Biochemistry

Jeremy M. Berg, John L. Tymoczko, Gregory J. Gatto, Jr, Lubert Stryer

Chapter 22

Fatty Acid Metabolism - all with Video Answers

Educators

Chapter Questions

Problem 1

Match'em. Match each term with its description.
(a) Triacylglycerol_______
(b) Perilipin_______
(c) Adipose triglyceride lipase_______
(d) Glucagon_______
(e) Acyl CoA synthetase_______
(f) Carnitine_______
(g) $\beta$ - 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- $\Delta^{3}$ double bond into a trans- $\Delta^{2}$ double bond
4. Reduces 2,4 -dienoyl intermediate to trans- $\Delta^{3}$ enoyl CoA
5. Storage form of fats
6. Required for entry into mitochondria
7. Requires vitamin $\mathrm{B}_{12}$
8. Acetoacetate
9. Means by which fatty acids are degraded
10. Stimulates lipolysis
11. Lipid-droplet-associated protein

Jessica Honkomp

Jessica Honkomp

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Problem 2

After lipolysis. Write a balanced equation for the conversion of glycerol into pyruvate. Which enzymes are required in addition to those of the glycolytic pathway?

Banhishikha Sinha

Banhishikha Sinha

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Problem 3

Forms of energy. The partial reactions leading to the synthesis of acyl CoA (equations 1 and $2, p .649$ ) 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.

Banhishikha Sinha

Banhishikha Sinha

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Problem 4

Activation fee. The reaction for the activation of fatty acids before degradation is (EQUATION CAN'T COPY)
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.

Ramesh Singh

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Problem 5

Proper sequence. Place the following list of reactions or relevant locations in the $\beta$ 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.

Banhishikha Sinha

Banhishikha Sinha

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Problem 6

Remembrance of reactions past. We have 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?

Banhishikha Sinha

Banhishikha Sinha

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Problem 7

A phantom acetyl CoA? In the equation for fatty acid degradation shown here, only seven molecules of CoA are required to yield eight molecules of acetyl CoA. How is this difference possible? $$ \begin{array}{l} \text { Palmitoyl } \mathrm{CoA}+7 \mathrm{FAD}+7 \mathrm{NAD}^{+} \\ \quad+7 \mathrm{CoA}+7 \mathrm{H}_{2} \mathrm{O} \longrightarrow \\ \quad 8 \text { acetyl } \mathrm{CoA}+7 \mathrm{FADH}_{2}+7 \mathrm{NADH}+7 \mathrm{H}^{+} \end{array} $$

Banhishikha Sinha

Banhishikha Sinha

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Problem 8

Comparing yields. Compare the ATP yields from palmitic acid and palmitoleic acid.

Banhishikha Sinha

Banhishikha Sinha

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Problem 9

Counting ATPs $1 .$ What is the ATP yield for the complete oxidation of $\mathrm{C}_{17}$ ( heptadecanoic) fatty acid? Assume that the propionyl CoA ultimately yields oxaloacetate in the citric acid cycle.

Banhishikha Sinha

Banhishikha Sinha

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Problem 10

Sweet temptation. Stearic acid is a $\mathrm{C}_{18}$ 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 $\mathrm{CO}_{2} ?$

Ramesh Singh

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Problem 11

The best storage form. 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 caprioic acid and is responsible for the "aroma" of goats. Why are fats better fuels than carbohydrates?

Banhishikha Sinha

Banhishikha Sinha

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Problem 12

From fatty acid to ketone body. Write a balanced equation for the conversion of stearate into acetoacetate.

Banhishikha Sinha

Banhishikha Sinha

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Problem 13

Generous, but not to a fault. 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 $\mathrm{C}_{16}$ fatty acid, into acetoacetate.

Banhishikha Sinha

Banhishikha Sinha

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Problem 14

Counting ATPs 2. How much energy is attained with the complete oxidation of the ketone body D-3hydroxybutyrate?

Banhishikha Sinha

Banhishikha Sinha

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Problem 15

Another view. Why might someone argue that the answer to problem 14 is wrong?

Banhishikha Sinha

Banhishikha Sinha

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Problem 16

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

Banhishikha Sinha

Banhishikha Sinha

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Problem 17

Refsum disease. Phytanic acid is a branched-chain fatty acid component of chlorophyll and is a significant component of milk. In susceptible people, phytanic acid can accumulate, leading to neurological problems. This syndrome is called Refsum disease or phytanic acid storage disease. (EQUATION CAN'T COPY)
(a) Why does phytanic acid accumulate?
(b) What enzyme activity would you invent to prevent its accumulation?

Banhishikha Sinha

Banhishikha Sinha

Numerade Educator

Problem 18

A hot diet. Tritium is a radioactive isotope of hydrogen and can be readily detected. A fully tritiated, six-carbon saturated fatty acid is administered to a rat, and a muscle biopsy of the rat is taken by concerned, sensitive, and discrete technical assistants. These assistants carefully isolate all of the acetyl CoA generated from the $\beta$ oxidation of the radioactive fatty acid and remove the CoA to form acetate. What will be the overall tritium-to-carbon ratio of the isolated acetate?

Dennis Howard

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Problem 19

Finding triacylglycerols in all the wrong places. Insulindependent diabetes is often accompanied by high levels of triacylglycerols in the blood. Suggest a biochemical explanation.

Banhishikha Sinha

Banhishikha Sinha

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Problem 20

Match 'em. Match the terms with the descriptions.
(a) ATP-citrate lyase_________
(b) Malic enzyme_________
(c) Malonyl CoA_________
(d) Acetyl CoA carboxylase_________
(e) Acyl carrier protein_________
(f) $\beta$ -Ketoacyl synthase_________
(g) Palmitate_________
(h) Eicosanoids_________
(i) Arachidonate_________
(j) AMP-activated protein kinase_________
1. Helps to generate NADPH from NADH
2. Inactivates acetyl CoA carboxylase
3. Molecule on which fatty acids are synthesized
4. A precursor of prostaglandins
5. Activated acetyl CoA
6. The end product of fatty acid synthase
7. Fatty acids containing
20 carbon atoms
8. Catalyzes the committed step in fatty acid synthesis
9. Catalyzes the reaction of acetyl ACP and malonyl $\mathrm{ACP}$
10. Generates cytoplasmic acetyl CoA

Jessica Honkomp

Jessica Honkomp

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Problem 21

Counterpoint. Compare and contrast fatty acid oxidation and synthesis with respect to
(a) site of the process
(b) acyl carrier
(c) reductants and oxidants
(d) stereochemistry of the intermediates
(e) direction of synthesis or degradation
(f) organization of the enzyme system

Banhishikha Sinha

Banhishikha Sinha

Numerade Educator

Problem 22

The fizz in fatty acid synthesis. During the initial in vitro studies on fatty acid synthesis, experiments were performed to determine which buffer would result in optimal activity. Bicarbonate buffer proved far superior to phosphate buffer. The researchers could not initially account for this result. From your perspective of many decades later, explain why the result is not surprising.

Rashmi Sinha

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Problem 23

A supple synthesis. Myristate, a saturated $\mathrm{C}_{14}$ fatty acid, is used as an emollient for cosmetics and topical medicinal preparations. Write a balanced equation for the synthesis of myristate.

Banhishikha Sinha

Banhishikha Sinha

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Problem 24

The cost of cleanliness. Lauric acid is a 12 -carbon fatty acid with no double bonds. The sodium salt of lauric acid (sodium laurate) is a common detergent used in a variety of products, including laundry detergent, shampoo, and toothpaste. How many molecules of ATP and NADPH are required to synthesize lauric acid?

Banhishikha Sinha

Banhishikha Sinha

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Problem 25

Proper organization. Arrange the following steps in fatty acid synthesis in their proper order.
(a) Dehydration
(b) Condensation
(c) Release of a $\mathrm{C}_{16}$ fatty acid
(d) Reduction of a carbonyl group
(e) Formation of malonyl ACP

Banhishikha Sinha

Banhishikha Sinha

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Problem 26

No access to assets. What would be the effect on fatty acid synthesis of a mutation in ATP-citrate lyase that reduces the enzyme's activity? Explain.

Banhishikha Sinha

Banhishikha Sinha

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Problem 27

The truth and nothing but. True or False. If false, explain.
(a) Biotin is required for fatty acid synthase activity.
(b) The condensation reaction in fatty acid synthesis is powered by the decarboxylation of malonyl CoA.
(c) Fatty acid synthesis does not depend on ATP.
(d) Palmitate is the end product of fatty acid synthase.
(e) All of the enzyme activities required for fatty acid synthesis in mammals are contained in a single polypeptide chain.
(f) Fatty acid synthase in mammals is active as a monomer.
(g) The fatty acid arachidonate is a precursor for signal molecules.
(h) Acetyl CoA carboxylase is inhibited by citrate.

Banhishikha Sinha

Banhishikha Sinha

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Problem 28

Odd fat out. Suggest how fatty acids with odd numbers of carbons are synthesized.

Banhishikha Sinha

Banhishikha Sinha

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Problem 29

Labels. Suppose that you had an in vitro fatty acidsynthesizing system that had all of the enzymes and cofactors required for fatty acid synthesis except for acetyl CoA. To this system, you added acetyl CoA that contained radioactive hydrogen $\left(^{3} \mathrm{H}, \text { tritium ) and carbon } 14\left(^{14} \mathrm{C}\right)$ as shown here. \right. (EQUATION CAN'T COPY)
The ratio of $^{3} \mathrm{H} /^{14} \mathrm{C}$ is $3 .$ What would the $^{3} \mathrm{H} /^{14} \mathrm{C}$ ratio be after the synthesis of palmitic acid $\left(\mathrm{C}_{16}\right)$ with the use of the radioactive acetyl CoA?

Rashmi Sinha

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Problem 30

A tight embrace. Avidin, a glycoprotein found in eggs, has a high affinity for biotin. Avidin can bind biotin and prevent its use by the body. How might a diet rich in raw eggs affect fatty acid synthesis? What will be the effect on fatty acid synthesis of a diet rich in cooked eggs? Explain.

Banhishikha Sinha

Banhishikha Sinha

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Problem 31

Alpha or omega? Only one acetyl CoA molecule is used directly in fatty acid synthesis. Identify the carbon atoms in palmitic acid that were donated by acetyl CoA.

Banhishikha Sinha

Banhishikha Sinha

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Problem 32

Now you see it, now you don't. Although $$\mathrm{HCO}_{3}^{-}$$ is required for fatty acid synthesis, its carbon atom does not appear in the product. Explain how this omission is possible.

Banhishikha Sinha

Banhishikha Sinha

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Problem 33

It is all about communication. Why is citrate an appropriate inhibitor of phosphofructokinase?

Banhishikha Sinha

Banhishikha Sinha

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Problem 34

Tracing carbon atoms. Consider a cell extract that actively synthesizes palmitate. Suppose that a fatty acid synthase in this preparation forms one molecule of palmitate in about 5 minutes. A large amount of malonyl CoA labeled with $^{14} \mathrm{C}$ in each carbon atom of its malonyl unit is suddenly added to this system, and fatty acid synthesis is stopped a minute later by altering the pH. The fatty acids are analyzed for radioactivity. Which carbon atom of the palmitate formed by this system is more radioactive $-\mathrm{C}-1$ or $\mathrm{C}-14 ?$

Banhishikha Sinha

Banhishikha Sinha

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Problem 35

An unaccepting mutant. The serine residues in acetyl CoA carboxylase that are the target of the AMP-activated protein kinase are mutated to alanine. What is a likely consequence of this mutation?

Banhishikha Sinha

Banhishikha Sinha

Numerade Educator

Problem 36

Sources. For each of the following unsaturated fatty acids, indicate whether the biosynthetic precursor in animals is palmitoleate, oleate, linoleate, or linolenate.
(a) 18: 1 cis- $\Delta^{11}$
(b) 18: 3 cis- $\Delta^{6}, \Delta^{9}, \Delta^{12}$
(c) 20: 2 cis- $\Delta^{11}, \Delta^{14}$
(d) 20: 3 cis- $\Delta^{5}, \Delta^{8}, \Delta^{11}$
(e) 22: 1 cis- $\Delta^{13}$
(f) $22: 6 \operatorname{cis}-\Delta^{4}, \Delta^{7}, \Delta^{10}, \Delta^{13}$
$\Delta^{16}, \Delta^{19}$

Banhishikha Sinha

Banhishikha Sinha

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Problem 37

Driven by decarboxylation. What is the role of decarboxylation in fatty acid synthesis? Name another key reaction in a metabolic pathway that employs this mechanistic motif.

Banhishikha Sinha

Banhishikha Sinha

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Problem 38

Kinase surfeit. Suppose that a promoter mutation leads to the overproduction of protein kinase A in adipose cells. How might fatty acid metabolism be altered by this mutation?

Banhishikha Sinha

Banhishikha Sinha

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Problem 39

Blocked assets. The presence of a fuel molecule in the cytoplasm does not ensure that the fuel molecule can be effectively used. Give two examples of how impaired transport of metabolites between compartments leads to disease.

Banhishikha Sinha

Banhishikha Sinha

Numerade Educator

Problem 40

Elegant inversion. Peroxisomes have an alternative pathway for oxidizing polyunsaturated fatty acids. They contain a hydratase that converts D-3-hydroxyacyl CoA into trans$\Delta^{2}$ -enoyl CoA. How can this enzyme be used to oxidize CoAs containing a cis double bond at an even-numbered carbon atom (e.g., the cis- $\Delta^{12}$ double bond of linoleate)?

Banhishikha Sinha

Banhishikha Sinha

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Problem 41

Arm in arm. Many eukaryotic enzymes, such as fatty acid synthase, are multifunctional proteins with multiple active sites covalently linked. What is the advantage of this arrangement?

Carlene Jimenez

Carlene Jimenez

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Problem 42

Covalent catastrophe. What is a potential disadvantage of having many catalytic sites together on one very long polypeptide chain?

Banhishikha Sinha

Banhishikha Sinha

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Problem 43

Missing acyl CoA dehydrogenases. A number of genetic deficiencies in acyl CoA dehydrogenases have been described. This deficiency presents early in life after a period of fasting. Symptoms include vomiting, lethargy, and sometimes coma. Not only are blood levels of glucose low (hypoglycemia), but starvation-induced ketosis is absent. Provide a biochemical explanation for these last two observations.

Banhishikha Sinha

Banhishikha Sinha

Numerade Educator

Problem 44

Effects of clofibrate. High blood levels of triacylglycerides are associated with heart attacks and strokes. Clofibrate, a drug that increases the activity of peroxisomes, is sometimes used to treat patients with such a condition. What is the biochemical basis for this treatment?

Banhishikha Sinha

Banhishikha Sinha

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Problem 45

A different kind of enzyme. Figure 22.36 shows the response of acetyl CoA carboxylase to varying amounts of citrate. Explain this effect in light of the allosteric effects that citrate has on the enzyme. Predict the effects of increasing concentrations of palmitoyl CoA.

Banhishikha Sinha

Banhishikha Sinha

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Problem 46

Variation on a theme. Thiolase is homologous in structure to the condensing enzyme. On the basis of this observation, propose a mechanism for the cleavage of 3 -ketoacyl CoA by CoA.

Banhishikha Sinha

Banhishikha Sinha

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Problem 47

Two plus three to make four. Propose a reaction mechanism for the condensation of an acetyl unit with a malonyl unit to form an acetoacetyl unit in fatty acid synthesis.

Banhishikha Sinha

Banhishikha Sinha

Numerade Educator

Problem 48

Ill-advised diet. Suppose that, for some bizarre reason, you decided to exist on a diet of whale and seal blubber, exclusively.
(a) How would lack of carbohydrates affect your ability to utilize fats?
(b) What would your breath smell like?
(c) One of your best friends, after trying unsuccessfully to convince you to abandon this diet, makes you promise to consume a healthy dose of odd-chain fatty acids. Does your friend have your best interests at heart? Explain.

Banhishikha Sinha

Banhishikha Sinha

Numerade Educator

Problem 49

Fats to glycogen. An animal is fed stearic acid that is radioactively labeled with $\left[^{14} \mathrm{C}\right]$ carbon. A liver biopsy reveals the presence of $^{14}$ C-labeled glycogen. How is this finding possible in light of the fact that animals cannot convert fats into carbohydrates?

Banhishikha Sinha

Banhishikha Sinha

Numerade Educator

Problem 50

Enzyme deficit. Pyruvate dehydrogenase deficiency, a severe condition with a poor prognosis, results in neurological dysfunction and unremitting lactic acidosis. One treatment is placing the patients on a low carbohydrate/high fat diet.
(a) Explain why the deficiency would be characterized by neurological dysfunction.
(b) Why does lactic acidosis result?
(c) Explain the rationale for the low carbohydrate/high fat diet.

Bhumika Jayee

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Problem 51

Right enzymes. Wrong location. Zwellweger syndrome is caused by a defect in enzyme importation into the peroxisomes. What disease of carbohydrate metabolism is caused by inappropriate cellular distribution of enzymes?

Joanna Quigley

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Problem 52

52. Mutant enzyme. Carnitine palmitoyl transferase I (CPTI) catalyzes the conversion of long-chain acyl CoA into acyl carnitine, a prerequisite for transport into mitochondria and subsequent degradation. A mutant enzyme was constructed with a single amino acid change at position 3 of glutamic acid for alanine. Graphs A through C show data from studies performed to identify the effect of the mutation.
(a) What is the effect of the mutation on enzyme activity when the concentration of carnitine is varied (Graph $A$ )? What are the $K_{\mathrm{M}}$ and $V_{\max }$ values for the wild-type and mutant enzymes? (FIGURE CAN'T COPY)
(b) What is the effect when the experiment is repeated with varying concentrations of palmitoyl CoA (Graph $\mathrm{B}$ )? What are the $K_{\mathrm{M}}$ and $V_{\max }$ values for the wild-type and mutant enzymes?(FIGURE CAN'T COPY)
(c) Graph C shows the inhibitory effect of malonyl CoA on the wild-type and mutant enzymes. Which enzyme is more sensitive to malonyl CoA inhibition?(FIGURE CAN'T COPY)
(d) Suppose that the concentration of palmitoyl $\operatorname{CoA}=$ $100 \mu \mathrm{M},$ that of carnitine $=100 \mu \mathrm{M},$ and that of malonyl $\mathrm{CoA}=10 \mu \mathrm{M} .$ Under these conditions, what is the most prominent effect of the mutation on the properties of the enzyme?
(e) What can you conclude about the role of glutamate 3 in CPTI function?

Banhishikha Sinha

Banhishikha Sinha

Numerade Educator

Problem 53

Partners. Colipase binds to lipid particles in the intestine and facilitates the subsequent binding and activation of pancreatic lipase. The lipase then hydrolyzes the lipids so that they can be absorbed by intestinal cells. Experiments were undertaken using site-directed mutagenesis (Section 5.2) to determine which amino acids in the colipase facilitated lipase binding and which activated the lipase. A portion of these experiments is presented below.
Figure A shows the results of two different amino acid substitutions on the ability of colipase to facilitate the binding of lipase to the lipid particles. In both panels, the blue circles show the control (no amino acid changes) data and the red circles the data with the altered amino acid. The first letter represents the normal amino acid, the number its position in the amino acid sequence, and the second letter the replacement amino acid.
(a) What is the amino acid alteration in the upper panel?(FIGURE CAN'T COPY)
(b) How does this mutation change the ability of colipase to bind the lipase to the lipid particle?
(c) What is the amino acid substitution in the lower panel?
(d) What is the effect of this substitution on the ability of the colipase to bind the lipase to the lipid particle?
Next, the activity of the bound lipase was examined, as shown in Figure $\mathrm{B}$. (FIGURE CAN'T COPY)
(e) What was the effect of the L16A mutation on lipase activity?
(f) What does this suggest about the lipase binding and activation properties of the colipase?
(g) What was the effect of the Y55A mutation on lipase activity?

Banhishikha Sinha

Banhishikha Sinha

Numerade Educator

Problem 54

Nip it in the bud. Soraphen A is a natural antifungal agent isolated from a myxobacterium. Soraphen $\mathrm{A}$ is also a potent inhibitor of acetyl CoA carboxylase, the regulatory enzyme that initiates fatty acid synthesis. As discussed earlier $(p .667)$ cancer cells must produce large amount of fatty acids to generate phospholipids for membrane synthesis. Thus, acetyl CoA carboxylase might be a target for anti-cancer drugs. Following are the results of experiments testing this hypothesis on a cancer line. Figure A shows the effect of various amounts of soraphen $\mathrm{A}$ on fatty acid synthesis as measured by the incorporation of radioactive acetate $\left(^{14} \mathrm{C}\right)$ into fatty acids.
(A)(FIGURE CAN'T COPY) (B)(FIGURE CAN'T COPY)
(a) How did soraphen $A$ alter fatty acid synthesis? How was synthesis affected by increasing concentrations of soraphen $\mathrm{A} ?$
Figure $\mathrm{B}$ shows the results obtained when fatty acid oxidation was measured, as the release of radioactive $\mathrm{CO}_{2}$ from added radioactive $\left(^{14} \mathrm{C}\right)$ palmitate, in the presence of soraphen $\mathrm{A}$.
(b) How did soraphen $A$ alter fatty acid oxidation?
(c) Explain the results obtained in $\mathrm{B}$ in light of the fact that soraphen A inhibits acetyl CoA carboxylase.
More experiments were undertaken to assess whether carboxylase inhibition did indeed prevent phospholipid synthesis. Again, cells were grown in the presence of radioactive acetate and phospholipids were subsequently isolated and the amount of $^{14} \mathrm{C}$ incorporated into the phospholipid was determined. The effect of soraphen A on phospholipid synthesis is shown in Figure $\mathrm{C}$.
(C)(FIGURE CAN'T COPY) (D)(FIGURE CAN'T COPY)
(d) Did the inhibition of carboxylase by the drug alter phospholipid synthesis?
(e) How might phospholipid synthesis affect cell viability?
Finally, as shown in Figure $\mathrm{D},$ experiments were performed to determine if the drug inhibits cancer growth in vitro by determining the number of cancer cells surviving upon exposure to soraphen A.
(f) How did soraphen $A$ affect cancer cell viability?

Rabeya Zahid

Numerade Educator