Getting exposure. Proteins are denatured by acid in the stomach. This denaturation makes them better substrates for proteolysis. Explain why this is the case.

Targeting for destruction. What are the steps required to attach ubiquitin to a target protein?

Not the dating service. Match the description on the right with the term on the left.

Wasted energy? Protein hydrolysis is an exergonic process, yet the 26S proteasome is dependent on ATP hydrolysis for activity.

Keto counterparts. Name the α-ketoacid that is formed by the transamination of each of the following amino acids:

A versatile building block.

The benefits of specialization. The archaeal proteasome contains 14 identical active β subunits, whereas the eukaryotic proteasome has 7 distinct β subunits. What are the potential benefits of having several distinct active subunits?

Propose a structure. The 19S subunit of the proteasome contains six subunits that are members of the AAA ATPase family. Other members of this large family are associated into homohexamers with sixfold symmetry. Propose a structure for the AAA ATPases within the 19S proteasome. How might you test and refine your prediction?

Effective electron sinks. Pyridoxal phosphate stabilizes carbanionic intermediates by serving as an electron sink. Which other prosthetic group catalyzes reactions in this way?

Cooperation. How do aminotransferases and glutamate dehydrogenase cooperate in the metabolism of the amino group of amino acids?

Taking away the nitrogen. What amino acids yield citric acid cycle components and glycolysis intermediates when deaminated?

One reaction only. What amino acids can be deaminated directly?

Useful products. What are the common features of the breakdown products of the carbon skeletons of amino acids?

Helping hand. Propose a role for the positively charged guanidinium nitrogen atom in the cleavage of argininosuccinate into arginine and fumarate.

Nitrogen sources. What are the immediate biochemical sources for the two nitrogen atoms in urea?

Counterparts. Match the biochemical on the right with the property on the left.

Line up. Identify structures A–D, and place them in the order that they appear in the urea cycle.

Completing the cycle. Four high-transfer-potential phosphoryl groups are consumed in the synthesis of urea according to the stoichiometry given in Section 23.4. In this reaction, aspartate is converted into fumarate. Suppose that fumarate is converted into oxaloacetate. What is the resulting stoichiometry of urea synthesis? How many high-transfer-potential phosphoryl groups are spent?

A good bet. A friend bets you a bazillion dollars that you can’t prove that the urea cycle is linked to the citric acid cycle and other metabolic pathways. Can you collect?

Inhibitor design. Compound A has been synthesized as a potential inhibitor of a urea-cycle enzyme. Which enzyme do you think compound A might inhibit? Explain your answer.

Ammonia toxicity. Glutamate is an important neurotransmitter whose levels must be carefully regulated in the brain. Explain how a high concentration of ammonia might disrupt this regulation. How might a high concentration of ammonia alter the citric acid cycle?

A precise diagnosis. The urine of an infant gives a positive reaction with 2,4-dinitrophenylhydrazine. Mass spectrometry shows abnormally high blood levels of pyruvate, α-ketoglutarate, and the α-ketoacids of valine, isoleucine, and leucine. Identify a likely molecular defect and propose a definitive test of your diagnosis.

Therapeutic design. How would you treat an infant who is deficient in argininosuccinate synthetase? Which molecules would carry nitrogen out of the body?

Damaged liver. As we will see later (Chapter 27), liver damage (cirrhosis) often results in ammonia poisoning. Explain why this is the case.

Argininosuccinic aciduria. Argininosuccinic aciduria is a condition that results when the urea-cycle enzyme argininosuccinase is deficient. Argininosuccinate is present in the blood and urine. Suggest how this condition might be treated while still removing nitrogen from the body.

Sweet hazard. Why should phenylketonurics avoid using aspartame, an artificial sweetener? (Hint: Aspartame is l-aspartyl-l-phenylalanine methyl ester.)

Déjà vu. N-Acetylglutamate is required as a cofactor in the synthesis of carbamoyl phosphate. How is N-acetylglutamate synthesized from glutamate?

Negative nitrogen balance. A deficiency of even one amino acid results in a negative nitrogen balance. In this state, more protein is degraded than is synthesized, and so more nitrogen is excreted than is ingested. Why would protein be degraded if one amino acid were missing?

Precursors. Differentiate between ketogenic amino acids and glucogenic amino acids.

A slight of hand. The end products of tryptophan degradation are acetyl CoA and acetoacetyl CoA, yet tryptophan is a gluconeogenic amino acid in animals. Explain.

Closely related. Pyruvate dehydrogenase complex and α-ketoglutarate dehydrogenase complex are huge enzymes consisting of three discrete enzymatic activities. Which amino acids require a related enzyme complex, and what is the name of the enzyme?

Supply lines. The carbon skeletons of the 20 common amino acids can be degraded into a limited number of end products. What are the end products and in what metabolic pathway are they commonly found?

Serine dehydratase. Write out a complete mechanism for the conversion of serine into aminoacrylate catalyzed by serine dehydratase.

Serine racemase. The nervous system contains a substantial amount of d-serine, which is generated from l-serine by serine racemase, a PLP-dependent enzyme. Propose a mechanism for this reaction. What is the equilibrium constant for the reaction l-serine ⇌ d-serine?

Multiple substrates. In Chapter 8, we learned that there are two types of bisubstrate reactions, sequential and double-displacement. Which type characterizes the action of ami-notransferases? Explain your answer.

Double duty. Degradation signals are commonly located in protein regions that also facilitate protein–protein interactions. Explain why this coexistence of two functions in the same domain might be useful.

Fuel choice. Within a few days after a fast begins, nitrogen excretion accelerates to a higher-than-normal level. After a few weeks, the rate of nitrogen excretion falls to a lower level and continues at this low rate. However, after the fat stores have been depleted, nitrogen excretion rises to a high level.

A serious situation. Pyruvate carboxylase deficiency is a fatal disorder. Patients with pyruvate carboxylase deficiency sometimes display some or all of the following symptoms: lactic acidosis, hyperammonemia (excess NH₄⁺ in the blood), hypoglycemia, and demyelination of the regions of the brain due to insufficient lipid synthesis. Provide a possible biochemical rationale for each of these observations.

Isoleucine degradation. Isoleucine is degraded to acetyl CoA and succinyl CoA. Suggest a plausible reaction sequence, based on reactions discussed in the text, for this degradation pathway.

Many roles. Pyridoxal phosphate is an important coenzyme in transamination reactions. We have seen this coenzyme before, in glycogen metabolism. Which enzyme in glycogen metabolism requires pyridoxal phosphate and what role does the coenzyme play in this enzyme?

Enough cycles to have a race. The glucose–alanine cycle is reminiscent of the Cori cycle, but the glucose–alanine cycle can be said to be more energy efficient. Explain why this is so.

Another helping hand. In eukaryotes, the 20S proteasome component in conjunction with the 19S component degrades ubiquitinated proteins with the hydrolysis of a molecule of ATP. Archaea lack ubiquitin and the 26S proteasome but do contain a 20S proteasome. Some archaea also contain an ATPase that is homologous to the ATPases of the eukaryotic 19S component. This archaeal ATPase activity was isolated as a 650-kDa complex (called PAN) from the archaeon Thermoplasma, and experiments were performed to determine if PAN could enhance the activity of the 20S proteasome from Thermoplasma as well as other 20S proteasomes.

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Protein degradation was measured as a function of time and in the presence of various combinations of components. Graph A shows the results.