are an important fuel source for a number of tissues. After their uptake, ketone bodies are converted into acetyl CoA and processed by the citric acid cycle.
The reaction for the activation of fatty acids before degradation is: This reaction is quite favorable because the equivalent of two molecules of ATP is hydrolyzed. Explain why, from a biochemical bookkeeping point of view, the equivalent of two molecules of ATP is used despite the fact that the left side of the equation has only one molecule of ATP.
To return the AMP to a form that can be phosphorylated by oxidative phosphorylation or substrate-level phosphorylation, another molecule of ATP must be expended in the reaction: ATP + AMP = 2ADP
Fatty Acids Are Processed in Three Stages
Triacylglycerols can be mobilized by the hydrolytic action of lipases that are under hormonal control. Glucagon and epinephrine stimulate triacylglycerol breakdown by activating the lipases. Insulin, in contrast, inhibits lipolysis. Fatty acids are activated to acyl CoAs, transported across the inner mitochondrial membrane by carnitine, and degraded in the mitochondrial matrix by a recurring sequence of four reactions: oxidation by FAD, hydration, oxidation by NAD+, and thiolysis by coenzyme A. The FADH2 and NADH formed in the oxidation steps transfer their electrons to O2 by means of the respiratory chain, whereas the acetyl CoA formed in the thiolysis step normally enters the citric acid cycle by condensing with oxaloacetate. Mammals are unable to convert fatty acids into glucose because they lack a pathway for the net production of oxaloacetate, pyruvate, or other gluconeogenic intermediates from acetyl CoA.
Why can't animals convert fats into glucose? Why are plants capable of such a conversion?
Two carbon atoms enter the cycle as an acetyl group, but two carbons leave the cycle as CO2 before oxaloacetate is generated. Consequently, no net synthesis of oxaloacetate is possible. In contrast, plants have two additional enzymes enabling them to convert the carbon atoms of acetyl CoA into oxaloacetate in the glyoxylate cycle (p. 355).
Stearic acid is a C18 fatty acid component of chocolate. Suppose you had a depressing day and decided to settle matters by gorging on chocolate. How much ATP would you derive from the complete oxidation of stearic acid to CO2?
You might hate yourself in the morning, but at least you won't have to worry about energy. To form stearoyl CoA requires the equivalent of 2 molecules of ATP. Total = 122 ATP
Place the following list of reactions or relevant locations in the b oxidation of fatty acids in the proper order. (a) Reaction with carnitine (b) Fatty acid in the cytoplasm (c) Activation of fatty acid by joining to CoA (d) Hydration (e) NAD+-linked oxidation (f) Thiolysis (g) Acyl CoA in mitochondrion (h) FAD-linked oxidation
b, c, a, g, h, d, e, f
(a) Triacylglycerol (b) Perilipin (c) Adipose triglyceride (d) Glucagon (e) Acyl CoA synthetase (f) Carnitine (g) b-Oxidation pathway (h) Enoyl CoA isomerase (i) 2,4-Dienoyl CoA reductase (j) Methylmalonyl CoA mutase (k) Ketone body 1. The enzyme that initiates lipid degradation 2. Activates fatty acids for degradation 3. Converts a cis-D3 double bond into a trans-D2 double bond 4. Reduces 2,4-dienoyl inter- mediate to trans-D3-enoyl CoA 5. Storage form of fats 6. Required for entry into mitochondria 7. Requires vitamin B12 8. Acetoacetate 9. Means by which fatty acids are degraded 10. Stimulates lipolysis 11. Lipid-droplet-associated protein
(a) 5; (b) 11; (c) 1; (d) 10; (e) 2; (f) 6; (g) 9; (h) 3; (i) 4; (j) 7; (k) 8
