USMLE USMLE Certifications USMLE-STEP-1 Questions & Answers

• Question 511:

  The level of iron in the body must be tightly regulated due to the severe toxicity associated with elevated levels in the circulation and within cells. Which of the following proteins is primarily responsible for iron homeostasis?

  A. ceruloplasmin

  B. ferritin

  C. haptoglobin

  D. metallothionein

  E. transferrin

  Correct Answer: E

• Question 512:

  Alaboratory analysis of isolated mitochondria demonstrates that oxygen consumption is normal when succinate is added, but extremely low when pyruvate and malate are used. The mitchondria are subsequently shown to have normal cytochromes, but reduced iron content. The reduced pyruvate/malate oxidation is due to a defect in which of the following respiratory components?

  A. cytochrome c

  B. cytochrome oxidase

  C. NADH-coenzyme Q reductase

  D. succinate dehydrogenase

  E. ubiquinone

  Correct Answer: C

• Question 513:

  Which of the following apoproteins is found exclusively associated with chylomicrons?

  A. apo A

  B. apo B48

  C. apo CII

  D. apo D

  E. apo E

  Correct Answer: B

• Question 514:

  A 9-month-old infant who suffered bouts of jaundice and was diagnosed with severe nonhemolytic icterus shortly after birth has died of kernicterus. During the periods of jaundice, serum analysis showed an increased concentration of indirect-reacting bilirubin with no detection of conjugated bilirubin. The premature death and early clinical findings in this infant suggest which of the following disorders?

  A. AIP

  B. Crigler-Najjar syndrome, type I

  C. Dubin-Johnson syndrome

  D. Gilbert syndrome

  E. Rotor syndrome

  Correct Answer: B

  Section: Biochemistry Jaundice is caused by an elevation in the circulating levels of bilirubin, the heme degradation by- product. Bilirubin, which is toxic, is rendered harmless by binding to albumin in the serum and by conjugation to glucuronate in the liver. Profound hyperbilirubinemia leads to encephalopathy (kernicterus), which results in death if untreated. The hepatic conjugation of bilirubin to glucuronate is catalyzed by bilirubin-UDPglucuronyltransferase (UGT). The conjugated form of bilirubin is less toxic due to its increased solubility. Hyperbilirubinemia can be of two types, unconjugated or conjugated. Defects in UGT will lead to unconjugated hyperbilirubinemia. The deficiency of UGT in Crigler-Najjar syndrome type I is complete (due to loss of coding exons in the UGT gene) and as a consequence affected individuals will die from the profound kernicterus. AIP (choice A) results from a defect in the activity of the porphyrin biosynthetic enzyme, PBG deaminase. This disorder results in neurovisceral symptoms and signs that can be highly variable and nonspecific, leading to frequent misdiagnosis. Both Dubin-Johnson syndrome (choice C) and Rotor syndrome manifest as conjugated hyperbilirubinemia. Both reflect a defect in biliary excretion and are relatively benign because the conjugated bilirubin is much less toxic than the unconjugated molecule. Gilbert syndrome (choice D) is caused by an abnormality in the TATA-box of the UGT promoter so expression of functional UGT is reduced, thus the reduced severity of the disorder.

• Question 515:

  A 3-month-old infant exhibits profound neurologic deficit in addition to being blind and deaf. Pathologic examination indicates renal cysts, hepatomegaly, and facial dysmorphism. Biochemical analysis reveals plasma accumulations of very long-chain fatty acids, abnormal intermediates of bile acid synthesis, and a marked deficiency of plasmalogens. These physical and biochemical features are characteristic of which of the following disorders?

  A. hyperpipecolic acidemia

  B. infantile Refsum disease

  C. neonatal adrenoleukodystrophy

  D. rhizomelic chondrodysplasia punctata (RCDP)

  E. Zellweger syndrome

  Correct Answer: E

  Section: Biochemistry Zellweger syndrome is the most severe of a group of diseases that result from defective assembly of the peroxisomes, leading to the characteristic symptoms observed in the patient. This syndrome is apparent at birth and leads to death within the first year. The cause of Zellweger syndrome is a failure to import newly synthesized peroxisomal proteins into peroxisomes. Hyperpipecolic academia (choice A), infantile Refsum disease (choice B), and neonatal adrenoleukodystrophy (choice C) are all much less severe disorders of the group that result from peroxisome dysfunction. Affected individuals with these latter disorders can survive into the third or fourth decade, albeit with deficits in vision, hearing, and cognitive function. It is suspected that the reduced severity of these three disorders, relative to Zellweger, relates to retention of partial gene function as opposed to complete loss. RCDP (choice D) is related to peroxisomal dysfunction at the level of their distribution and structure. The phenotype of RCDP differs from that of Zellweger syndrome in that patients have striking shortening of the proximal limbs, coronal clefts of vertebral bodies, and severely abnormal endochondrial bone formation.

• Question 516:

  You are tending to a patient with a high tendency to bleed. He bruises easily and has bleeding from his gums. Analysis of coagulation factors in his blood shows normal levels of factor V but low levels of factor

  VIII.

  Injection of factor VIII provides only minimal benefit and you find that the injected protein is rapidly degraded. Using a platelet aggregation test, you find that combination of your patient's serum with normal platelets results in only 20% of the platelet aggregation seen with both samples from a normal individual. Based on these findings, you determine that your patient is deficient in which of the following factors of coagulation?

  A.

  factor X

  B.

  factor XII

  C.

  fibrinogen

  D.

  thrombin

  E.

  von Willebrand factor

  Correct Answer: E

  Section: Biochemistry The von Willebrand factor is associated with subendothelial connective tissue and serves as a bridge between platelet glycoprotein GPIb/IX and collagen. This activity ensures that platelets can adhere to the exposed subendothelial surfaces at the site of tissue injury. In addition, von Willebrand factor and factor VIII exist in a noncovalently bound complex in the plasma. The interaction of factor VIII and von Willebrand factor greatly stabilizes factor VIII. For example, following infusion of factor VIII into patients with hemophilia A (caused by loss of factor VIII) the protein exhibits a serum halflife of around 12 hours. Conversely, when infused into patients with severe von Willebrand disease, VWD (lack of von Willebrand factor), the half-life of factor VIII is less than 2 hours. Therefore, individuals suffering from VWD will also have significantly reduced levels of circulating factor VIII. This fact results in the observation that patients with VWD exhibit symptoms of both platelet dysfunction and hemophilia. Deficiency in any of the other coagulation factors (choices AD) would not result in decreased stability of factor VIII observed as a reduction in circulating levels of this protein.

• Question 517:

  Glucagon binding to liver cells induces an increase in intracellular cAMP concentration. The rate- limiting step in cholseterol biosynthesis is regulated as a consequence of this glucagon-mediated rise in cAMP. The effect of increased cAMP on the rate of cholesterol biosynthesis occurs because of which of the following?

  A. AMP-activated protein kinase (AMPK) is activated and directly phosphorylates human menopausal gonadotropin (HMG)-CoA reductase, leading to an increase in the activity of the latter enzyme.

  B. Cyclic AMP-dependent protein kinase (PKA) is activated and directly phosphorylates HMG-CoA reductase, reducing the activity of the latter enzyme.

  C. PKA is activated and phosphorylates AMP-regulated kinase, which then phosphorylates and activates HMGCoA reductase.

  D. Removal of phosphate from HMG-CoA reductase increases its activity. Activated PKA results in a reduced level of phosphate removal from HMG-CoA reductase so that the latter enzyme is kept less active.

  E. The increased cAMP directly inhibits HMG-CoA reductase.

  Correct Answer: D

  Section: Biochemistry Regulation of HMG-CoAreductase (the ratelimiting enzyme of cholesterol biosynthesis) activity is complex and involves a number of distinct enzyme activities (below figure).

  

  Since cholesterol biosynthesis consumes large amounts of energy, it needs to be regulated in response to energy demands, particularly in hepatocytes. The principal site for the action of the hypoglycemic response hormone, glucagon, is the liver. Glucagon binding to hepatocytes triggers the liver to stop catabolizing carbohydrate and to divert carbon atoms into the gluconeogenesis pathway. This change in hepatic metabolism, in response to glucagon, comes about through a change in the phosphorylation state of numerous enzymes. One of these enzymes is HMG-CoA reductase. HMG-CoA reductase is most active when in the nonphosphorylated state. The enzyme is phosphorylated and rendered less active through the action of AMP-regulated kinase. AMP levels rise as the energy charge in the cell declines and thus the cell is able to recognize this change, at the level of HMG-CoA reductase activity, by inducing its phosphorylation and inhibition. In order to reverse the effect of HMG-CoA phosphorylation the phosphates must be removed. This occurs through the action of HMG-CoA reductase phosphatase. HMGCoAreductase phosphatase is regulated through the action of protein phosphatase inhibitor-1 (PPI1). In turn the activity of PPI-1 is regulated by its state of phosphorylation; it is more active when phosphorylated. When glucagon binds to hepatocytes, the result is a glucagon receptormediated activation of adenylate cyclase, which in turn produces cAMP from ATP. The effect of cAMP is to activate cAMPdependent protein kinase which then phosphorylates a number of substrates. With respect to glucagonmediated regulation of cholesterol metabolism, PKA phosphorylates PPI-1. Phosphorylated PPI-1 is more active at inhibiting HMG-CoA reductase phosphatase so that the removal of phosphate from HMG-CoA reductase is inhibited. This keeps HMG-CoA reductase in the phosphorylated and less active state. AMPK is not directly affected by glucagon-mediated increases in the levels of cAMP (choice A). Although glucogon action leads to an increase in PKA activity, the latter enzyme does not itself phosphorylate HMG-CoA reductase (choice B). The activity of AMP-regulated kinase is affected by its level of phosphorylation but it is not phosphorylated by PKA(choice C). Cyclic AMPitself does not have a direct effect on HMG-CoAreductase (choice E).

• Question 518:

  The forensic analytical technique identified as DNA fingerprinting refers to which of the following processes?

  A. the establishment of a complete collection of cloned fragments of DNA

  B. the identification of sequences of DNA to which specific proteins bind, thereby rendering them resistant to digestion by DNA-degrading nucleases

  C. the specific association of complimentary strands of DNA to one another

  D. the synthetic oligonucleotide-directed enzymatic amplification of specific sequences of DNA

  E. the use of repeat sequences to establish a unique pattern of fragments for any given individual

  Correct Answer: E

  Section: Biochemistry DNAfingerprinting refers to the process of using polymorphic repeat sequences to establish a unique pattern of DNA fragments for any given individual. The polymorphic repeats that are identifiable by the fingerprinting technique are hypervariable repeats such as variable number tandem repeats (VNTRs). The bands are detected by Southern blotting enzyme-digested chromosomal DNA and probing the blot with various different VNTR probes. The generation of a DNA library (choice A) refers to the establishment of a complete collection of cloned fragments of DNA, either from genomic sources or cDNA. DNA footprinting (choice B) refers to the identification of sequences of DNA to which specific proteins bind, thereby rendering the DNA at that site resistant to digestion by DNA degrading nucleases. Hybridization (choice C) refers to the specific association of complimentary strands of DNA to one another. The PCR technique (choice D) uses synthetic oligonucleotides to direct the enzymatic amplification of specific sequences of DNA.

• Question 519:

  Severe combined immunodeficiency disease (SCID) is characterized by a complete lack of cell- mediated and humoral immunity. This disorder results from a deficiency in which of the following enzymes?

  A. adenosine deaminase

  B. asparatate transcarbamoylase

  C. HGPRT

  D. orotic acid decarboxylase

  E. purine nucleotide phosphorylase

  Correct Answer: A

  Section: Biochemistry ADA catalyzes the deamination of adenosine to inosine during the catabolism of purines. Loss of ADAleads to significantly elevated levels of phosphorylated deoxyadenosine (in particular deoxyadenosine triphosphate, dATP). Levels of dATP in ADA deficiency can reach 50 times normal. High concentrations of dATP inhibit ribonucleotide reductase, which is required for the generation of deoxynucleotides from ribonucleotides. The inhibition of ribonucleotide reductase leads to severely impaired cellular DNA synthesis. Since lymphocytes must be able to proliferate dramatically in response to antigenic challenge, the loss of ADA activity results in a near complete lack of immune function. ATC (choice B) is a component of a multifunctional enzyme, which catalyzes the rate- limiting reaction of pyrimidine biosynthesis. No known deficiencies in this enzyme have been identified, likely due to the embryonic lethality predicted if the enzyme were defective. HGPRT (choice C) catalyzes the salvage of hypoxanthine to IMP and guanine to GMP. Deficiency in HGPRT results in Lesch-Nyhan syndrome. Orotic acid decarboxylase (choice D) catalyzes the decarboxylation of OMP to UMP. Deficiency in this enzyme results in orotic aciduria, type II. PNP (choice E) is also a purine catabolic enzyme, which converts inosine to hypoxanthine and guanosine to guanine. Deficiency in PNP leads to a mild immunodeficiency.

• Question 520:

  Correct targeting of newly synthesized hydrolytic enzymes to the lysosomes requires which of the following modifications?

  A. attachment of mannose-6-phosphate to the enzymes

  B. gamma-carboxylation of glutamate residues in the enzymes

  C. O-linkage of carbohydrate to the enzymes

  D. prenylation of the enzymes

  E. proteolytic activation following transport to the lysosome

  Correct Answer: A

  Section: Biochemistry Enzymes that are targeted to the lysosomes undergo a specific two-step modification in the Golgi complex. The first step in the modification involves the attachment of an alpha- acetylglucosamine 1- phosphate residue to the six position of a mannose residue on the high man-nose carbohydrate portion of lysosomal enzymes. The second step involves removal of the N-acetylglucosamine residue exposing the mannose-6phosphate marker. The presence of mannose-6-phosphate is necessary for targeting lysosomal enzyme to the lysosomes and deficiencies in the enzyme responsible for the first reaction in the modification lead to severe developmental abnormalities. Carboxylation of glutamate residues (choice B) is necessary to the function of several enzymes of the coagulation cascades. Lysosomal enzymes are not modified by attachment of carbohydrate through O-linkage (choice C). Many membraneanchored proteins undergo lipid modification by prenylation (choice D) such as the protein product of the protooncogene RAS. Although many enzymes are activated by proteolytic processing (choice E), this is not required for targeting lysosomal enzymes to the lysosome.