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The answer is d. (Scriver, pp 4517-4554; Murray, pp 163-167.) Glucose-6-phosphate dehydrogenase (G6PD) is the first enzyme of the pentose phosphate pathway, a side pathway for glucose metabolism whose primary purpose is to produce ribose and NADPH. Its deficiency (305900) is the most common enzymopathy, affecting 400 million people worldwide. It contrasts with glycolysis in its use of NADP rather than NAD for oxidation, its production of carbon dioxide, its production of pentoses (ribose, ribulose, xylulose), and its production of the high-energy compound PRPP (5-phosphoribosyl-1-pyrophosphate) rather than ATP. Production of NADPH by the pentose phosphate pathway is crucial for reduction of glutathione, which in turn removes hydrogen peroxide via glutathione peroxidase. Erythrocytes are particularly susceptible to hydrogen peroxide accumulation, which oxidizes red cell membranes and produces hemolysis. Stresses like newborn adjustment, infection, or certain drugs can increase red cell hemolysis in G6PD-deficient individuals, leading to severe anemia, jaundice, plugging of renal tubules with released hemoglobin, renal failure, heart failure, and death. Since the locus encoding G6PD is on the X chromosome, the deficiency exhibits X-linked recessive inheritance with severe affliction in males and transmission through asymptomatic female carriers. Ribose-5-phosphate produced by the pentose phosphate pathway is an important precursor for ribonucleotide synthesis, but alternative routes from fructose-6-phosphate allow ribose synthesis in tissues without the complete cohort of pentose phosphate enzymes or with G6PD deficiency. The complete pentose phosphate pathway is active in liver, adipose tissue, adrenal cortex, thyroid, erythrocytes, testis, and lactating mammary gland. Skeletal muscle has only low levels of some of the enzymes of the pathway but is still able to synthesize ribose through fructose-6-phosphate.
The answer is b. (Murray, pp 163-172. Scriver, pp 1553-1588.) Lactose in breast milk and infant formula is converted by intestinal lactase to glucose and galactose that are efficiently absorbed. In galactosemia (230400), deficiency of galactose-1-phosphate uridyl transferase prevents the conversion of galactose into glucose-6-phosphate by the liver or erythrocytes. Most other organs do not metabolize galactose. The severe symptoms of galactosemia are caused by the reduction of galactose to galactitol (dulcitol) in the presence of the enzyme aldose reductase. High levels of galactitol cause cataracts, the accumulation of galactose-1phosphate contributes to liver disease, and the accumulation of galactose metabolites in urine can be measured as reducing substances by the Clinitest method. Any carbohydrate, including glucose, with a C1 aldehyde registers as a reducing substance by Clinitest, so a Dextrostix (glucose only) test is often performed as a control. In normal children, galactose is first phosphorylated by ATP to produce galactose-1-phosphate in the presence of galactokinase. Next, galactose-1-phosphate uridyl transferase transfers UDP from UDP-glucose to form UDP-galactose and glucose-1-phosphate. Under the action of UDP-galactose-4-epimerase, UDP-galactose is epimerized to UDP-glucose. Finally, glucose-1-phosphate is isomerized to glucose6-phosphate by phosphoglucomutase. Infants with suspected galactosemia must be withdrawn from breast-feeding or lactose formulas and placed on nonlactose formulas such as Isomil.
The answer is e. (Murray, pp 92-101. Scriver, pp 2261-2274. ) Under aerobic conditions, pyruvate is oxidized by pyruvate dehydrogenase to acetyl-CoA, which enters the citric acid cycle. The citric acid cycle generates reducing equivalents in the form of FADH and NADH that are converted to oxygen by the electron transport chain to yield abundant ATP. Under anaerobic conditions such as heavy exercise, pyruvate must be converted to lactate to recycle NADH to NAD+ to allow glycolysis to continue. In mitochondrial disorders resulting from mutations in cytochromes or pyruvate dehydrogenase, there is deficient NADH oxidation and ATP production. Lactate will accumulate as it does normally in tissues without mitochondria (erythrocytes) or in tissues with exercise stress (like muscle). The lactate can accumulate in serum, causing a decreased pyruvate to lactate ratio and lactic acidosis that are typical signs of mitochondrial disease. These abnormalities also occur with circulatory failure (shock) or hypoxemia, so they are suspect for inborn errors only when cardiorespiratory function is normal. Glycolysis produces only 2 ATP compared to the coupling of citric acid intermediates with electron transport that produces 12 ATP per cycle; tissues highly dependent on the respiratory chain (nerves, muscle, retina) are predominantly affected in mitochondrial disorders—for example, Leigh disease. Suggestive signs like the decreased pyruvate/lactate ratio must be followed by more specific tests like muscle biopsy (ragged red fibers), eye examination (retinal pigmentation), or mitochondrial DNA analysis (deletions, point mutations) to diagnose highly variable mitochondrial diseases.
The answer is b. (Murray, pp 151-162. Scriver, pp 1327-1406.) Transamination of alanine to pyruvate, like that of other amino acids, provides citric acid cycle intermediates leading to oxaloacetate and gluconeogenesis. Urea is excreted (incorrect answer a) although fumarate from the urea cycle is a precursor to oxaloacetate, conversion of acetyl-CoA to malonyl-CoA initiates fatty acid synthesis (incorrect answer c), and diversion of oxaloacetate to citrate rather than pyruvate or glucose 6-P to glucose 1-P rather than glucose would decrease gluconeogenesis (incorrect answers d, e). Many amino acids are degraded and transaminated to yield citric acid cycle intermediates, including arginine, histidine, proline, and glutamine to glutamate; and then α-ketoglutarate, tyrosine, and phenylalanine to fumarate, asparagine to aspartate, and then to oxaloacetate. Others such as cysteine, glycine, serine, and threonine can be converted to alanine and transaminated to pyruvate that directly contributes to gluconeogenesis (through pyruvate carboxylase and phosphoenolpyruvate carboxykinase). During the early phases of starvation, the catabolism of proteins is at its highest level. Anabolic enzymes, which are not utilized during starvation, are targeted for degradation (with ubiquitin) and their synthesis repressed. The transamination of amino acids is a first step in amino acid degradation and also yields ketoacids for gluconeogenesis. The protein and amino acid degradation with ketogenesis results in a negative nitrogen balance, increasing ammonia and urea levels in the urine (fromnthe urea cycle). The glucose formed from gluconeogenic amino acids becomes the major source of blood glucose following depletion of liver glycogen stores. Completenoxidation of this glucose, as well as the ketone bodies formed from ketogenic amino acids, leads to a relative increase in the CO2 and H2O formed from amino acid
carbon skeletons.
The answer is A: Pancreatic glucokinase. The boy has developed MODY (maturity onset diabetes of the young), and one variant of MODY is a mutated glucokinase (an inheritable disorder) such that the Km for glucose has increased, and insulin release only occurs when hyperglycemia is present. Both an increase in ATP and NADPH are required for the pancreatic β-cell to release insulin. When pancreatic glucokinase has an increased Km for glucose, ATP levels can only increase at greater than normal levels of glucose. Thus, moderate hyperglycemia is not suffi cient to induce insulin release. As insulin release occurs from the pancreas, liver, muscle, or intestinal hexokinase will not affect the process. The pancreas does not express hexokinase, only glucokinase. MODY is a monogenetic autosomal dominant disease of insulin secretion. There are at least six amino acid substitutions known in a number of different proteins. MODY1 is a mutation in the transcription factor HNF4-α:∼ MODY2 is a mutation in pancreatic glucokinase. MODY3 is a mutation in the t ranscription factor HNF1-α while MODY4 contains a mutation in insulin promoter factor 1. MODY5 is a mutation in another transcription factor, HNF1-β. MODY6 is a mutation in neurogenic differentiation factor 1. MODY is not insulin resistance. Therefore, all the other aspects of insulin resistance syndrome are not present (obesity, hypertension, and hypertriglyceridemia). Since MODY is autosomal dominant, it can be traced through the family tree. It was thought at one time that the patient had to be young to present with this disorder, but patients up to age 50 have been reported. It is not type 1 diabetes mellitus as no islet cell antibodies are present. Glucokinase is acting as a glucose sensor for the β-cell. A mutated, less sensitive sensor leads to mildly elevated blood glucose levels.
The answer is C: Galactokinase. The child has nonclassical galactosemia, a defect in galactokinase. With this disorder, galactose cannot be accumulated within cells, and so it accumulates in the blood, spilling over to the urine. Because of its high level, the galactose can enter the eye and be reduced to galactitol by aldose reductase, trapping the galactitol within the eye. As galactitol accumulates, an osmotic imbalance is created, leading to cataract formation. However, since galactose1-phosphate is not accumulating (as occurs in classical galactosemia, a defect in galactose-1-phosphate uridylyl transferase), the other effects seen with classical galactosemia (hypoglycemia and neurological deficit) do not occur. The sugar that is accumulating in the urine is galactose, which contains an aldehyde, which generates a positive response in a reducing test. A defect in fructokinase leads to fructosuria, a benign condition (fructose is not a substrate for aldose reductase, as it is a ketose and not an aldose). A defect in hexokinase would lead to elevated glucose levels, and can lead to sorbitol production in the lens of the eye, but the urine reducing sugar test was negative for glucose. A defect in aldolase would lead to the intracellular accumulation of metabolites, but not a great increase in circulating galactose. Refer to the fi gure in the answer to question 3 of this chapter for the pathway of galactose metabolism and the enzyme defects in both classical and nonclassical galactosemia.
The answer is D: 22.5 moles of ATP per mole of citrate. The following steps (see the figure on page 95) are required for the complete oxidation of citrate to carbon dioxide and water. First, citrate goes to isocitrate, which goes to α-ketoglutarate (this last step generates carbon dioxide and NADH, which can give rise to 2.5 ATP). The α-ketoglutarate is further oxidized to succinyl-CoA, plus carbon dioxide and NADH (this is the second carbon released as CO2, and another 2.5 ATP). Succinyl-CoA is converted to succinate, generating a GTP (at this point, fi ve high-energy bonds have been created, plus two carbons lost as carbon dioxide). Succinate goes to fumarate, with the generation of FADH2 (another 1.5 ATP), fumarate is converted to malate, and malate leaves the mitochondria (via the malate/aspartate shuttle) for further reactions. Once in the cytoplasm, the malate is oxidized to oxaloacetate, generating NADH (another 2.5 ATP if the malate/ aspartate shuttle is used). At this point, citrate has been converted to cytoplasmic oxaloacetate, with the generation of ten high-energy bonds and the loss of two carbons as carbon dioxide. The oxaloacetate is then converted to phosphoenolpyruvate and carbon dioxide at the expense of a high-energy bond (GTP, the phosphoenolpyruvate carboxykinase reaction). The high-energy bond is recovered in the next step, however, as PEP is converted to pyruvate, generating an ATP. Thus, at this point in our conversion, citrate has gone to pyruvate, plus three CO2, with a net yield of ten ATP (or high-energy bonds). The p yruvate reenters the mitochondria and is oxidized to acetyl-CoA and carbon dioxide, also generating NADH (another 2.5 ATP). When this acetyl-CoA goes around the TCA cycle, two carbon dioxide molecules are produced, along with another ten high-energy bonds. The net total is therefore six carbon dioxide molecules and 22.5 high energy bonds for the complete oxidation of citrate.
The answer is B: Phosphoglucomutase. For this woman to synthesize lactose, she needs to synthesize the precursors UDPgalactose and glucose, both of which are available from glucose. Glucose is converted to glucose-6-phosphate by hexokinase in the breast, and then phosphoglucomutase will convert this to glucose-1-phosphate (G1P). The G1P will react with UTP in the glucose-1-phosphate uridyl transferase reaction, producing UDPglucose. The C4 epimerase will then produce UDPgalactose from UDPglucose. The UDPgalactose then condenses with free glucose (using lactose synthase) to produce lactose and UDP. The other enzymes listed as answers are not required to produce lactose from the single precursor glucose. Fructokinase is unique for fructose metabolism. Aldolase is a glycolytic enzyme, which is defi cient in hereditary fructose intolerance. Phosphohexose isomerase coverts glucose6-phosphate to fructose-6-phosphate, which is not required for lactose synthesis. Classical galactosemia (severe, type 1) is a deficit of galactose-1-phosphate uridyl transferase. Patients cannot metabolize galactose, and the accumulating galactose-1-phosphate interferes with glycogen degradation. Nonclassical galactosemia (type 2) is a deficit in galactokinase, such that galactose cannot be phosphorylated. The complications in type 1 galactosemia due to the accumulation of galactose-1phosphate are not seen in type 2 galactosemia. In either case, the missing enzymes are not required for the synthesis of lactose.
The answer is D: ABCG5. The patient has sitosterolemia, an accumulation of plant sterols (phytosterols) in cells and tissues. Under normal conditions, phytosterols can diffuse into the epithelial cells, but they are actively transported back into the intestinal lumen by an ABC-cassette (ATP-binding) containing protein, ABCG5 (the other protein responsible for phytosterol effl ux is ABCG8).Those sterols which make it to the liver are exported by the same proteins in the liver to
the bile duct, where they will be released along with the bile during fat digestion. In the absence of activity of either ABCG5 or ABCG8, the phytosterols are packaged into chylomicrons and are eventually delivered to the liver, where they are packaged into VLDL. While human cells cannot utilize phytosterols, their increased presence interferes with the synthesis of cholesterol and the normal cholesterol recycling within the affected patient. Patients with this disorder develop premature coronary artery disease. It has been hypothesized that the high levels of plant sterols in the circulating lipoprotein particles accelerate the deposition of these sterols in the walls of the arteries, promoting atherosclerosis. This disorder is not due to mutations in either apo B100 or apo B48, as both VLDL and chylomicrons are synthesized normally in the patient. The defect is not in ABC1, as the patient does not display the symptoms of Tangier disease. The defect is also not in MTTP, as a defect in that protein leads to abetalipoproteinemia.