Flashcards in Bio chem Enz contd 8-2 Deck (32):
Statins are competitive inhibitors of HMG-CoA reductase that decrease de novo cholesterol production in the liver. Statins also upregulate LDL receptors on the liver's surface by increasing ?
LDL clearance from the bloodstream.
Rotenone is a reversible competitive inhibitor of NADH. As a result, the Michaelis-Menten constant (Km) increases, because rotenone competes with NADH at the enzymatic active site. However, the maximum reaction rate (Vmax) does not change, because it can eventually be achieved by?
increasing the amount of substrate (ie, NADH) available to the enzymes.
The Km is the substrate concentration at which half of the enzyme in the sample is saturated. Km is inversely related to the affinity of the enzyme for its substrate. The Vmax is the highest velocity the enzyme can achieve and is directly proportional to the enzyme concentration.
In biochemistry, there are three important kinds of inhibitors that are important to remember.?
Reversible, competitive inhibitors (eg, rotenone): have no effect on Vmax and increase Km
Irreversible inhibitors: decrease Vmax and have no effect on Km
Noncompetitive inhibitors: decrease Vmax and have no effect on Km
Inhibition does not cause a decrease in Km while Vmax remains unchanged.
An increase in Km while the Vmax decreases is not a ?
known pattern of inhibition.
Unchanged Km and a decrease in Vmax describes noncompetitive inhibition and irreversible inhibitors.
Inhibition does not result in unchanged Km and Vmax.
During a physiology lecture, the factors affecting hemoglobin affinity to oxygen are discussed. The professor discusses that one rare cause of congenital polycythemia is a genetic defect leading to an increased affinity of hemoglobin for oxygen, because of the inability to produce a particular chemical that normally works to decrease the affinity of hemoglobin for oxygen. The effect seen in this type of congenital polycythemia is presented diagrammatically as a shift in the oxygen-hemoglobin dissociation curve in one direction.
Which of the following conditions is most likely to cause a shift in the oxygen-hemoglobin dissociation curve in the same direction?
Increased carboxyhemoglobin levels
Exposure to carbon monoxide converts hemoglobin to carboxyhemoglobin, causing a ?
left shift in the oxygen-hemoglobin dissociation curve.
Lowering pH decreases the affinity of hemoglobin for oxygen, resulting in a right shift of the oxygen-hemoglobin dissociation curve.
Elevated 2,3-diphosphoglycerate levels causes decreased affinity of hemoglobin for oxygen, resulting in ?
a right shift of the oxygen-hemoglobin dissociation curve.
Increased adult hemoglobin compared to fetal hemoglobin would cause decreased affinity of hemoglobin for oxygen, resulting in a right shift.
Increased temperature would also result in a right shift of the oxygen-hemoglobin dissociation curve.
This infant was born prematurely in respiratory distress due to surfactant deficiency. Surfactant is a surface-active lipoprotein complex produced by type II alveolar cells that reduces surface tension and prevents atelectasis in the alveoli. Because the lungs are the last organ to develop in the fetus, infants born prematurely are often deficient in surfactant.
Phosphatidylcholine is a key component of surfactant and is made with dietary choline or choline released from phospholipid turnover (see phosphatidycholine chemical structure; red circles denote fatty acids). De novo synthesis of choline requires the addition of?
methyl groups. A modified form of methionine, S-adenosyl-L-methionine, is the universal methyl group donor in methylation reactions. The ability of S-adenosyl-L-methionine to donate a methyl group in a variety of synthetic pathways makes methionine a critical amino acid beyond its role in protein synthesis.
Of the amino acids listed, methionine is the only one that can be converted into a cofactor that donates methyl groups. Phosphatidylcholine has additional relevance as a major component of RBC membranes, myelin, and lipoproteins.
Glycine and serine are nonessential amino acids and have ?
no free methyl group in their structures.
Valine and threonine are essential amino acids and do have terminal methyl groups. However, these amino acids cannot donate their methyl groups.
An 11-month-old girl is brought to her pediatrician because of severe developmental delay. The mother reports that she is a recent immigrant and did not have access to perinatal screening tests. The pediatrician orders a genetic test, which reveals that the child has two mutated copies of an enzyme responsible for the hydroxylation of an amino acid to form another amino acid.
Had this mutation been discovered at birth, what would have most effectively prevented the development of intellectual disability in this child?
A diet with reduced amounts of the substrate amino acid for the deficient enzyme
The child's presentation is characteristic of phenylketonuria (PKU), an autosomal recessive disorder caused by a mutation in the gene coding for the enzyme phenylalanine hydroxylase. The diagram shows that phenylalanine hydroxylase converts phenylalanine to tyrosine using the cofactor tetrahydrobiopterin. The deficiency of the enzyme leads to increased phenylalanine levels in the serum, which cause progressive intellectual disability. In the United States PKU is normally screened for at birth, but this child did not benefit from perinatal screening. PKU can be effectively treated by decreasing the dietary intake of phenylalanine and increasing dietary intake of tyrosine.
Tetrahydrobiopterin supplementation has had some success in reducing phenylalanine levels in a subset of patients with phenylketonuria, but this has not been as effective as decreasing the intake of phenylalanine.
Patients who are discovered to have phenylketonuria at birth and are treated with ?
phenylalanine-restricted diets can have normal development. It is unclear whether patients need to maintain this diet for life, but current recommendations are to maintain a phenylalanine-restricted diet for as long as possible.
A recombinant version of phenylalanine hydroxylase has not been developed, but gene therapy has been tested in mice, with poor results. Because the enzymatic activity takes place intracellularly, an injectable recombinant enzyme would not gain entry into cells and could not recreate the biologic functions of the enzyme.
Inhibitor X represents a competitive inhibitor, and inhibitor Y represents a noncompetitive inhibitor. The binding of a competitive inhibitor lowers the affinity of the enzyme for the substrate (increased Michaelis-Menten constant, or Km), but the maximum velocity (Vmax) of the reaction remains unchanged. Increasing the concentration of substrate can overcome the effects of a competitive inhibitor. Binding of a noncompetitive inhibitor does not change the affinity of the enzyme for the substrate (Km is unchanged), but it does decrease?
the maximum velocity. The best answer is that competitive inhibitor X will effect no change in Vmax and that the noncompetitive inhibitor Y will decrease Vmax.
The binding of a competitive inhibitor lowers the affinity of the enzyme for the substrate, but the maximum velocity of the reaction remains unchanged. The binding of a noncompetitive inhibitor does not?
change the affinity of the enzyme for the substrate, but the maximum velocity is decreased.
This young adult patient presents with jaundice and scleral icterus in the context of a recent gastrointestinal (GI) illness, while appearing otherwise healthy. The patient’s jaundice and scleral icterus is the result of an accumulation of bilirubin or its conjugates in body tissues, often characterized by high plasma bilirubin levels and deposition of yellow bilirubin pigments in the skin, sclerae, mucous membranes, and other less visible tissues. A number of disease states lead to bilirubin accumulation in plasma, such as hemolysis, which increases the rate of bilirubin formation. However, this patient’s laboratory findings indicate that the accumulation of bilirubin is due to?
an indirect (unconjugated) hyperbilirubinemia. This presentation is consistent with Gilbert syndrome, a mild impairment of bilirubin conjugation due to decreased levels of UDP glucuronyl transferase.
Obstruction of the biliary tract alone typically leads to a direct (conjugated) hyperbilirubinemia, not the indirect (unconjugated) hyperbilirubinemia seen in this patient. This is because the hepatocytes that perform conjugation remain functional when the biliary tract is obstructed.
Absence of the protein transporting bilirubin from the hepatocyte into the bile characterizes Dubin-Johnson syndrome, a clinically irrelevant disease arising from a?
genetic mutation that causes the liver to turn grossly, but harmlessly, black, and which does not require treatment.
Impaired function of heme oxygenase, which is responsible for the initial breakdown of the porphyrin ring extracted from RBCs to form biliverdin and ultimately unconjugated bilirubin, would lead to a decrease in bilirubin production, which is not consistent with the hyperbilirubinemia seen in this patient’s lab findings.
Absent UDP glucuronyl transferase function characterizes Crigler-Najjar syndrome, of which there are two subtypes. The more severe form is seen in ?
neonates, and the less severe type occurs later in childhood or adolescence. Both subtypes manifest with marked hyperbilirubinemia due to indirect hyperbilirubinemia.
Gilbert syndrome is a disorder in which the only significant abnormality is mild, unconjugated hyperbilirubinemia. Gilbert syndrome is caused by a ?
decreased expression of UDP glucuronyl transferase that is generally asymptomatic, but manifests as jaundice in times of stress, such as fasting or GI illness.
This patient has difficulty lifting objects and pointing, which indicates weakness; hypotonia (poor tone on passive range of motion); and a normal blood glucose. The systolic murmur that increases with the Valsalva maneuver likely represents hypertrophic cardiomyopathy. These symptoms and positive periodic acid–Schiff (PAS) staining of a muscle biopsy specimen are suggestive of?
Pompe disease (type 2 glycogen storage disease), which is caused by a deficiency in the lysosomal enzyme lysosomal acid a-glucosidase.
A patient with Cori disease, which is caused by a-1,6-glucosidase deficiency, would have hypoglycemia.
Von Gierke disease is caused by a deficiency of ?
glucose-6-phosphatase, and it is a more severe form of glycogen storage disease than Cori disease. A patient with von Gierke disease would be expected to have severe hypoglycemia.
Galactose-1-phosphate uridyltransferase deficiency causes classic galactosemia, which is associated with infantile cataracts.
A patient with McArdle disease, which is caused by ?
myoglycogen phosphorylase deficiency, is likely to have symptoms related to the musculoskeletal system (eg, muscle pain) rather than cardiac symptoms.
Pompe disease leads to hypotonia, left ventricular enlargement, and heart failure; however, a patient with Pompe disease will have a normal fasting blood glucose level. This disorder is caused by an accumulation of ?
glycogen secondary to deficiency of lysosomal acid α-glucosidase. Excessive lysosomal accumulation of glycogen causes positive PAS staining of muscle biopsy samples.
This patient who presents with delayed development, an abnormal gait, nystagmus, sun-sensitive dermatitis, and diarrhea is likely to have a niacin deficiency. The elevated level of neutral amino acids in the urine indicates reduced absorption as a consequence of Hartnup disease, in which the kidney transporter of neutral amino acids is defective.
Tryptophan, a neutral amino acid, is an essential precursor for niacin synthesis in the liver. Patients with Hartnup disease can develop the symptoms of?
niacin deficiency (or pellagra) specifically as a result of the decreased uptake of tryptophan.
A deficiency of cystine is likely to be seen in cystinuria, which is caused by a defective transporter that results in reduced cystine reabsorption and increased cystine stone formation. Like tryptophan, leucine, threonine, and valine, are also neutral amino acids, but their deficiency would not lead to findings of pellagra, manifest in this patient as diarrhea and dermatitis, although dementia may also be seen. Deficiency of lysine, a basic amino acid, leads to?
nonspecific symptoms such as poor appetite, fatigue, and anemia. Phenylalanine is also considered to be a neutral amino acid; however, when phenylalanine levels are elevated, a diagnosis of phenylketonuria, not pellagra, should be considered.
This patient presents with knee pain, a tear in his right anterior cruciate ligament, and dark urine. During surgery for repair of the tear in his anterior cruciate ligament, surgeons find unusually pigmented cartilage, which is most suggestive of alkaptonuria. This is the result of a congenital deficiency of? otherwise healthy.
homogentisic acid oxidase, the third enzyme in the tyrosine degradation pathway (pathway shown in the image).
Due to this deficiency, homogentisic acid builds up in the body and polymerizes to form alkapton bodies. The alkapton bodies then deposit to cause dark urine and dark cartilage. Patients also sometimes suffer from arthralgias and decreased joint mobility, but are
Impaired renal absorption of cystine can result in cystinuria, which presents with pediatric nephrolithiasis. Elevated homocysteine results in homocystinuria, characterized by premature atherosclerosis and osteoporosis in Marfanoid patient. Leucine and valine are deranged in maple-syrup urine disease. Abnormally high methionine can result in?
hypermethioninemia, and is caused by defects in one of several enzymes that degrade methionine.
This patient presents with tachypnea, cyanosis, grunting noises, and nostril flaring. These symptoms in a newborn all point to a diagnosis of neonatal respiratory distress syndrome (NRDS), a lung disease most commonly associated with prematurity that is a result of inadequate pulmonary surfactant production. Other risk factors include delivery by c-section, perinatal infection, and uncontrolled maternal diabetes. The pathophysiology involves type II pneumocytes, which produce ?
endogenous surfactant, composed of a mixture of lipids (70% dipalmitoylphosphatidylcholine) and proteins.
Surfactant is secreted into the alveolar space. The presence of surfactant reduces the surface tension at the air/liquid interface in the lung, and prevents alveolar collapse at end-expiration. Because this infant lacks sufficient surfactant to keep his alveoli open at low volumes, he experiences respiratory distress. NRDS can present at birth; however, infants can also appear healthy at birth and develop symptoms that progress during the first 48 hours of life. Administration of the exogenous surfactant phosphatidylcholine improves outcomes in infants with NRDS.
Ampicillin-sulbactam would be useful for treating neonatal infections such as sepsis. Glucocorticoid administered to the mother prior to preterm delivery would prevent alveolar collapse. Intravenous Immunoglobulin is used to treat a number of neonatal diseases, including vertically-transmitted infections, hepatitis B virus, and sepsis. Nasal CPAP is a useful mechanism for?
stabilization prior to correcting the neonate’s underlying issue of inadequate surfactant.
Homocystinuria is an inborn error of metabolism caused by a defect in cystathionine synthase, the enzyme that converts homocysteine to cystathionine. In addition to Marfan-like features and subluxation of the lens, these patients are at increased risk of a ?
variety of cardiovascular derangements, including premature vascular disease and death. Atherosclerosis is rare in children. Atherosclerosis in a child is highly suggestive of homocystinuria.
Lysine is another of the essential amino acids. (Recall the mnemonic PVT TIM HALL to remember the 10 essential amino acids: Phenylalanine, Valine, Tryptophan, Threonine, Isoleucine, Methionine, Histidine, Arginine, Lysine, and Leucine. Note that arginine and histidine are conditionally essential). Lysine is not related to homocystinuria.
Phenylalanine accumulates in patients with phenylketonuria (PKU). The stereotypical patient with PKU presents with severe intellectual disability, seizures, and a "mousy" odor.
Tryptophan is an amino acid often confused with tyrosine. It is an essential amino acid and does not have any relationship to homocystinuria. Tryptophan is converted into ?
niacin (vitamin B3), and its deficiency can lead to pellagra (the "3 Ds" of Diarrhea, Dermatitis, and Dementia).
In phenylketonuria (PKU), a deficiency of phenylalanine hydroxylase results in an inability to convert phenylalanine to tyrosine, making the latter an essential amino acid in patients with PKU. It has no role in homocystinuria.
A 6-year-old girl exhibits vision problems during a screening at school, and the school nurse tells the parents the child should be fitted for glasses. Her mother is upset, because her daughter is already much taller than her classmates, has an awkward gait, and was recently diagnosed with scoliosis. She is afraid that the glasses will only add to her daughter's problems at school, where her classmates frequently tease her. When the ophthalmologist observes that the patient's right lens is dislocated, he suspects that her symptoms are in fact related to an enzyme deficiency.
This patient most likely has difficulty metabolizing which substrate?
Homocystinuria is an autosomal recessive disorder caused by a defect in cystathionine synthase, which converts homocysteine to cystathionine. Individuals with this disorder have multisystemic complications and often suffer subluxation of the lens, premature vascular disease (thrombotic complications), and early death. For the USMLE, know the various metabolic disorders and their classic presentations.
This patient’s symptoms include diarrhea, confusion, and an erythematous maculopapular rash on sun-exposed areas. These symptoms are most consistent with pellagra. Pellagra is characterized by the four Ds of niacin (vitamin B3) deficiency: Dermatitis, Diarrhea, Dementia, and Death. Pellagra is treated with niacin (vitamin B3). Excessive niacin supplementation can cause?
facial flushing due to release of prostaglandins from dermal Langerhans cells, resulting in vasodilation. Facial flushing can be avoided if this patient is pretreated with antiprostaglandins, such as aspirin.