Exam 2 Book Questions

Question 1

The rate limiting step of the metabolic pathway that synthesizes glucose de novo from noncarbohydrate precursors is:

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Metabolism Review Q’s

Answer 1

Fructose 1,6-BP+H20 –> Fructose 6-P+Pi

The rate limiting step of gluconeogenesis (the pathway that synthesizes glucose de novo from noncarbohydrate precursors) is catalyzed by fructose 1,6-biphosphate.

It is a phosphatase that hydrolyzes a phosphate group (Pi) from the carbon 1 position of fructose 1,6-biphosphate, thus generating fructose 6-phosophate.

Question 2

Which enzyme is involved in the conversion of the amino acid nitrogen into a compound that directly provides the urea nitrogen?

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Answer 2

Aspartate aminotransferase (AST)

AST leads to the production of aspartate through a transamination reaction. Aspartate feeds into the urea cycle, and its nitrogen atom is incorporated into urea.

Question 3

Which enzyme can utilize ammonia for the synthesis of the a-amino group of an amino acid?

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Answer 3

Glutamate dehydrogenase

Glutamate dehydrogenase can, under conditions of abundant energy, react ammonia ion (NH4+) with a-ketoglutarate to form glutamate.

Subsequently, the amino group of glutamate can be transferred to an a-keto acid to form its corresponding amino acid (i.e., transamination of pyruvate to alanine).

Aminotransferases and their associated pyridoxal phosphate cofactor catalyze the transamination reactions.

Question 4

A 26 year old man is attempting to improve his performance as an amateur weightlifter. To thus end, he purchases a bottle of lysine supplements at a health food store because he has heard this will help build muscle tissue. To speed up his progress in training, he takes 10 times the amount of lysine recommended on the container. After 4 weeks, he presents to his physician with skin rashes, intestinal discomfort, and general lethargy. After learning of the lysine supplements, his physician notes that the symptoms may be due to negative nitrogen balance. An elevated level of BUN (blood urea nitrogen) supports this diagnosis. The excess intake of lysine was likely impairing the intestinal absorption of what?

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Answer 4

Arginine, histidine

Arginine, histamine, and lysine are all basic amino acids. The will compete with one another for the same transport mechanisms.

Question 5

Glutamate dehydrogenase carries out the oxidative deamination of glutamate in liver mitochondria. The products of this reaction are:

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Answer 5

a-Ketoglutarate, NH4+, NADH

Glutamate dehydrogenase, operating in the catabolic direction, yields NH4+, the reduced form of nicotinamide adenine dinucleotide (NADH), and a-ketoglutarate as products.

The cofactor for oxidative deamination of glutamate is NAD+, which is reduced for NADH during the reaction.

The NADH produced can be used as a reducing agent during ATP synthesis.

Question 6

The shift in equilibrium of the glutamate dehydrogenase reaction toward the formation of glutamate when the cells are in ammonia toxicity state will deplete the brain cells of which important metabolic intermediate?

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Answer 6

a-Ketoglutarate

The shift in the equilibrium of the glutamate dehydrogenase reaction toward the formation of glutamate will yield glutamate and the oxidized form of nicotinamide adenine dinucleotide (NAD+) as products, depleting cells of a-ketoglutarate.

Question 7

In a research project studying diabetic complications, juvenile female Wistar rats were injected with streptozotocin, a substance that selectively destroys the B cells in the islets of Langerhans on the pancreas. Int he following weeks, the rats developed polydipsia., polyuria (producing half their body weight in urine every day), and wasting of adipose tissue and muscles. When tested with a urine nitroprusside dipstick, the urine tested negative for ketone bodies, The fatty acids contained in the lost adipose tissue were likely converted to what?

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Answer 7

B-hydroxybutyrate

Under the conditions of diabetic ketoacidosis, the liver has an excess of NADH and therefore reduces acetoacetate, the primary ketone body, to β-hydroxybutyrate.

Thus, the ratio of acetoacetate:β-hydroxybutyrate, which is normally ~ 1:1, changes to 1:10 in ketoacidosis. Urine test sticks for ketone bodies contain nitroprusside sodium, a compound that gives a cherry red complex with ketones. Because β-hydroxybutyrate does not have a ketone group (even though it is called a ketone body!), it cannot be detected by this test.

Thus, in the one situation where knowledge of the ketone bodies in urine is clinically most necessary, this test is likely to give a false-negative result. Use of β-hydroxybutyrate dehydrogenase test strips with blood will give the correct result.

Question 8

Which process would you expect to be more active in the liver in the fasting than the fed state?

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Answer 8

Carnitine palmitoyl transferase-I (CPT-I)

Glucagon in the fasting state stimulates the production of cAMP in hepatocytes, which stimulates protein kinase A (PKA).

PKA phosphorylates and inactivates acetyl CoA carboxylase, thereby reducing its product malonyl CoA, thus activating CPT-1, the rate limiting enzyme for fatty acid oxidation.

Question 9

A 2 year old boy presents to his physician with nystagmus, photosensitivity, and a failure to thrive. Laboratory tests reveal that serum concentrations of amino acids are unremarkable, but levels of neutral amino acids in the urine are elevated. The patient is diagnosed with Hartnup disease. Daily supplementation of which compounds would alleviate the severity of symptoms of this disorder?

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Answer 9

Nicotinic acid

The reabsorption of the neutral amino acid tryptophan in the kidneys is defective in Hartnup disease. Tryptophan is a significant source of niacin in the body.

Nicotinamide-containing molecules such as NAD+ and NADP+ are synthesized from tryptophan.

Thus, treatment involves supplementation with nicotinic acid.

Question 10

A 6 month old male infant is admitted to the ER with vomiting, lethargy, and irritability. Diagnostic tests reveal plasma ammonia levels of 200 um. The mother reveals that one of her male siblings died in infancy after a similar episode, although she herself has never had such an episode. Based on the high ammonium levels and the family history, the physician suspects that the patient has a deficiency in ornithine transcarbamoylase (OTC), an X-linked disorder. To test this diagnosis, the physician orders additional tests on levels of particular metabolites in the blood plasma and urine. High levels of which of the following metabolites would support the diagnosis of OTC deficiency?

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Answer 10

Orotic acid

A deficiency in OTC results in a buildup of carbamoyl phosphate in the mitochondria of hepatocytes. The excess carbamoyl phosphate diffuses into the cytosol, where it can be converted to orotic acid in the pyrimidine biosynthetic pathway.

The amount of carbamoyl phosphate generated by CPS I in mitochondria is much greater than that by CPS II in cytosol. This excess carbamoyl phosphate spills over into the cytoplasm and bypasses the normal rate-limiting step of CPS II.

The increased flux through the pyrimidine synthetic pathway causes orotate accumulation because UMP synthase cannot handle all the orotate being produced. High levels of orotic acid in the urine, combined with hyperammonemia, are characteristics of OTC deficiency.

Question 11

Which event is involved in the breakdown of muscle glycogen to glucose-1-phopshate in response to increased epinephrine?

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Answer 11

Conversion of inactive phosphorylase to active phosphorylase

Epinephrine in muscle acts via β-adrenergic receptors that activate adenylyl cyclase and hence stimulate the production of cyclic adenosine monophosphate (cAMP).

The latter then triggers a protein kinase–mediated cascade that eventually phosphorylates phosphorylase, converting it to the active form, leading to glycogenolysis.

Question 12

A 15 year old girl is running away from a perceived attack to survive. Which enzyme in her muscle is inactivated by phosphorylation?

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Answer 12

Glycogen synthase

Glycogen synthase is inactivated through phosphorylation by protein kinase A (PKA) in response to glucagon (in liver) and epinephrine (in liver and muscle).

Question 13

The carbon skeleton of which of the following amino acids can be utilized in the synthesis of both glucose and ketone bodies?

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Answer 13

Tyrosine and threonine

Tyrosine and threonine are known to have both glucogenic and ketogenic properties because they are both degraded to products that can be used in the synthesis of glucose and ketone bodies.

The glucogenic products of tyrosine and threonine are fumarate and succinyl coenzyme A (succinyl CoA), respectively. The ketogenic products are acetyl CoA and acetoacetate.

Question 14

The infantile form of Parkinson disease is due to the defects in tyrosine hydroxylase. Such patients may show low levels of what?

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Answer 14

Dopamine

Dopamine is derived from dihydroxphenylalanine (dopa), an oxidative product of tyrosine. Tyrosine, in turn, is formed from phenylalanine.

Question 15

Certain amino acids can increase the concentration of blood glucose because their carbon chain can be converted into what?

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Answer 15

Oxaloacetate

The TCA cycle intermediate, oxaloacetate, can be diverted from the TCA cycle to initiate gluconeogenesis.

The carbon atoms of other TCA cycle intermediates that are incorporated into oxaloacetate are also important in gluconeogenesis.

Question 16

What is a proper of acetyl CoA carboxylase (ACC), the rate limiting enzyme for de novo fatty acid synthesis in the body?

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Answer 16

It requires biotin as a cofactor

Carboxylases use biotin as a cofactor, which is formed by the reaction of biotin with the ε-amino group of a lysine residue in the enzyme.

Question 17

B-Oxidation of an odd-chan fatty acid produces several two-carbon and one three-carbon molecules. The latter enters that TCA cycle in the form of which compound?

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Answer 17

Succinyl CoA

β-Oxidation of an odd-chain fatty acid gives several molecules of acetyl CoA and one molecule of propionyl CoA. Propionyl CoA. Isocitrate is also produced from the amino acids threonine, methionine, valine, and isoleucine.

It is converted into succinyl CoA via propionyl CoA carboxylase (biotin- dependent), methylmalonyl CoA racemase, and methylmalonyl CoA mutase (vitamin B12–dependent).

Failure of the latter reaction leads to methylmalonic aciduria, either because of the inability to activate vitamin B12 (which manifests as acidosis and anemia) or because of a defect in the enzyme itself (which manifests as acidosis only).

A defect in propionyl CoA carboxylase leads to propionic acidemia with ketoacidosis and protein intolerance.

Question 18

A professional runner is at the 20 km mark of a marathon. Which enzyme of glycogen metabolism or regulation will be phosphorylated and active in his body at this time?

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Answer 18

Glycogen synthase kinase 3 (GSK-3)

In this metabolic situation, the liver will supply glucose from its glycogen stores into the bloodstream to keep blood glucose levels up against a high muscular demand.

(Note that the depletion of liver glycogen stores, known by runners as “hitting the wall” occurs after ~30km.) Protein kinase A (PKA) will be active as a consequence of high glucagon levels and will phosphorylate phosphorylase kinase into the active form.

This, in turn, switches on glycogen phosphorylase by serine phosphorylation, ensuring the breakdown of glycogen to glucose 1-phosphate. Plasma insulin will be low, and hence also the activity of protein kinase B (PKB).

Thus, GSK-3 will not be phosphorylated, but is subject to dephosphorylation by protein phosphatase 1.

Consequently, GSK-3 will be in the active, unphosphorylated form. It will in turn phosphorylate, and hence inactivate, glycogen synthase.

The high cyclic adenosine monophosphate (cAMP) concentrations in the liver cells will also allosterically activate glucose 6-phosphastase and release glucose from the cell.

Question 19

A 7 year old girl is presented to a pediatric unit for weakness in her upper limbs. She is the first child of a third-degree consanguineous marriage; perinatal and neonatal history was unremarkable. At 5 months of age, she suffered from an infection during which hepatomegaly and a few hypoglycemic seizures were documented. Liver and muscle enzymes were elevated in her serum. Anthropometric measurements (height and weight) are at a fifth percentile. A physical exam reveals the liver 7 cm below the costal margin, as well as mild weakness in the distal muscles with normal tendon reflexes. Liver and muscle biopsies reveal large amounts of glycogen with short outer branches. What enzyme is most likely to be defective?

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Answer 19

Amylo-1,6-glucosidase (deb ranching enzyme)

The debranching enzyme breaks down the 1 → 6 branch points of glycogen. A defective debranching enzyme leads to incomplete removal of the branch points.

This results in cardio- megaly, muscle weakness, fasting hypoglycemia, dyslipidemia, and eventually cardiomyopathy (Cori disease, glycogenolysis, GSD III).

It is managed by ketogenic diet (i.e., high-fat, low-carbohydrate, adequate protein diet) with frequent meals.

Question 20

The product of which of enzyme regenerates the antioxidant required to neutralize reactive oxygen species such as hydrogen peroxide (H2O2) in the red blood cells?

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Answer 20

Glucose 6-phosphate dehydrogenase

The erythrocyte does not have mitochondria; its metabolism is largely limited to glycolysis and the pentose phosphate pathway.

The products of the former are ATP and lactate; the latter produces NADPH plus intermediates of glycolysis (glyceraldehyde 3-phosphate and fructose 6-phos- phate).

NADPH is used to regenerate reduced glutathione (GSH) via the reaction GSSG + NADPH+ H+ ⇌ 2 GSH + NADP+ and protect the erythrocyte from oxidative damage.

A lack of NADPH (e.g., in glucose 6-phosphate dehydrogenase deficiency) leads to Heinz body anemia.

Question 21

A genetic defect in N-acetyl glutamate (NAG) synthase may lead to what?

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Answer 21

Hyperammonemia

Ammonium ion (NH4+) generated from the deamination of glutamate or glutamine is condensed with bicarbonate to generate carbamoyl phosphate in the mitochondria.

This ligation reaction is catalyzed by carbamoyl phosphate synthetase I (CPS-I). CPS-I activity is absolutely dependent on the allosteric activator, N-acetyl glutamate (NAG).

NAG is produced by NAG synthase also located in the mitochondria. A genetic defect in N-acetyl glutamate (NAG) synthase will have the same effect as a defect in CPS-I and lead to hyperammonemia.

Question 22

The coenzyme involved in transamination and many other amino acid transformations is derived from what?

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Answer 22

Pyridoxine

The cofactor for transaminases is pyridoxal phosphate, which is derived from pyridoxine (vitamin B6).

Pyridoxal phosphate is covalently bound to the active site of aminotransferases. The cofactor acts as an intermediate acceptor of the amino group, forming pyridoxamine phosphate.

In the reverse reaction, pyridoxamine phosphate reforms pyridoxal phosphate upon transfer of the amino group to an α-keto acid substrate.

Question 23

In maple syrup urine disease (now called branched-chain aminoaciduria), the defective metabolic step involves what?

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Answer 23

Oxidative decarboxylation

Defective oxidative decarboxylation of the α-keto acids that are produced from the branched-chain amino acids (isoleucine, leucine, and valine) is the cause of maple syrup urine disease.

This defective metabolic step leads to the accumulation of the branched-chain keto acid by-products in blood and urine. The mixture of these ketones in urine has the odor of maple syrup.

The treatment for maple syrup urine disease is to restrict dietary intake of the essential branched-chain amino acids.

A significant challenge of this treatment is to provide sufficient amounts of these amino acids for protein synthesis, while restricting metabolism of the amino acids to prevent accumulation of these amino acids and their α-keto acid byproducts.

Question 24

Which among the following conversion reaction will be defective in patients with B12 deficiency?

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Answer 24

Argininosuccinate to fumarate and arginine

Methylmalonyl CoA is converted to succinyl CoA by methylmalonyl CoA mutase that requires B12 (Cobalamin).

Methylmalonyl CoA is formed in the metabolic pathway of several amino acids, including isoleucine, valine, threonine, and methionine (as well as from the degradation of odd-chain fatty acids).

A deficiency in methylmalonyl CoA mutase results in the metabolic disorder methylmalonic acidemia.

Question 25

An 8 year old girl presents with the following symptoms: onset of osteoporosis, ectopic lentil (lens detachments), and mild mental retardation. The patient was diagnosed with homocystinuria. A treatment regimen was prescribed that included dietary restriction of a particular essential amino acid and dietary supplements of vitamin B12, B6, and folic acid. What amino acid was restricted, and what biosynthetic reaction would be affected by the vitamin supplements?

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Answer 25

Methionine; enhance the conversion of homocysteine to methionine

1Homocystinuria occurs due to a block in the biosynthetic pathway from homocysteine to either cysteine or methionine.

This results in a buildup of excess blood plasma levels of homocysteine, and in homocystinuria.

As methionine is a precursor to homocysteine (through the production and utilization of S-adenosylmethionine), restricting the dietary levels of methionine reduces homocysteine levels.

The B12 supplement enhances the conversion of homocysteine to methionine because this reaction, which uses a folic acid derivative, is catalyzed by homocysteine methyltransferase.

This enzyme requires cobalamin, a vitamin B12–derived cofactor, for its activity. Supplementation with B6 would lower homocysteine by increasing its conversion to cysteine.

It is recommended that dietary restriction of methionine and vitamin supplements be used together in the treatment of homocystinuria.

The levels of the essential amino acid methionine in the diet should be relatively low so that methionine will be used preferentially in protein synthesis, and the vitamin supplements will be useful in prompting the rapid conversion of homocysteine (once it is formed) to methionine and cysteine, to prevent the excess buildup of homocysteine.

Question 26

A 1-year-old girl is brought to a family physician because of concerns about her development. She had an uncomplicated birth in a developing country at term. The mother reports that her daughter is not achieving normal milestones for a baby of her age. She also reports an unusual “mousy” odor of her urine and some hypopigmentation of skin and hair. On exam, the girl shows muscle hypotonia and microcephaly. To the physician’s surprise, a test for phenylalanine hydroxylase activity comes back normal. Her metabolic deficiency might also affect the synthesis of which of the following hormones?

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Answer 26

Serotonin

The patient is suffering from a rare form of phenylketo- nuria (PKU) caused by a deficiency of dihydrobiopterin reduc- tase.

This affects phenylalanine, tyrosine, and tryptophan hydroxylases, and hence the conversion of phenylalanine to tyrosine, tyrosine to dopa, and tryptophan to serotonin.

Question 27

Metabolic adjustment to diabetes mellitus type 1 is similar to that of long-term starvation in that there is a decrease in what?

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Answer 27

Fatty acid synthesis

In diabetes mellitus type 1, fatty acid wasting is seen. Fatty acid synthesis occurs in the fed state, which is signaled by insulin.