Questions Chapter 1-2-3-4-5-19

A female neonate did well until approximately age 24 hours, when she became lethargic. A sepsis workup proved negative. At 56 hours, she started showing focal seizure activity. The plasma ammonia level was found to be 887 μmol/l (normal 5-35 μmol/l). Quantitative plasma amino acid levels revealed a marked elevation of citrulline but not argininosuccinate. 19.3 Which one of the following enzymic activities is most likely to be deficient in this patient? A. Arginase B. Argininosuccinate lyase C. Argininosuccinate synthetase D. Carbamoyl phosphate synthetase I E. Ornithine transcarbamoylase 19.4 Which one of the following would also be elevated in the blood of this patient? A. Asparagine B. Glutamine C. Lysine D. Urea 19.5 Why might supplementation with arginine be of ben- efit to this patient?

19.3 Correct answer = C. Genetic deficiencies of each of the five enzymes of the urea cycle, as well as deficiencies in N-acetyglutamate synthase, have been described. The accumulation of citrulline (but not argininosuccinate) in the plasma of this patient means that the enzyme required for the conver- sion of citrulline to argininosuccinate (argininosuccinate synthetase) is defective, whereas the enzyme that cleaves argininosuccinate (argininosuccinate lyase) is functional. 19.4Correct answer = B. Deficiencies of the enzymes of the urea cycle result in the failure to synthe- size urea and lead to hyperammonemia in the first few weeks after birth. Glutamine will also be elevated because it acts as a nontoxic storage and transport form of ammonia. Therefore, elevated glutamine always accompanies hyperammonemia. Asparagine and lysine do not serve this sequester- ing role. Urea would be decreased due to impaired activity of the urea cycle. [Note: Alanine would also be elevated in this patient.] 19.5 the arginine will be cleaved by arginase to urea and ornithine. Ornithine will be combined with carbamoyl phosphate by ornithine transcarbamo- ylase to form citrulline. Citrulline, containing one waste nitrogen, will be excreted.

A 30-year-old woman of Northern European ancestry presents with progressive dyspnea (shortness of breath). She denies the use of cigarettes. Family his- tory reveals that her sister also has problems with her lungs. Which one of the following etiologies most likely explains this patient's pulmonary symptoms? A. Deficiency in dietary vitamin C B. Deficiency of α1-antitrypsin C. Deficiency of prolyl hydroxylase D Decreased elastase activity E. Increased collagenase activity

Correct Answer = B. α1-Antitrypsin (AAT) deficiency is a genetic disorder that can cause pulmonary damage and emphysema even in the absence of cigarette use. A deficiency of AAT permits increased elastase activity to destroy elastin in the alveolar walls. AAT deficiency should be suspected when chronic obstructive pulmonary disease develops in a patient younger than age 45 years who does not have a history of chronic bronchitis or tobacco use or when multiple family members develop obstructive lung disease at an early age. Choices A, C, and E refer to collagen, not elastin

A 2-year-old child presents with metabolic acidosis after ingesting an unknown number of flavored aspirin tablets. At presentation, her blood pH was 7.0. Given that the pKa of aspirin (salicylic acid) is 3, calculate the ratio of its ionized to un-ionized forms at pH 7.0.

Correct answer = 10,000 to 1. pH = pKa + log [A-]/[HA]. Therefore, 7 = 3 + × and × = 4. The ratio of A- (ionized) to HA (un- ionized), then, is 10,000 to 1 because the log of 10,000 is 4.

5.1 In cases of ethylene glycol poisoning and its characteristic metabolic acidosis, treatment involves correction of the acidosis, removal of any remaining ethylene glycol, and administration of an inhibitor of alcohol dehydrogenase (ADH), the enzyme that oxidizes ethylene glycol to the organic acids that cause the acidosis. Ethanol (grain alcohol) frequently is the inhibitor given to treat ethylene glycol poisoning. Results of experiments using ADH with and without ethanol are shown to the right. Based on these data, what type of inhibition is caused by the ethanol? A. Competitive B. Feedback C. Irreversible D. Noncompetitive ADH requires oxidized nicotinamide adenine dinucleotide (NAD+) for catalytic activity. In the reaction catalyzed by ADH, an alcohol is oxidized to an aldehyde as NAD+ is reduced to NADH and dissociates from the enzyme. The NAD+ is functioning as a (an): A. apoenzyme. B. coenzyme‐cosubstrate. C. coenzyme‐prosthetic group. D. cofactor. E. heterotropic effector. For Questions 5.3 and 5.4, use the graph below which shows the changes in free energy when a reactant is converted to a product in the presence and absence of an enzyme. Select the letter that best represents: 5.3 The free energy of activation of the catalyzed forward reaction. 5.4 The free energy of the reaction.

Correct answer = A competitive inhibitor increases the apparent Km for a given substrate. This means that, in the presence of a competitive inhibitor, more substrate is needed to achieve 1⁄2 Vmax. The effect of a competitive inhibitor is reversed by increasing substrate concentration ([S]). At a sufficiently high [S], the reaction velocity reaches the Vmax observed in the absence of inhibitor.A 5.2Correct answer = B. Coenzymes‐cosubstrates are small organic molecules that associate transiently with an enzyme and leave the enzyme in a changed form. Coenzyme‐prosthetic groups are small organic molecules that associate permanently with an enzyme and are returned to their original form on the enzyme. Cofactors are metal ions. Heterotropic effectors are not substrates. 5.3 and 5.4Correct answers = B; D. Enzymes (biocatalysts) provide an alternate reaction pathway with a lower free energy of activation. However, they do not change the free energy of the reactant or product. A is the free energy of the uncatalyzed reaction. C is the free energy of the catalyzed reverse reaction.

Choose the ONE best answer. Which one of the following statements concerning the hemoglobins is correct? A. HbA is the most abundant hemoglobin in normal adults. B. Fetal blood has a lower affinity for oxygen than does adult blood because HbF has an increased affinity for 2,3-bisphosphoglycerate. C. The globin chain composition of HbF is α2δ2. D. HbA1c differs from HbA by a single, genetically deter- mined amino acid substitution. E. HbA2 appears early in fetal life.

Correct answer = A. HbA accounts for over 90% of the hemoglobin in a normal adult. If HbA1c is included, the percentage rises to approximately 97%. Because 2,3-bisphosphoglycerate (2,3-BPG) reduces the affinity of hemoglobin for oxygen, the weaker interaction between 2,3-BPG and HbF results in a higher oxygen affinity for HbF relative to HbA. HbF consists of α2γ2. HbA1c is a glycosylated form of HbA, formed nonenzymically in red cells. HbA2 is a minor component of normal adult hemoglobin, first appearing shortly before birth and rising to adult levels (about 2% of the total hemoglobin) by age 6 months.

4 β-Lysine 82 in HbA is important for the binding of 2,3-bisphosphoglycerate. In Hb Helsinki, this amino acid has been replaced by methionine. Which of the following should be true concerning Hb Helsinki? A. It should be stabilized in the taut, rather than the relaxed, form. B. It should have increased O2 affinity and, consequently, decreased delivery of O2 to tissues. C. Its O2-dissociation curve should be shifted to the right relative to HbA. D. It results in anem

Correct answer = B. Substitution of lysine by methionine decreases the ability of negatively charged phosphate groups in 2,3-bisphospho- glycerate (2,3-BPG) to bind the β subunits of hemoglobin. Because 2,3-BPG decreases the O2 affinity of hemoglobin, a reduction in 2,3- BPG should result in increased O2 affinity and decreased delivery of O2 to tissues. The relaxed form is the high-oxygen-affinity form of hemoglobin. Increased O2 affinity (decreased delivery) results in a left shift in the O2-dissociation curve. Decreased O2 delivery is

In the transamination reaction shown to the right, which of the following are the products X and Y? A. Alanine, α-ketoglutarate B. Asparate, α-ketoglutarate C. Glutamate, alanine D. Pyruvate, aspartate

Correct answer = B. Transamination reactions always have an amino acid and an α-keto acid as substrates. The products of the reaction are also an amino acid (corresponding to the α-keto sub- strate) and an α-keto acid (corresponding to the amino acid substrate). Three amino acid α-keto acid pairs commonly encountered in metabolism are: alanine/pyruvate, aspartate/oxaloacetate, and glutamate/α-ketoglutarate. In this question, glutamate is deaminated to form α-ketoglutarate, and oxaloacetate is aminated to form aspartate.

1.1 Which one of the following statements concerning the titration curve for a nonpolar amino acid is correct? The letters A through D designate certain regions on the curve below. A. Point A represents the region where the amino acid is deprotonated. B. Point B represents a region of minimal buffering. C. Point C represents the region where the net charge on the amino acid is zero. D. Point D represents the pK of the amino acid's carboxyl group. E. The amino acid could be lysine.

Correct answer = C. C represents the isoelectric point, or pI, and as such is midway between pK1 and pK2 for a nonpolar amino acid. The amino acid is fully protonated at Point A. Point B rep- resents a region of maximum buffering, as does Point D. Lysine is a basic amino acid, and has an ionizable side chain.

A 67-year-old man presented to the emergency department with a 1-week history of angina and shortness of breath. He complained that his face and extremities had a "blue color." His medical history included chronic stable angina treated with isosorbide dinitrate and nitroglycerin. Blood obtained for analysis was brown colored. Which one of the following is the most likely diagnosis? A. Carboxyhemoglobinemia B. Hemoglobin SC disease C. Methemoglobinemia D. Sickle cell anemia E. β-Thalassemia

Correct answer = C. Oxidation of the heme component of hemoglobin to the ferric (Fe3+) state forms methemoglobin. This may be caused by the action of certain drugs such as nitrates. The methemoglobinemias are characterized by chocolate cyanosis (a brownish blue coloration of the skin and mucous membranes and chocolate-colored blood) as a result of the dark-colored methemoglobin. Symptoms are related to tissue hypoxia and include anxiety, headache, and dyspnea. In rare cases, coma and death can occur. [Note: Benzocaine, an aromatic amine used as a topical anesthetic, is a cause of acquired methemoglobinemia.]

2.2 A particular point mutation results in disruption of the α-helical structure in a segment of the mutant protein. The most likely change in the primary structure of the mutant protein is: A. glutamate to aspartate. B. lysine to arginine. C. methionine to proline. D. valine to alanine.

Correct answer = C. Proline, because of its secondary amino group, is incompatible with an α-helix. Glutamate, aspartate, lysine, and arginine are charged amino acids, and valine is a branched amino acid. Charged and branched (bulky) amino acids may disrupt an α-helix

Which one of the following statements concerning the binding of oxygen by hemoglobin is correct? A. The Bohr effect results in a lower affinity for oxygen at higher pH values. B. Carbon dioxide increases the oxygen affinity of hemoglobin by binding to the C-terminal groups of the polypeptide chains. C. The oxygen affinity of hemoglobin increases as the percentage saturation increases. D. The hemoglobin tetramer binds four molecules of 2,3-bisphosphoglycerate. E. Oxyhemoglobin and deoxyhemoglobin have the same affinity for protons.

Correct answer = C. The binding of oxygen at one heme group increases the oxygen affinity of the remaining heme groups in the same molecule. A rise in pH results in increased affinity for oxygen. Carbon dioxide decreases oxygen affinity because it lowers the pH; more- over, binding of carbon dioxide to the N-termini stabilizes the taut, deoxy form. Hemoglobin binds one molecule of 2,3-bisphosphoglycerate. Deoxyhemoglobin has a greater affinity for pro- tons and, therefore, is a weaker acid.

4.3 A 7-month-old child "fell over" while crawling and now presents with a swol- len leg. Imaging reveals a fracture of a bowed femur, secondary to minor trauma, and thin bones (see x-ray at right). Blue sclerae are also noted. At age 1 month, the infant had multiple frac- tures in various states of healing (right clavicle, right humerus, and right radius). A careful family history has ruled out nonaccidental trauma (child abuse) as a cause of the bone fractures. Which pair- ing of a defective (or deficient) molecule and the resulting pathology best fits this clinical description? A. Elastin and emphysema B. Fibrillin and Marfan disease C. Type I collagen and osteogenesis imperfecta (OI) D. Type V collagen and Ehlers-Danlos syndrome (EDS) E. Vitamin C and scurvy 4.4 How and why is proline hydroxylated in collagen?

Correct answer = C. The child most likely has osteogenesis imperfecta. Most cases arise from a defect in the genes encoding type I collagen. Bones in affected patients are thin, osteoporotic, often bowed, and extremely prone to fracture. Pulmonary problems are not seen in this child. Individuals with Marfan syndrome have impaired structural integrity of the skeleton, eyes, and cardiovascular system. Defects in type V col- lagen cause the classic form of EDS characterized by skin extensibility and fragility and joint hypermobility. Vitamin C deficiency is character- ized by capillary fragility.

Which one of the following statements concerning the peptide shown below is correct? Val-Cys-Glu-Ser-Asp-Arg-Cys A. The peptide contains asparagine. B. The peptide contains a side chain with a secondary amino group. C. The peptide contains a side chain that can be phos- phorylated. D. The peptide cannot form an internal disulfide bond. E. The peptide would move to the cathode (negative electrode) during electrophoresis at pH 5.

Correct answer = C. The hydroxyl group of serine can accept a phosphate group. Asp is aspartate. Proline contains a secondary amino group. The two cysteine residues can, under oxidizing conditions, form a disulfide (covalent) bond. The net charge on the peptide at pH 5 is negative, and it would move to the anode.

In comparing the α-helix to the β-sheet, which state- ment is correct only for the β-sheet? A. Extensive hydrogen bonds between the carbonyl oxygen (C=O) and the amide hydrogen (N-H) of the peptide bond are formed. B. It may be found in typical globular proteins. C. It is stabilized by interchain hydrogen bonds. D. it is an example of secondary structure. E. It may be found in supersecondary structures.

Correct answer = C. The β-sheet is stabilized by interchain hydrogen bonds formed between sepa- rate polypeptide chains and by intrachain hydro- gen bonds formed between regions of a single polypeptide. The α-helix, however, is stabilized only by intrachain hydrogen bonds. Statements A, B, D, and E are true for both of these secondary structural elements.

An 80-year-old man presented with impairment of higher intellectual function and alterations in mood and behavior. His family reported progressive disorientation and memory loss over the last 6 months. There is no family history of dementia. The patient was tentatively diagnosed with Alzheimer disease. Which one of the following best describes Alzheimer disease? A. It is associated with β-amyloid, an abnormal protein with an altered amino acid sequence. B. It results from accumulation of denatured proteins that have random conformations. C. It is associated with the accumulation of amyloid precursor protein. D. It is associated with the deposition of neurotoxic amyloid β peptide aggregates. E. It is an environmentally produced disease not influenced by the genetics of the individual. F. It is caused by the infectious β-sheet form of a host- cell protein.

Correct answer = D. Alzheimer disease is associated with long, fibrillar protein assemblies consisting of β-pleated sheets found in the brain and elsewhere. The disease is associated with abnormal processing of a normal protein. The accumulated altered protein occurs in a β-pleated sheet configuration that is neurotoxic. The amyloid β that is deposited in the brain in Alzheimer disease is derived by proteolytic cleavages from the larger amyloid precursor protein, a single transmembrane protein expressed on the cell surface in the brain and other tissues. Most cases of Alzheimer disease are sporadic, although at least 5% of cases are familial. Prion diseases, such as Creutzfeldt-Jakob, are caused by the infectious β-sheet form (PrPSc ) of a host- cell protein (PrPC).

2 Which one of the following statements about amino acids and their metabolism is correct? A. Free amino acids are taken into the enterocytes by a proton-linked transport system. B. In healthy, fed individuals, the input to the amino acid pool exceeds the output. C. Liver uses ammonia to buffer protons. D. Muscle-derived glutamine is metabolized in liver and kidney tissue to ammonia plus a gluconeogenic precursor. E. The first step in the catabolism of most amino acids is their oxidative deamination. F. The toxic ammonia generated from the amide nitrogen of amino acids is transported through blood as arginine.

Correct answer = D. Glutamine, produced by the catabolism of branched-chain amino acids in muscle, is deamidated to ammonia plus gluta- mate. The glutamate is deaminated to ammonia plus α-ketoglutarate, which can be used for glu- coneogenesis. Free amino acids are taken into enterocytes by a sodium-linked transport system. Healthy, fed individuals are in nitrogen balance, in which nitrogen input equals output. Liver converts ammonia to urea, and kidney uses ammonia to buffer protons. Amino acid catabolism begins with transamination that generates glutamate. The glutamate undergoes oxidative deamination. T oxic ammonia is transported as glutamine and alanine. Arginine is synthesized and hydrolyzed in the hepatic urea cycle.

.1 Which one of the following statements concerning protein structure is correct? A. Proteins consisting of one polypeptide have quaternary structure that is stabilized by covalent bonds. B. The peptide bonds that link amino acids in a protein most commonly occur in the cis configuration. C. The formation of a disulfide bond in a protein requires the participating cysteine residues to be adjacent in the primary structure. D. The denaturation of proteins leads to irreversible loss of secondary structural elements such as the α-helix. E. The primary driving force for protein folding is the hydrophobic effect.

Correct answer = E. The hydrophobic effect, or the tendency of nonpolar entities to associate in a polar environment, is the driving force of protein folding. Quaternary structure requires more than one polypeptide, and, when present, it is stabilized primarily by noncovalent bonds. The peptide bond is almost always trans. The two cysteine residues participating in disulfide bond formation may be a great distance apart in the amino acid sequence of a polypeptide (or on two separate polypeptides) but are brought into close proximity by the three-dimensional folding of the polypeptid

What would be true about the extent of red blood cell sickling in individuals with HbS and hereditary persis- tence of HbF?

Decreased. HbF reduces HbS concentration. It also inhibits polymerization of deoxy HbS.

Why is hemoglobin C disease a nonsickling disease?

In HbC, the polar glutamate is replaced by polar lysine rather than by nonpolar valine as in HbS.

4.4 How and why is proline hydroxylated in collagen?

Proline is hydroxlylated by prolyl hydroxylase, an enzyme of the rough endoplasmic reticulum that requires O2, Fe2+, and vitamin C. Hydroxylation increases interchain hydrogen bond formation, strengthening the triple helix of collagen. Vitamin C deficiency impairs hydroxylation.

What is the differential basis of the liver and lung pathology seen in α1-antitrypsin deficiency?

With α1-antitrypsin (AAT) deficiency, the cirrho- sis that can result is due to polymerization and retention of AAT in the liver, its site of synthesis. The alveolar damage is due to the retention- based deficiency of AAT (a protease inhibitor) in the lung such that elastase (a protease) is unopposed.