Fatty Acids Degradation

What are the three stages of triacylglycerol utilization?

stage 1: triacylglycerols are degraded to fatty acids and glycerol, which are released from the adipose tissue and transported to the energy-requiring tissues.

stage 2: the fatty acids are activated and transported into mitochondria for degradation.

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.

Outline the control of triacylglycerol mobilization.

Glucagon and epinephrine trigger 7TM receptors in adipose tissue that activate adenylate cyclase. The increased level of cyclic AMP then stimulates protein kinase A, which phosphorylates two key proteins: perilipin, and lipase.

The phosphorylation of perilipin restructures the fat droplet and 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.

The partial reactions leading to the synthesis of acyl CoA (equations 1 and 2, Section 27.1) are freely reversible. The equilibrium constant for the sum of these reactions is close to 1, meaning that the energy levels of the reactants and products are about equal, even though a molecule of ATP has been hydrolyzed. Explain why these reactions are readily reversible.

The ready reversibility is due to the high-energy nature of the thioester in the acyl CoA.

Write the complete reaction for fatty acid activation.

RCOO- + CoA +ATP +H2O --> RCO-CoA +AMP + 2Pi

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+)

thiolysis by coenzyme A

The enzyme that initiates lipid degradation

Adipose triglyceride lipase

Means by which fatty acids are degraded

β-Oxidation pathway

Lipid-droplet-associated protein

Perilipin

Activates fatty acids for degradation

Acyl CoA synthetase

Place the following list of reactions or relevant locations in the β 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

1. Fatty acid in the cytoplasm

2. Activation of fatty acid by joining to CoA

3. Reaction with carnitine

4. Acyl CoA in mitochondrion

5. FAD-linked oxidation

6. Hydration

7. NAD+-linked oxidation

8. Thiolysis

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, but when glycogen stores are depleted, the effect of the deficiency is especially apparent.

Compare the ATP yields from palmitic acid and palmitoleic acid.

Palmitic acid yields 106 molecules of ATP. Palmitoleic acid will yield 1.5 fewer molecules of ATP than palmitic acid, for a total of 104.5 molecules of ATP.

What is the ATP yield for the complete oxidation of C17 (heptadecanoic) fatty acid? Assume that the propionyl CoA ultimately yields oxaloacetate in the citric acid cycle.

100 ATPs

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?

The total for glucose is 30 ATP.

The total for Hexanoic acid is 36 ATP.

Liver is the primary site of ketone-body synthesis. However, ketone bodies are not used by the liver but are released for other tissues to use. The liver does gain energy in the process of synthesizing and releasing ketone bodies. Calculate the number of molecules of ATP generated by the liver in the conversion of palmitate, a C-16 fatty acid, into acetoacetate.

PALMITATE + COA + ATP ---> PALMITOYL COA + AMP + 2 Pi

PALMITOYL COA + 7 FAD + 7 NAD + 7 COASH + H2O---> 8 ACETYL COA + 7 FADH2 + 7 NADH + 7 H+

THE 8 MOLECULES OF ACETYL COA COMBINE TO FORM 4 MOLECULES OF ACETOACETATE FOR RELEASE INTO THE BLOOD AND SO THEY DO NOT CONTRIBUTE TO THE ENERGY YIELD IN THE LIVER.

FADH2 = 10.5 ATP

NADH = 17.5 ATP

2 USED TO FORM PALMITOYL COA

26 NET ATP WERE GENERATED FOR USE BY THE LIVER

An old biochemistry adage is that fats burn in the flame of carbohydrates. What is the molecular basis of this adage?

For fats to be combusted, they must be converted into acetyl CoA, and the acetyl CoA must be processed by the citric acid cycle. In order for acetyl CoA to enter the citric acid cycle, there must be a supply of oxaloacetate. Oxaloacetate can be formed by the metabolism of glucose to pyruvate and the subsequent carboxylation of pyruvate to form oxaloacetate.

Why are liver cells not capable of using ketone bodies as a fuel?

CoA transferase that converts acetoacetate into acetoacetyl CoA, which is subsequently cleaved into two molecules of acetyl CoA. The lack of the enzyme allows liver to produce ketone bodies but not to use them.

Insulin-dependent diabetes is often accompanied by high levels of triacylglycerols in the blood. Suggest a biochemical explanation for the high blood levels of triacylglycerols.

In the absence of insulin, lipid mobilization will take place to an extent that it overwhelms the ability of the liver to convert the lipids into ketone bodies.

Why can't animals convert fats into glucose? Why are plants capable of such a conversion?

Plants are able to perform the glyoxylate cycle in which fats are converted to glucose while animals cannot.

What is the purpose of protein degradation during the initial stages of starvation?

The carbon skeletons of the released amino acids are used to synthesize glucose for use by the brain and red blood cells.

How is the loss of muscle protein delayed during starvation?

Muscle shifts from glucose to fatty acids for fuel. This switch lessens the need to degrade protein for glucose formation.

During fatty acid mobilization, glycerol is produced. This glycerol is not wasted. Write a balanced equation for the conversion of glycerol into pyruvate. What enzymes are required in addition to those of the glycolytic pathway?

GLYCEROL + 2 NAD+ + Pi + ADP ---> PYRUVATE + ATP + H2O + 2 NADH + 2 H+

We encountered reactions similar to the oxidation, hydration, and oxidation reactions of fatty acid degradation earlier in our study of biochemistry. What other pathway employs this set of reactions?

The citric acid cycle