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Chapter 6: Carbohydrate Metabolism

Terms in this set (396)

The answer is A.

Wernicke syndrome manifests with the triad of ophthalmoplegia, ataxia, and confusion. It is lethal in 10-20% of patients. Foci of hemorrhage and necrosis in the mamillary bodies and periaqueductal gray matter are found on autopsy. This condition occurs due to chronic thiamine deficiency, a condition common in patients with alcoholism.

Thiamine (vitamin B1) participates in a number of reactions of glucose metabolism. It is a cofactor for the following enzymes:

1. Pyruvate dehydrogenase converts pyruvate (the end-product of glycolysis) into acetyl CoA (which enters the citric acid cycle).

2. α-ketoglutarate dehydrogenase is an enzyme of the citric acid cycle.

3. Transketolase is an enzyme of the hexose monophosphate pathway. It converts pentoses (derived from glucose) to glyceraldehyde 3 P (an intermediary of glycolysis).

Thiamine deficiency, therefore, results in decreased glucose utilization, which is especially pronounced in the CNS. If a patient with chronic thiamine deficiency is given a glucose infusion without thiamine supplementation, acute cerebral damage occurs. An increase in erythrocyte transketolase levels after thiamine infusion is diagnostic for thiamine deficiency. (In actual practice, if a patient might be an alcoholic or appears to be very malnourished, presume that the patient is thiamine deficient and give thiamine supplementation with glucose infusion.)

(Choices B and D) Neither erythrocyte glutathione reductase, nor NAD are used for the diagnosis of thiamine deficiency.

(Choice C) Erythrocyte glucose-6-phosphate dehydrogenase (G6 PD) catalyzes a rate-limiting step in the pentose phosphate pathway. This pathway is necessary for NADPH production and the function of the erythrocyte antioxidant system. Decreased glucose-6-phosphate dehydrogenase levels cause hemolytic anemia.

(Choice E) Methylmalonic acid is a product of fatty acid oxidation. It is converted to succinyl CoA by methylmalonyl CoA mutase. This enzyme uses B12 as a coenzyme. Methylmalonic acid levels are increased in vitamin B12 deficiency.

(Choice F) Protoporphyrin is one of the precursors of heme. An increased erythrocyte protoporphyrin concentration is the hallmark of erythropoietic protoporphyria (EPP):

however, this elevation is nonspecific and can be seen in other conditions such as iron-

deficient anemia and lead poisoning.

Educational Objective:
Chronic thiamine (B1) deficiency leads to the diminished ability of cerebral cells to utilize glucose. The mechanism is decreased function of the enzymes that use vitamin B1 as a cofactor (pyruvate dehydrogenase, a-ketoglutarate dehydrogenase, and transketolase). Thiamine deficiency can be diagnosed by measuring erythrocyte transketolase activity.
The answer is B.

Marked riboflavin deficiency is rare in the United States, but can be seen in chronic alcoholics and the severely malnourished. Clinical manifestations of marked riboflavin deficiency include angular stomatitis, cheilitis, glossitis, seborrhea dermatitis, eye changes (kg, keratitis, corneal neovascularization), and anemia. The diagnosis is established with performance of the erythrocyte glutathione reductase assay or evaluation of the urinary riboflavin excretion.

Metabolic modifications of riboflavin occur most frequently in the cells of the heart, liver, and kidney. Typically, riboflavin is first phosphorylated to become the coenzyme flavin mononucleotide (FMN). It can then either be integrated into a coenzyme-flavin complex or can be further phosphorylated into flavin adenine dinucleotide (FAD). FMN and FAD are required cofactors for flavoproteins, which are enzymes that participate in numerous reduction-oxidation reactions within the human body. In the course of these reactions, the FMN and FAD cofactors are transformed into their reduced, energy-carrying states (FMNH.. and FADH..) through the acceptance of electrons.

The riboflavin-containing coenzymes are key constituents of the electron transport chain; FMN is a component of complex I, while FAD is a component of complex II. FAD is an electron carrier in the tricarboxylic acid cycle (TCA) and serves as a cofactor for succinate dehydrogenase, which is an enzyme that mediates the conversion of succinate into fumerate.
The answer is E.

Lactose (galactosyl beta-1 ,4-glucose or milk sugar) is a disaccharide present in milk. lt is synthesized in the mammary gland by formation of a 1,4 glycosidic linkage between glucose and galactose. Lactose in the diet is catabollzed into glucose and galactose by an intestinal brush-border disaccharidase called lactase (a type of beta-galactosidase more specifically known as lactase-phlorizin hydrolase). Lactose intolerance is characterized by gastrointestinal upset upon ingestion of foods containing lactose, such as dairy products, and is caused by a deficiency of lactase (Answer E). Primary lactose intolerance is a very common disorder, particularly in people of African and Asian descent In contrast to most other races, subjects of Northern European descent maintain lactase activity throughout their life.

Secondary lactase deficiency occurs in association with a number of small intestinal mucosal diseases such as celiac sprue and viral gastroenteritis. The underlying pathophysiology of this disorder is due to the fact that lactase is concentrated within epithelial cells in the microvilli of the small intestine (the brush border). When these cells are damaged in gastroenteritis, the damaged cells slough off and are replaced by immature cells that have low concentrations of lactase.

The other answer choice options are important in the metabolism of galactose to either glucose or lactose. Galactose is first phosphorylated to galactose-1 -phosphate by the enzyme galactokinase (Choice B). Next, galactose-1 -phosphate uridyltransferase (GALT) catalyzes the conversion of UDP-glucose and galactose-1 phosphate to UDP galactose and glucose-1-phosphate (Choice C). UDP-galactose is then epimerized to UDP-glucose by UDP-galactose-4 epimerase, after which it can participate in the appropriate glucose-related metabolic pathways. Alternatively, UDP-galactose can be converted to galactosyl beta-1,4 glucose (lactose) by lactose synthase within the mammary glands as part of the formation of milk (Choice D).

Galactosemia is an illness that is distinct from lactose intolerance, and it is characterized by symptoms that start soon after the initiation of breastfeeding. Galactosemia can be caused by a deficiency of GALT (Type 1), galactokinase (Type 2), or UDP-glucose 4-epimerase (Type 3). Excess galactose in patients with galactosemia is converted to galactitol by aldose reductase (Choice A), and high levels of galactitol are responsible for many of the symptoms associated with galactosemia (especially cataract formation).

Educational objective:
Secondary lactase deficiency can occur after viral gastroenteritis or other diseases that damage the intestinal epithelium. This disease causes abdominal distention, flatulence, and diarrhea after lactose ingestion.
The answer is A.

Non-glucose monosaccharldes (kg, galactose, mannose, fructose) enter the glycolytic pathway at different points as intermediates of glycolysls. Of these, fructose is the only one whose metabolites bypass phosphofructokinase. one of the key enzymes involved in regulating the rate of glycolysis. As a result, fructose is metabolized by the liver faster than the other monosaccharides and is rapidly cleared from the bloodstream following dietary absorption.

Metabolism of fructose in the liver begins with phosphorylation by fructokinase to fructose-1 -phosphate (F1 ). Aldolase B can use both fructose-1.6-bisphosphate and F1P as substrates, it converts F1P into dihydroxyacetone phosphate (DHAP) and glyceraldehyde. Glyceraldehyde can be either phosphorylated to glyceraldehyde-3 phosphate by triokinase or converted to DHAP. DHAP is converted by triose phosphate isomerase to glyceraldehyde-3-phosphate, which continues down the glycolytic pathway.

(Choices B, C, D, and E) Galactose-1-phosphate, glucose-1-phosphate, glucose-6-phosphate, and mannose-6-phosphate enter glycolysis upstream of phosphofructokinase, a major rate-limiting enzyme of glycolysis. This slows down the rate of their metabolism relative to fructose and its metabolites (eg, F1P).

Educational Objective:
Dietary fructose is phosphorylated in the liver to F1P and is rapidly metabolized because it bypasses PFK-1, the major rate-limiting enzyme of glycolysis. Other sugars (eg, glucose, galactose, mannose) enter glycolysis prior to PFK-1 and as a result are metabolized more slowly.
The answer is B. The child has classic galactosemia, a defect in galactose-1-phosphate uridylyltransferase. Due to the accumulation of galactose-1-phosphate, galactokinase is inhibited, and free galactose accumulates within the blood and tissues. The accumulation of galactose in the lens of the eye provides substrate for aldose reductase, converting galactose to its alcohol form (galactitol). The accumulation of galactitol leads to an osmotic imbalance across the lens, leading to cataract formation. Additionally, the increased galactose-1-phosphate, at very high levels in the liver, blocks phosphoglucomutase activity, resulting in ineffective glucose production from glycogen (phosphorylase degradation of glycogen will produce glucose-1-phosphate, but this cannot be converted to glucose-6-phosphate if phosphoglucomutase activity is inhibited). A defect in galactokinase will lead to nonclassical galactosemia, with cataract formation, but none of the feeding problems associated with classical galactosemia (associated with the accumulation of galactose-1-phosphate) are observed in nonclassical galactosemia. None of the other enzymes listed, if deficient, will give rise to the symptoms produced, particularly cataract formation. A defect in glycogen synthase would lead to reduced glycogen levels and fasting hypoglycemia. A defect in fructokinase leads to fructosuria (fructose in the urine), but no overt symptoms of disease. The figure below indicates the pathway for galactose metabolism and the defects in classical and nonclassical galactosemia.
The answer is B. For this woman to synthesize lactose, she needs to synthesize the precursors UDP-galactose 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 UDP-glucose. The C4 epimerase will then produce UDP-galactose from UDP-glucose. The UDP-galactose 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 deficient in hereditary fructose intolerance. Phosphohexose isomerase converts glucose-6-phosphate to fructose-6-phosphate, which is not required for lactose synthesis. Classical galactosemia (severe, type 1) is a deficit of galactose-1-phosphate For this woman to synthesize lactose, she needs to synthesize the precursors UDP-galactose 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 UDP-glucose. The C4 epimerase will then produce UDP-galactose from UDP-glucose. The UDP-galactose 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 deficient in hereditary fructose intolerance. Phosphohexose isomerase converts glucose- 6-phosphate to fructose-6-phosphate, which is not required for lactose synthesis. Classical galactosemia (severe, type 1) is a deficit of galactose-1-phosphate.
The answer is B.

This patient has diabetes mellitus and presents with hyperosmolar hyperglycemia, a metabolic derangement often precipitated by infection (pneumonia in this case) and characterized by dehydration hyperglycemia. and hyperosmolarity without significant ketoacidosis. `
His cataracts likely formed from oversaturation of the polyol pathway secondary to long-term hyperglycemia.

Aldose reductase converts glucose into sorbitol during the first step in the polyol pathway of glucose metabolism. Sorbitol cannot readily cross cell membranes and is therefore trapped inside the cells within which it is famed. If the enzyme sorbitol dehydrogenate (sometimes referred to as polyol dehydrogenate) is also present in the cell, it can convert sorbitol into fructose. This pathway, known as the poly pathway, is especially active in the seminal vesicles, as spent use fructose as their primary energy source. Other tissues, such as the retina, renal papilla, and Schwann eels, have much less sorbitol dehydrogenase activity.

The human lens does contain significant levels of sorbitol dehydrogenase, (see references), which allows for the production of fructose. However. this enzyme has a significantly lower Vmax in the sorbitol-to-fructose direction than in the reverse direction. When glucose levels are low, the limited forward activity of this enzyme is sufficient to convert enough sorbitol into fructose to prevent sorbitol accumulation. In contrast. states of long-standing hyperglycemia lead to the production of an excessive amount of sorbitol that is trapped in the cells. This increases the osmotic pressure and facilitates the influx of water into the lens cells. leading to the development of hydropic lens fibers that degenerate. Eventually, this results in lens opacification and cataract formation. In addition to osmotic cell injury, oxidative stress resulting from the depletion of NADPH contributes to cataract formation and other diabetic complications such as neuropathy and retinopathy.
The answer is E.

The 2 major processes that maintain plasma glucose between meals are glycogenolysis and gluconeogenesis. Glycogenolysis is the primary source of glucose for the first 12-18 hours of fasting. Once hepatic glycogen stores become depleted, gluconeogenesis becomes the major process used by the body to keep blood glucose levels within the normal range. During gluconeogenesis, glucose is famed from lactate, glycerol, and glycogenic amino acids. This process uses many of the enzymes involved in glycolysis. However, hexokinase, phosphofructokinase, and pyruvate kinase are unidirectional and must be bypassed by distinct gluconeogenic enzymes.

The first committed step of gluconeogenesis is the biotin-dependent carboxyiation of pyruvate to oxaloacetate by mitochondrial pyruvate carboxylase. Oxaloacetate is subsequently converted to malate by malate dehydrogenase to facilitate exit from the mitochondria, and then is converted back to oxaloacetate by cytosolic malate dehydrogenase (malate shuttle). In the cytosol, phosphoenolpyruvate carboxykinase (PEPCK) converts oxeloacetate to phosphoenolpyruvate. Therefore. pyruvate carboxylase and PEPCK work together to bypass pyruvate kinase. The 2 other unique gluconeogenic enzymes are fructose 1,6-bisphosphatase (bypasses phosphofructokinase) and glucose-6-phosphatase (bypasses hexokinase).

(Choice A) Conversion of acetoacetyl-CoA to 3-hydroxy-3 methylglutaryl-CoA occurs during the synthesis of cholesterol and ketone bodies. Ketone body synthesis is increased in starvation situations, however, ketone bodies cannot be used to synthesize glucose.

(Choice B) Palmitic acid is the first fatty acid produced from acetyl CoA during lipogenesis in the fed state. However, during prolonged fasting, lipolysis predominates and leads to the generation of glycerol and fatty acids.

(Choice C) Conversion of fructose 6-phosphate to fructose 1,6 -bisphosphate occurs during glycolysis and is catalyzed by phosphofructokinase. During starvation, glycolysis is minimized and gluconeogenesis predominates.

(Choice D) The first step of glycogenolysis is breakage of 1-4 glycosidic linkage to for glucose-1-phosphate. After 24 hours of fasting, maintenance of blood glucose levels is achieved mostly through gluconeogenesis, not by glycogenolysis.

Educational Objective:
After 12-18 hours of fasting, gluconeogenesis becomes the principal source of blood glucose. Gluconeogenesis uses many glycolytic enzymes. but hexokinase, phosphofructokinase, and pyruvate kinase need to be bypassed as they are unidirectional. The initial steps of gluconeogenesis involve the conversion of pyruvate to oxaloacetate and oxaloacetate to phosphoenolpyruvate by pyrwate carboxylase and phosphoenolpyruvate carboxykinase. respectively.
The answer is B.

Glycolysis can occur in aerobic or anaerobic conditions. In aerobic environments, the NADH created during the conversion of glyceraldehyde 3-phosphate to 1,3-bisphosphoglycerate is regenerated to NAD through oxidation within the mitochondrial electron transport chain. The amount of NAD in cells is limited, therefore, regeneration of NAD from NADH is essential. In anaerobic conditions (and in erythrocytes under aerobic conditions), pyruvate cannot be oxidatively decarboxylated to acetyl CoA. Instead, pyruvate is converted to lactate by the enzyme lactate dehydrogenase. The conversion of pyruvate to lactate also serves to re-oxides NADH to NAD in the absence of oxygen.

Erythrocytes are unique cells because they do not have mitochondria and cannot generate energy from the citric acid cycle. Glycolysis is the major pathway used by RBCs to produce energy. 2,3 bisphosphoglycerate (BPG) is generated as a byproduct of glycolysis from 1,3-BPG by the enzyme bisphosphoglycerate mutase (producing no ATP). It is catabolized to 3-phosphoglycerate by bisphosphoglycerate phosphatase (also producing no ATP). During normal glycolysis, 1,3-BPG is converted to 3-phosphoglycerate by the enzyme phosphoglycerate kinase, which does produce ATP in the process. By generating 2,3-BPG rather than proceeding with regular glycolysls, RBCs sacrifice the net ATP gem achieved in normal glycolysis.

The major function of RBCs is to carry hemoglobin-bound oxygen from the lungs to the peripheral tissues, and 2.3-BPG is a very important regulator of oxygen-binding to hemoglobin. increased 2,3-BPG concentrations within erythrocytes enable increased oxygen delivery in the peripheral tissues in the presence of lower blood oxygen concentrations because 2,3-BPG allosterically decreases the affinity of hemoglobin for oxygen. The conversion of 1,3-BPG to 2,3-BPG is increased in hypoxia and chronic anemia,
The answer is C.

Metabolism of glucose through the hexose monophosphate (HMP) shunt serves two major functions: 1. production of NADPH as a reducing equivalent. and 2. synthesis of ribose 5-phosphate for nucleotide synthesis. The HMP shunt consists of two different types of reactions: oxidative (irreversible) and non-oxidative (reversible) reactions. All reactions of HMP shunt occur exclusively in the cytoplasm. In the oxidative portion of HMP shunt, glucose 6-phosphate is first converted to 6-phosphogluconolactone producing one molecule of NADPH. This reaction is catalyzed by glucose 6-phosphate dehydrogenase, the rate limiting enzyme of the HMP shunt In the second reaction of the oxidative portion of HMP shunt, 6 phosphogluconolactone is hydrolyzed to ribulose 5-phosphate by 6-phosphogluconate dehydrogenase producing a second molecule of NADPH. The non-oxidative reactions of the HMP are primarily designed to generate ribose 5-phosphate from intermediates of glycolysis.

Erythrocytes utilize the reactions of the HMP shunt to generate large amounts of NADPH to maintain glutathione in a reduced state by the action of glutathione reductase. Reduced glutathione is important in protecting erythrocytes from oxidative damage resulting from oxidant drugs and oxidizing environmental toxins. In erythrocytes, the HMP shunt is the only major pathway that generates NADPH. Thus, defects in the oxidative portion of the HMP shunt result in poor protection of these cells against free radicals, hydrogen peroxide and other forms of oxidant stress.

Oxidative damage to red cells causes denatured hemoglobin to form insoluble Heinz bodies resulting in erythrocyte destruction in the spleen. Additionally, oxidative stress results in stiffening of the erythrocyte membrane and hemolysis in die microvasculature due to an inability of the erythrocyte to deform and fit through capillary beds. The patient described in the vignette most likely has glucose 6-phosphate dehydrogenase deficiency (G6PD). G6PD is an X-linked disorder that results in episodes of hemolysis during oxidative and infective stress. The patient in this vignette was likely prescribed trimethoprim-sulfamethoxazole for UTI this drug has oxidant properties end can precipitate hemolysis in patients with this disease.

Educational Objective:
Glucose 6-phosphate dehydrogenase deficiency is a common X-linked disorder of the hexose monophosphate pathway that results in episodes of hemolytic anemia due to oxidative stress.
The answer is D.

The spleen is an organ of the reticuloendothelial system that contains approximately 25% of body's lymphoid tissue. One of the main functions of the spleen in adult humans is maintenance of erythrocyte quality in the red pulp by removal of senescent and defective red blood cells. The spleen accomplishes this function through the unique organization of its parenchyma and vasculature. Antibody production and B cell affinity maturation occur in the white pulp of the spleen, and the spleen also serves to remove antibody-coated bacteria and other opsonized material and cells from the circula.tion. An increase in any of these normal functions may result in splenomegaly.

Pyruvate kinase is the enzyme in the glycolytic pathway that converts phosphoenolpyruvate to pyruvate resulting in the generation of a molecule of ATP. Pyruvate kinase is allosterically stimulated by fructose 1,6-bisphosphate. which is produced from fructose-6-phosphate by the enzyme phosphofructokinase. Allosteric stimulation of pyruvate kinase by fructose 1,6-bisphosphate results in stimulation of glycolysis. Red blood cells do not contain mitochondria, so the main metabolite of glycolysis is lactate. Any deficiency of glycolysis in red blood cells leads to hemolysis because of insufficient production of ATP and defective maintenance of red blood cell architecture. Excessive erythrocyte destruction by the spleen causes splenomegaly due to work hypertrophy (choice D). Work hypertrophy results from hypertrophy of the reticuloendothelial cells of the splenic parenchyma as these cells are involved in the removal of damaged RBCs.

Educational Objective:
Pyruvate kinase deficiency causes hemolytic anemia due to failure of glycolysis and resultant failure to generate sufficient ATP to maintain erythrocyte structure. In this case, splenic hypertrophy results from increased work of the splenic parenchyma, which must remove these deformed erythrocytes from the circulation.
The answer is D.

The patient described in this question stem has a clinical presentation of bilateral cataracts, but he is otherwise asymptomatic. This presentation is most consistent with galactokinase deficiency, a form of galactosemia that causes a benign disorder characterized by cataracts without hepatocellular manifestations. Classic galactosemia, by comparison, results from galactose-1-phosphate uridyl transferase (GALT) deficiency, this is the most common form of galactosemia. Patients with GALT deficiency present with vomiting, lethargy and failure to thrive soon after feeding is begun. Other clinical findings of this disorder include impaired liver function, hyperchloremic metabolic acidosis, and aminoaciduria. This disorder results in severe symptoms after initiation of breast feeding. A normal newborn obtains a large amount of their daily calories from lactose present in breastmilk. Following degradation of lactose and absorption of galactose and glucose, galactose is phosphorylated to galactose-1 -phosphate by the enzyme gatactokinase. A deficiency of galactokinase results in elevation of galactose levels. Excess circulating galactose is converted to galactitol by aldose reductase and to galactonic acid by galactose oxidase. while galactonic acid can be metabolized by the HMP shunt, galactitol accumulates in cells. Excess galactitol is responsible for the formation of cataracts in patients with galactokinase deficiency. Dietary restriction of lactose results in improvement in symptoms in all forms of galactosemia.

Educational Objective:
Galactitol accumulates in the lens of patients with galactosemia and causes osmotic damage leading to cataract formation. Galactitol is formed from excess circulating galactose in galactosemia by aldose reductase.
The answer is B.

Glycogen is broken down by the enzyme glycogen phosphorylase, which is regulated through phosphorylation (active state) and dephosphorylation (inactive state). Phosphorylase kinase (PK) is the enzyme responsible for the phosphorylation of glycogen phosphorylase, whereas phosphoprotein phosphatase catalyzes its dephosphorylation.

PK is regulated differently in liver than in muscles. Glycogen stored in the liver is used to maintain blood glucose levels during the fasting state, whereas glycogen in the muscles is used to provide energy for muscle contraction. In the liver, PK is activated primarily through the binding of epinephrine and glucagon to Gs-protein-coupled receptors, which increases cAMP concentrations and causes phosphorylation of PK (via protein kinase A).

Skeletal muscle lacks glucagon receptors, but muscle PK can still be phosphorylated in response to an epinephrine-induced increase in cAMP concentrations. However, increased intracellular calcium is a more powerful activator of muscle PK. Release of sarcoplasmic calcium following neuromuscular acetylcholine stimulation allows for synchronization of skeletal muscle contraction and glycogen breakdown, providing the energy necessary for anaerobic muscle contraction. Epinephrine can also act on alpha-1 adrenergic receptors found in muscle and liver to increase intracellular calcium and promote glycogenolysis.

Educational Objective:
Synchronization of glycogen degradation with skeletal muscle contraction occurs due to release of sarcoplasmic calcium following neuromuscular stimulation. Increased intracellular calcium causes activation of phosphorylase kinase, stimulating glycogen phosphorylase to increase glycogenolysis.
The answer is B.

Debranching enzyme deficiency (Cori disease) usually presents in infancy or childhood with both liver and muscle involvement. Symptoms include hypoglycemia, hepatomegely, and ketoacidosis. Muscle weakness and hypotonla help to extinguish the condition from other glycogen storage diseases with hepatic involvement (eg, von Gierke). Hepatic fibrosis is common, but fatty infiltration is not usually seen. A key distinguishing feature is cytosolic accumulation of glycogen with abnormally short outer chains (limit dextrins).

During glycogenolysis, glycogen phosphorylase shortens glycogen chains by cleaving α-1,4-glycosidic linkages between glucose residues, liberating glucose-1-phosphate in the process. This occurs until 4 residues remain before a branch point (the limit dextrin). At this point, debranchlng enzyme performs 2 enzymatic functions: 1) glucosyltransferase cleaves the outer 3 residues of the 4 glucose residues left by glycogen phosphorylase and transfers them to a nearby branch, and 2) α-1 ,6-glucosidase removes the single remaining branch residue, producing free glucose and a linear glycogen chin that can be further shortened by glycogen

Educational Objective:
Debranching enzyme deficiency (Con disease) leads to accumulation of glycogen with abnormally short outer chains (limit dextrins) due to the inability to degrade α-1,6-glycosidic branch points. Patients present with hypoglycemia, ketoacidosis, hepatomegaly, and muscle weakness and hypotonia.
The answer is C.

The patient described in the vignette has characteristic features of galactosemia. Classic galactosemia is caused by impaired galactose-1 phosphate metabolism Lactose degradation by the intestinal disaccharidase lactase leads to the formation of galactose and glucose; this enzyme is defective in lactose deficiency. Galactose is then phosphorylated to galactose-1 -phosphate by the enzyme galactokinase. Galactose-1-phosphate is then converted to glucose-1-phosphate by epimerization. This reaction requires the transfer of uridine diphosphate (UDP) from UDP-glucose catalyzed by galactose-1-phosphate uridyltransferase (GALT) generating UDP galactose and glucose-1-phosphate. UDP-galactose-4 epimerase. In breast tissue. α -1 ,4 glycosidic linkage between glucose and galactose is formed resulting in galactosyl-1,4-glucose (lactose or milk sugar).

Galactosemia can result from defects in any of the three enzymes involved in galactose metabolism, however, the most common form of galactosemia, classic galactosemia, occurs from a deficiency of galactose-1-phosphate uridyltransferase. The clinical features of this illness include vomiting, lethargy and failure to thrive soon after breastfeeding is begun. Galactosemia can result in impaired liver function, hyperchioremic metabolic acidosis, and aminoaciduria. Dietary restriction of lactose results in improvement in symptoms.

Excess galactose in patients with galactosamia is converted to galactitol by galactose reductase or to galactonic acid by galactose oxidase. While galactonic acid can be metabolized by the HMP shunt, galactitol accumulates within the cells. Untreated galactosemia typically culminates in irreversible eye and liver damage. Galactokinase deficiency typically causes less severe manifestations with cataract being the most common manifestation.

Educational Objective:
Classic galactosemia results from a deficiency of galactose-1-phosphate uridyltransferase, this defect is the most common cause of galactosemia. The clinical features of this illness include vomiting, lethargy and failure to thrive soon after breastfeeding is begun.
The answer is A.

Fructokinase deficiency has no clinical manifestations. It generally presents as an accidental finding of a reducing substance in the urine that is not glucose. It is autosomal recessive and no treatment is required. Fructokinase catalyzes the first step of dietary fructose metabolism by converting fructose to fructose-1 -phosphate with a deficiency of the enzyme fructose levels increase in the blood, but almost all of it is excreted in the urine because there is no renal threshold for fructose.

Fructose-1,6-bisphosphate aldolase deficiency is a severe condition of infants that occurs with the ingestion of fructose-containing foods, The enzyme deficiency affects the liver, kidney, and intestine, Fructose-1,6 biphosphate aldolase (choice B) catalyzes the hydrolysis of fructose-1,6-bisphosphate into dihydroxyacetone phosphate and glyceraldehyde phosphate. It also hydrolyzes fructose-1-phosphate. With this deficiency, there is a rapid accumulation of fructose-1 -phosphate and severe toxicity when exposed to fructose.

Galactokinase (choice C) catalyzes the phosphorylation of galactose. with deficiency, there is an accumulation of galactose in peripheral blood. Several tissues. including the lens of the eye have an enzyme (aldose reductase) that catalyzes the conversion of galactose to galactitol. As galactitol accumulates in the lens, it causes osmotic damage. Cataracts are usually the sole manifestation

Galactose-1-phosphate uridyltransferase [choice D) deficiency results in classic galactosemia; without prompt diagnosis and treatment, the infant will die. Without the enzyme, the patient is unable to metabolize galactose-1-phosphate and it accumulates in tissues, causing injury to the kidneys, liver, and brain. The process may begin prenatally due to transplacental transport of galactose, After birth, with the initiation of feeding milk these infants have jaundice, have failure to thrive, and also develop cataracts

Glucose-6-phosphatase deficiency (choice E) manifests as a glycogen storage disease (Von Gierire disease). With the deficiency, there is inadequate hepatic conversion of glucose-6-phosphate to glucose and the patient is susceptible to fasting hypoglycemia Children typically present at 3-4 months of age with hypoglycemic seizures. In addition to severe hypoglycemia, there is growth retardation, increased serum lactate, increased cholesterol, increased triglycerides, and hepatosplenomegaly and kidney enlargement These last two findings result in a protuberant abdomen, Liver adenomas develop in many patients and may undergo malignant transformation.
The answer is A.

Under normal conditions, when oxygen is readily available, the pyruvate generated in glycolysis enters the mitochondria and is convened into acetyl-CoA by the action of pyruvate dehydrogenase, In severe exercise. particularly by individuals in poor physical condition, the oxygen demands of the skeletal muscle may exceed the ability of the heart and lungs to provide oxygen. In this setting, the muscles switch to anaerobic glycolysis and the pyruvate that is produced is converted to lactate by the action of lactate dehydrogenase, Much of the lactic acid thereby produced is released into the bloodstream where it causes a metabolic acidosis. In addition to the setting of severe exercise. lactic acidosis can also be seen in tissue hypoxia (seizures. cardiac failure. hypotension. carbon monoxide poisoning, severe anemia), with drug toxicity and toxins (phenformin, catecholamines, salicylate, isoniazid, cyanide), in congenital defects in gluconeogenic enzymes, and in many severe illnesses.

In chronic obstructive pulmonary disease (COPD), patients are asked to exercise as part of their treatment. Exercise builds muscle mass that patients with COPD often do not have. COPD patients work hard to breathe; the muscles have a low threshold for anaerobic glycolysis that leads to lactic acidosis. The patient then tries to compensate for the lactic acidosis by respiratory alkalosis; however, because of the COPD he cannot compensate effectively. Exercise increases the muscle mass, leading to an increase in mitochondria. This in turn leads to more ATP, less anaerobic glycolysis, and a less dramatic need for respiratory compensation.
The answer is C.

Glycogen phosphorylase shortens the glycogen chain by cleaving the alpha 1,4 glycosidic linkages between glucose residues by simple phosphorylation. This occurs until four residues are remaining on the end of a glycogen polymer before a 1 ,6 glycosidic branch point. These glucose residues remaining before a branch point are referred to "limit dextrins". The debrancher enzyme acts on the glycogen polymer at this point. Debrancher enzyme contains two enzymatic activities. The first enzymatic action is a transferase action that transfers the outer three residues of the four- glucose residues left by glycogen phosphorylase on the 1, 6 chains and transfers these three residues to the 1,4 chain. The second action is an amylo-1 6-glucosidase action that cleaves the 1 6 glucosidic bond at the branch point to liberate a free glucose molecule. Glycogen phosphorylase can then resume cleaving alpha 1, 4 glycosidic linkages leading to the formation of glucose-1-phosphate, which is then converted to glucose-6-phosphate by the enzyme phosphoglucomutase.

In debranching enzyme deficiency (Con disease), the clinical presentation includes hypoglycemia, hypertriglyceridemia, lactic acidosis, and hepatomegaly. These manifestations are common with other glycogen storage diseases; however, debranching enzyme can be differentiated from other glycogen storage diseases by demonstrating accumulation of abnormally short outer dextrin-like structures in the cytosol of hepatocytes and muscle cells with an absence of fatty infiltration of liver on histopathology. Debranching enzyme deficiency can affect both liver and muscle cells.
The answer is E.

This patient most likely has hereditary fructose intolerance caused by a deficiency in the enzyme aldolase B. During the normal metabolism of fructose (a 6-carbon sugar similar to glucose), fructose is ingested, taken up into liver cells, and phosphorylated by fructokinase, trapping
fructose intracellularly. For fructose-1-phosphate to be utilized for energy, it is then cleaved into glyceraldehyde and dihydroxyacetone phosphate by the enzyme aldolase B. These 3-carbon structures, as well as their downstream products, are then utilized by an array of metabolic pathways, including glycolysis, the Krebs cycle, gluconeogenesis, and glycogen synthesis.

Hereditary fructose intolerance is an autosomal recessive disorder with an incidence of 1 in 20,000 bi1ths. It typically presents with vomiting and lethargy in infants after the introduction of fructose into the diet/ Note that breast milk contains the sugars glucose and galactose (in the form of the disaccharide lactose) and thus does not cause symptoms in infants. However, symptoms will appear once the child is switched to baby formula or a normal diet, which both contain fructose. The absence of aldolase B causes significant impairment in the metabolism of fructose. In these patients, after an ingestion of a fructose-containing meal, fructose-1-phosphate cannot be processed by aldolase B, and thus accumulates in hepatocytes. The build-up of fructose-1-phosphate depletes the cellular stores of free phosphate. Glycogen is unable to break down, which causes hypoglycemia .

Of all the choices listed, hypoglycemia correctly identifies the metabolic derangement experienced by patients after ingestion of a fructose load. To prevent the life-threatening consequences of hereditary fructose intolerance, including cirrhosis and severe hypoglycemia, affected individuals must follow a strict diet devoid of both fructose and sucrose.
The answer is E.For monosaccharides such as glucose, galactose, and fructose to be absorbed after ingestion, they need to first pass through the apical side of the gastrointestinal (GI) epithelium and then again through the basolateral side of the epithelium into the blood, as illustrated in the diagram. The apical side of the GI epithelium has numerous microvilli with numerous dedicated transporters. Both glucose and galactose traverse the apical membrane by the action of the transporter sodium-dependent
glucose transporter 1 (SGLTl). SGLTl is a symporter, in that it simultaneously transports sodium and either monosaccharide into the cell. It is able to draw these monosaccharides into the epithelial cells along with sodium because of the sodium gradient created by the sodium-potassium adenosine triphosphatase
(ATPase) at the basolateral membrane. Fructose, on the other hand, traverses the apical epithelial membrane via a sodium-independent monosaccharide transporter (GLUT- S). After glucose, galactose, and fructose enter the epithelial cells of the small intestine, they all traverse the basolateral membrane into the bloodstream via another transporter, GLUT- 2. Therefore, a medication that would inhibit the absorption of glucose and galactose, but not fructose, would have to work by inhibiting the absorption of glucose and galactose at the apical membrane. Inhibition of the SGLTl symporter could be achieved by impairing the sodium gradient, established by the basolateral Na+;K+ ATPase, which helps drive these monosaccharides into the cel l.
The answer is A. 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 sufficient 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 transcription 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 3-sensor leads to mildly elevated blood glucose levels.
The answer is F. In contrast to the case with glycolysis, the only site of substrate-level phosphorylation in the tricarboxylic acid cycle is the step catalyzed by succinyl CoA synthetase. In this step, the cleavage
of CoA from succinyl CoA to produce succinate is the utilization of a high-energy bond of CoA to phosphorylate GDP with organic phosphate to produce GTP. Since NADH generated by glycolysis in the cytoplasm cannot pass across the mitochondrial membrane, shuttles are used to bring the electrons into the mitochondria for oxidative phosphorylation. In the glycerol phosphate shuttle, NADH + H+ in the cytoplasm reduces dihydroxyacetone phosphate to glycerol phosphate, which is capable of entering the mitochondria. In the mitochondria, the glycerol phosphate is oxidized back to dihydroxyacetone phosphate, which can then diffuse back out into the cytoplasm. During this process, flavin (FADH2) is reduced and is capable of generating 2 ATP via oxidation by the respiratory chain. In contrast, the malate-aspartate shuttle allows the formation of 3 ATP equivalents for each mole of cytoplasmic NADH + H+ generated. The malate-aspartate shuttle is found mainly in the heart and liver. The process of oxidative phosphorylation that is coupled to electron transport occurs because of the proton gradient maintained across the mitochondrial membrane. ATP is formed by mitochondrial ATPase by the movements of protons across this gradient. In the presence of substances like 2,4-dinitrophenol (DNP), oxidation of oxidative phosphorylation is uncoupled. This occurs because DNP carries the protons across the mitochondrial membrane, shortcircuiting the phosphorylations that normally occur. While this reaction is not biologically useful, it does mimic the normal uncoupling of phosphorylation that can occur under certain biologic conditions and is used to generate heat to maintain body temperature. This occurs in certain mammals adapted to cold, newborn mammals, and hibernating animals. In these animals, this process of thermogenesis occurs in specialized brown adipose tissue. The uncoupling protein is called thermogenin. Since electron transport is tightly coupled to phosphorylation, under physiologic conditions electrons do not flow through the electron transport chain to O2 unless ADP is simultaneously phosphorylated to ATP. If the level of ADP is low, oxidative phosphorylation does not occur at as high a rate and the rate of oxygen consumption in tissue decreases. Respiratory control is the regulation of the rate of oxidative phosphorylation by ADP levels.
The answer is D. The following steps 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, five 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 pyruvate 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 E. The patient described above most likely has hereditary fructose intolerance. Hereditary fructose intolerance is an autosomal recessive disorder that results from aldolase B deficiency, and typically presents around the age of breast milk weaning and introduction of foods containing fructose, with symptoms of hypoglycemia, jaundice, and vomiting. The patients symptoms, along with the presence of reducing substance in the urine (i.e„ fructose), makes hereditary fructose intolerance the likely diagnosis. Aldolase B normally catalyzes the conversion of fructose-1 phosphate to dihydroxyacetone-phosphate and glyceraldehyde-3-phosphate. Fructokinese, the enzyme upstream of aldolase B, uses 1 adenosine triphosphate (ATP) to catalyze the irreversible reaction of fructose to fructose-I phosphate. However, the fructose-1-phosphate in the liver is unable to escape because aldolase B is the only enzyme that uses this carbohydrate as a substrate. Fructose-1-phosphate accumulation leads to liver cirrhosis end jaundice. The buildoup of fructose-1-phosphate results in phosphate trapping thet depletes both phosphate and ATP stores, which in turn inhibits gluconeogenesis and glycogenolysis, and the regeneretion of ATP. These metabolic changes result in hypoglycemia, defined clinicelly as blood glucose < 70 mg/dL, which manifests clinically as tremors, palpitations, anxiety, diaphoresis, altered mental status, and lethargy. Depleting phosphate end ATP leads to increased AMP, which stimulates the activity of AMP deaminase. AMP deaminase catalyzes the conversion of AMP to IMP, which is ultimately converted to uric acid. Therefore, patients with aldolase B deficiency may present with hyperuricemia.