Question 1

The waste nitrogen from skeletal amino acid catabolism is diverted to the liver for incorporation into urea in which of the following compounds?
A) alanine
B) asparagine
C) aspartate
D) glutamate
E) phenylalanine

Accepted Answer

Alanine transports nitrogen from muscle to the liver, where it is converted to urea. Alanine transaminase has an important function in the delivery of skeletal muscle carbon and nitrogen (in the form of alanine) to the liver. In skeletal muscle, pyruvate is transaminated to alanine, thus affording an additional route of nitrogen transport from muscle to liver. In the liver, alanine transaminase transfers the ammonia to a-ketoglutarate and regenerates pyruvate. The pyruvate can then be diverted into gluconeogenesis. This process is referred to as the glucose-alanine cycle.

Question 2

When the body becomes acidotic the liver and the kidneys play central roles in reactions designed to reduce the pH of the blood. Which of the following constitutes the primary critical hepatic reaction occurring during periods of acidosis?
A) ammonia incorporation into glutamate forming glutamine
B) ammonia incorporation into a-ketoglutarate forming glutamate
C) glutamine conversion to glutamate releasing ammonia
D) glutamine conversion toa-ketoglutarate releasing ammonia
E) increased production of urea to dispose of ammonia

Accepted Answer

Major reactions that involve the regulation of plasma pH as well as the level of circulating ammonia involve the hepatic and renal enzymes glutamate dehydrogenase (GDH), glutamine synthase (GS), and glutaminase. The liver compartmentalizes GS and glutaminase in order to control the flow of ammonia into glutamine or urea. Under acidotic conditions the liver diverts ammonia to glutamine via the GS reaction. The glutamine then enters the circulation. In fact, glutamine is the major amino acid of the circulation and its role is to ferry ammonia to and from various tissues. In the kidneys, glutamine is hydrolyzed by glutaminase (yielding glutamate) releasing the ammonia to the urine. There the ammonia ionizes to ammonium ion, NH₄⁺, which reduces the circulating concentration of hydrogen ion resulting in an increase in the pH. Additionally, the glutamate can be converted to a-ketoglutarate yielding another mole of ammonia, which is ionized by hydrogen ions further increasing the pH.

Question 3

Glutamate dehydrogenase is an extremely important enzyme involved in nitrogen homeostasis. This enzyme catalyzes a reversible reaction that either incorporates or liberates ammonium ion. When catalyzing the reaction in the direction of ammonium ion liberation, the enzyme is allosterically activated by which of the following?
A) adenosine diphosphate (ADP)
B) adenosine triphosphate (ATP)
C) citrate
D) glutamine
E) guanosine triphosphate (GTP)

Accepted Answer

ADP is an allosteric activator of glutamate dehydrogenase when catalyzing the reaction in the direction of ammonium ion liberation, promoting energy production.  Glutamate dehydrogenase uses both nicotinamide nucleotide cofactors; NAD+ in the direction of nitrogen liberation and NADPH for nitrogen incorporation. The reaction catalyzing the liberation of ammonia and a-ketoglutarate from glutamate is a key anaplerotic process linking amino acid metabolism with TCA cycle activity. This reaction allows glutamate to play an important role in energy metabolism. Glutamate dehydrogenase provides an oxidizable carbon source used for the production of energy as well as a reduced electron carrier, NADH. In the forward reaction, as shown in Figure 29-3, glutamate dehydrogenase is important in converting free ammonia and a-ketoglutarate to glutamate, forming one of the 20 amino acids required for protein synthesis. As expected for a branch point enzyme with an important link to energy metabolism, glutamate dehydrogenase is regulated by the cell energy charge

Question 4

Which of the following represents the major compound of the circulation responsible for transport of nitrogen?
A) alanine
B) asparagine
C) glutamate
D) glutamine
E) uric acid

Accepted Answer

Glutamine is the major carrier of nitrogen in the blood, transporting excess nitrogen from tissues to the liver for excretion.  Glutamine is the major amino acid found in the circulatory system. Its role there is to carry ammonia to and from various tissues but principally from peripheral tissues to the kidney, where the amide nitrogen is hydrolyzed by the enzyme glutaminase; this process regenerates glutamate and free ammonium ion, which is excreted in the urine.

Question 5

Under acidotic conditions the liver will divert which of the following compounds to the kidneys as a means to increase the pH?
A) ammonia
B) asparagine
C) glutamate
D) glutamine
E) urea

Accepted Answer

Under acidotic conditions, the liver converts glutamate to glutamine, which is then transported to the kidneys. In the kidneys, glutamine is deaminated to produce ammonia, which helps to buffer excess hydrogen ions and increase the pH. Major reactions that involve the regulation of plasma pH as well as the level of circulating ammonia involve the hepatic and renal enzymes glutamate dehydrogenase (GDH), glutamine synthase (GS), and glutaminase. The liver compartmentalizes GS and glutaminase in order to control the flow of ammonia into glutamine or urea. Under acidotic conditions the liver diverts ammonia to glutamine via the GS reaction. The glutamine then enters the circulation. In fact, glutamine is the major amino acid of the circulation and its role is to ferry ammonia to and from various tissues. In the kidneys, glutamine is hydrolyzed by glutaminase (yielding glutamate) releasing the ammonia to the urine. There the ammonia ionizes to ammonium ion, NH₄⁺, which reduces the circulating concentration of hydrogen ion resulting in an increase in the pH. Additionally, the glutamate can be converted to a-ketoglutarate yielding another mole of ammonia, which is ionized by hydrogen ions further increasing the pH

Question 6

You are examining a 6-month-old infant who is experiencing feeding difficulty and generalized hypotonia of the limbs. Additional symptoms reported to you by the infant's parents are strange eye movements tending to cause the eyeballs to rotate up that occur several times a day. Laboratory results indicate significant aminoaciduria and aminoacidemia. Which of the following enzymes is most likely defective in the infant?
A) l-amino acid oxidase
B) asparaginase
C) carbamoyl phosphate synthetase I
D) glutamate dehydrogenase
E) glutaminase

Accepted Answer

In the peroxisomes of mammalian tissues, especially liver, there exists a minor enzymatic pathway for the removal of amino groups from amino acids. l-amino acid oxidase is FMN-linked and has broad specificity for the l-amino acids. A number of substances, including oxygen, can act as electron acceptors from the flavoproteins. If oxygen is the acceptor the product is hydrogen peroxide, which is then rapidly degraded by the catalases found in liver and other tissues. Missing or defective l-amino acid oxidase is commonly associated with oculogyric crisis (OGC; spasmodic movements of the eyeballs that lasts several minute to hours) and causes generalized hyperaminoacidemia and hyperaminoaciduria, generally leading to neurotoxicity and early death.

Question 7

A deficiency of argininosuccinate synthetase (ASD) can be suspected in a neonate with elevated serum ammonia. To discriminate the fact that the hyperammonemia is indeed due to ASD and not due to a deficiency in other urea cycle enzymes, one can assay for the serum concentration of citrulline and orotic acid. Which of the following would best describe the expected findings?
A) both citrulline and orotate levels will be low
B) citrulline levels will be absent but orotate will be elevated
C) citrulline levels will be low but orotate levels will be elevated
D) citrulline levels will be 300 times normal, orotate will be near normal

Accepted Answer

In argininosuccinate synthetase deficiency, citrulline accumulates because it cannot be converted to argininosuccinate, leading to elevated citrulline levels. Orotate levels remain near normal because the block is after carbamoyl phosphate, which is the precursor for orotate. A urea cycle disorder (UCD) is likely in a neonate that has elevated serum ammonia appearing, not before, but between 24 and 48 hours after a normal term delivery. There are 3 hallmark symptoms associated with UCD. These are hyperammonemia, encephalopathy, and respiratory alkalosis. Thus, elevated serum ammonia is not, in and of itself, indicative of a specific defect in the urea cycle. An analysis of the levels of various amino and organic acids in the plasma and urine is the primary key to determining which defect led to the elevation in serum ammonia. Differential diagnosis of neonatal hyperammonemia as a consequence of a UCD can be accomplished by measurement of plasma citrulline and urinary orotic acid levels. Shown in Figure 29-9 is the standard differential diagnosis chart for determining which of the 4 possible neonatal UCDs are the causes of the hyperammonemia. First, the hyperammonemia appears in the absence of any significant acidosis or ketosis. If analysis of serum citrulline demonstrates that it is >1000 _mM, it is confirmed that the clinical symptoms are due to a deficiency in argininosuccinate synthetase. In this circumstance, it is not necessary to assay for levels of urinary orotic acid, but they would be expected to be normal.

Question 8

A newborn that developed seizures 2 days after birth was diagnosed with elevated serum NH4+, glutamate, and alanine. A neonatal urea cycle defect was suspected so a urinalysis was performed to assay for orotic acid and serum assayed for citrulline. The levels of both were found not to be elevated. A defect in which enzyme of the urea cycle would most likely account for the symptoms observed in this infant?
A) arginase
B) argininosuccinate lyase
C) argininosuccinate synthetase
D) carbamoyl phosphate synthetase I (CPS-I)
E) ornithine transcarbamoylase (OTC)

Accepted Answer

The absence of elevated orotic acid and citrulline levels suggests a defect in carbamoyl phosphate synthetase I (CPS-I), as this enzyme deficiency would lead to hyperammonemia without the accumulation of orotic acid or citrulline.  Differential diagnosis of neonatal hyperammonemia, as a consequence of a UCD can be accomplished by measurement of plasma citrulline and urinary orotic acid levels. Refer to Figure 29-9 which shows the standard differential diagnosis chart for determining which of the 4 possible neonatal UCDs are the causes of the hyperammonemia. First, the hyperammonemia appears in the absence of any significant acidosis or ketosis. If analysis of serum cuitrulline demonstrates undetectable levels, then deficiencies in argininosuccinate lyase and argininosuccinate synthetase can be eliminated as causes of the symptoms. Assay for levels of urinary orotic acid will allow a discrimination between carbamoyl phosphate synthetase I and ornithine transcarbamoylase deficiencies. Since the levels of orotic acid were found to be insignificant, the symptoms must be due to deficiency in carbamoyl phosphate synthetase I.

Question 9

A 2-day-old infant is brought to the ER suffering a seizure. Analysis of serum NH4+ reveals it to be quite high. Suspecting a urea cycle impairment the ER physician initiates hemodialysis which reduces the NH₄⁺ levels. Subsequent to the hemodialysis the infant is treated with supplemental arginine which maintains the reduction in serum NH₄⁺. The ability of arginine to render this effect stems from it's role in activating the synthesis of an activator of one of the enzymes of the urea cycle. Which of the following represents this potent activator whose synthesis is induced by arginine? A) argininosuccinate B) bicarbonate ion C) fumarate D) N-acetylcysteine E) N-acetylglutamate

Accepted Answer

Arginine stimulates the synthesis of N-acetylglutamate, which is an essential activator of carbamoyl phosphate synthetase I, the first enzyme in the urea cycle.

Question 10

A child was born at home and developed seizures 2 days after birth. Upon examination in the ER it was found that the infant had elevated serum NH₄⁺, glutamate, and alanine. The ER physician suspected that the child was suffering from a defect in the urea cycle and ordered a urinalysis to assess the level of orotic acid and the serum was assayed for the level of citrulline. Orotic acid levels were above normal and citrulline was barely detectable. A defect in which enzyme of the urea cycle would most likely account for the symptoms observed in this infant? A) arginase B) argininosuccinate lyase C) argininosuccinate synthetase D) carbamoyl phosphate synthetase I (CPS-I) E) ornithine transcarbamoylase (OTC)

Accepted Answer

The elevated orotic acid and low citrulline levels suggest a defect in ornithine transcarbamoylase (OTC), which leads to accumulation of carbamoyl phosphate that is converted to orotic acid.

Question 11

An individual harboring a mutation in OTC would be expected to exhibit which of the following measurable abnormalities?
A) citrullinemia
B) elevated urinary excretion of argininosuccinic acid
C) elevation in blood orotic acid
D) excess production of foam cells
E) uric acid deposition in the joints

Accepted Answer

A mutation in the OTC (ornithine transcarbamylase) gene leads to an accumulation of carbamoyl phosphate, which is then converted to orotic acid, resulting in elevated blood orotic acid levels.  A deficiency in OTC results in one of the urea cycle defect diseases, which are the major causes of hyperammonemia in the newborn. Differentiation of which urea cycle enzyme is defective and causing the hyperammonemia can be accomplished by analysis of the levels of the various intermediates in the cycle (see Figure 29-9). Since a defect in OTC prevents incorporation of carbamoyl phosphate into ornithine, the carbamoylphosphate will leave the mitochondria and serve as a precursor for the synthesis of the pyrimidine nucleotides in excess of the need, leading to an elevation of orotic acid (pyrimidine intermediate) in the blood.

Question 12

A 2-day-old infant boy delivered by normal labor (with no known prenatal risk factors) has become lethargic and requires stimulation for feeding. When vomiting and hyperventilation ensued, routine laboratory results showed blood urea nitrogen (BUN) less than 1 mg/dL. The infant quickly lapses into a coma and was placed on a ventilator. Bulging of the fontanel suggested an intracranial hemorrhage, but a CT scan revealed only cerebral edema. Within several hours, the infant dies. Death is ascribed to sepsis; however, a postmortem analysis of the plasma samples taken at admission showed dramatically elevated serum ammonia and citrulline levels 100 times normal. Which of the following represents the enzyme deficiency associated with these severe neonatal symptoms?
A) argininosuccinate synthetase
B) carbamoylphosphate synthetase I
C) 3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase
D) medium-chain acyl-CoA dehydrogenase
E) pyruvate carboxylase

Accepted Answer

The symptoms and elevated serum ammonia and citrulline levels suggest a urea cycle disorder, specifically a deficiency in argininosuccinate synthetase, which leads to citrullinemia. The clinical presentation of patients with defects in several enzymes of urea synthesis is virtually identical. These enzymes are CPS-I, ornithine transcarbamoylase (OTC), argininosuccinate synthetase (AS), and argininosuccinase. The hallmark of these urea cycle enzyme defects is a normal birth with no known prenatal risk factors. Within 24-72 hours after birth the infant becomes lethargic and requires stimulation for feeding. Additional symptoms develop within hours, including vomiting, increased lethargy, hypothermia, and hyperventilation. The hyperventilation is often misdiagnosed as pulmonary disease. Sepsis is often suspected. Routine blood work indicates a reduced BUN. Lack of proper intervention will lead to coma and death. Correct analysis of hyperammonemia is paramount to proper treatment as this is indicative of a urea cycle defect when presenting in the newborn. Analysis of plasma amino acids can aid in the differentiation of which enzyme is defective. Elevated citrulline (to 100 times normal levels) results from a deficiency in AS.

Question 13

Neonatal urea cycle defects are usually misdiagnosed because of a failure to assess which of the following?
A) level of ammonia in the blood
B) level of argininosuccinate in the blood
C) level of citrulline in the blood
D) level of orotic acid in the urine
E) odor of acetone on the breath

Accepted Answer

Neonatal urea cycle defects often lead to hyperammonemia, so measuring the level of ammonia in the blood is crucial for diagnosis.  Seemingly normal full-term infants suffering from urea cycle defects will usually become lethargic and need stimulation to feed within 24-72 hours after birth. When presented in the emergency many will be comatose. One obvious outward clinical sign will be a bulging fontanel due to the ammonia-induced encephalopathy. If a correct diagnosis of hyperammonemia is not made in a timely manner these infants will die.

Question 14

Which of the following would most likely be associated with a negative nitrogen balance?
A) consuming a high-protein diet
B) neonatal development
C) post-starvation feeding
D) pregnancy
E) surgical recovery

Accepted Answer

Unlike fats and carbohydrates, nitrogen has no designated storage depots in the body. Since the half-life of many proteins is short (on the order of hours), increased dietary intake of protein will result in an concomitant increase in amino acid degradation resulting in increased nitrogen excretion. When more nitrogen is excreted than is incorporated into the body, an individual is in negative nitrogen balance. Normal, healthy adults are generally in nitrogen balance, with intake and excretion being very well matched. Young growing children, adults recovering from major illness, and pregnant women are often in positive nitrogen balance. Their intake of nitrogen exceeds their loss as net protein synthesis proceeds.

Question 15

An unconscious 37-year-old man is brought to the ER. His wife reports that they were at home having dinner celebrating his birthday. She indicates that normally he does not drink but they were having champagne for the celebration. She indicates that shortly after they finished the bottle he became disorientated and irritable and then he began experiencing delusions. When he began to have a seizure she called 911. By the time the ambulance arrived he was unconscious. Blood tests taken when he was admitted show significantly elevated serum ammonia. A deficiency in which of the following enzymes is most likely the cause of this patients symptoms?
A) alanine transaminase
B) asparaginase
C) citrin
D) glutamate dehydrogenase
E) glutaminase

Accepted Answer

A deficiency in citrin, which is involved in the urea cycle, can lead to elevated ammonia levels, causing symptoms like disorientation, irritability, delusions, and seizures.  Citrullinemia type II (CTLN2) is caused by deficiency in the gene encoding the mitochondria transporter citrin (SLC25A13). Manifestations of CTLN2 are recurrent hyperammonemia with neuropsychiatric symptoms including nocturnal delirium, aggression, irritability, hyperactivity, delusions, disorientation, restlessness, drowsiness, loss of memory, flapping tremor, convulsive seizures, and coma. The symptoms of CTLN2 are often provoked by alcohol and sugar intake, as well as by certain medications, and/or surgery.

Question 16

A child was born at home and developed seizures 2 days after birth. Upon examination in the ER it was found that the infant had elevated serum NH₄⁺, glutamate, and alanine. The ER physician suspected that the child was suffering from a defect in the urea cycle. Which of the following is the most appropriate course of action to take with this patient? A) administer arginine via IV B) administer glucose via IV C) change the infants formula to one with no protein D) give the infant fluids and continue to monitor symptoms E) immediate hemodialysis

Accepted Answer

The answer of A child was born at home and...

Question 17

Which of the following vitamins is critically important in the overall process of nitrogen transfer from a-amino acids to a-keto acids? A) riboflavin B) thiamine C) vitamin B₆ D) vitamin B₁₂ E) vitamin C

Accepted Answer

Vitamin B₆ is critically important in the overall process of nitrogen transfer from a-amino acids to a-keto acids. It is a coenzyme for a number of enzymes involved in amino acid metabolism, including transaminases, which catalyze the transfer of amino groups from one amino acid to another.

Question 18

Under which of the following conditions would you most likely expect the glutamate dehydrogenase reaction to proceed in the direction of glutamate synthesis?
A) high ATP:ADP ratio
B) high NADH levels
C) high NADPH levels
D) low NADH levels
E) low NADPH levels

Accepted Answer

Glutamate dehydrogenase utilizes both nicotinamide nucleotide cofactors; NAD+ in the direction of nitrogen liberation and NADP+ for nitrogen incorporation. In the forward reaction (as shown in Figure 29-3) glutamate dehydrogenase is important in converting free ammonia and a-ketoglutarate to glutamate. The reverse reaction is a key anapleurotic process linking amino acid metabolism with TCA cycle activity. In the reverse reaction, glutamate dehydrogenase provides an oxidizable carbon source used for the production of energy as well as a reduced electron carrier, NADH. As expected for a branch point enzyme with an important link to energy metabolism, glutamate dehydrogenase is regulated by the cell energy charge. ATP and GTP are positive allosteric effectors of the formation of glutamate, whereas ADP and GDP are positive allosteric effectors of the reverse reaction. Thus, when the level of ATP is high, conversion of glutamate to a-ketoglutarate and other TCA cycle intermediates is limited; when the cellular energy charge is low, glutamate is converted to ammonia and oxidizable TCA cycle intermediates.

Question 19

The most abundant end product of nitrogen metabolism in humans is which of the following?
A) allantoin
B) ammonium ion
C) glutamine
D) urea
E) uric acid

Accepted Answer

Glutamate plays the central role in mammalian nitrogen flow, serving as both a nitrogen donor and nitrogen acceptor. Glutamine is the nitrogen repository found in the circulatory system. Its role there is to carry ammonia to and from various tissues but principally from peripheral tissues to the kidney. In the kidneys, glutamine is hydrolyzed by glutaminase (yielding glutamate) releasing the ammonia to the urine. Additionally, the glutamate can be converted to a-ketoglutarate yielding another mole of ammonia which is excreted.

Question 20

Which of the following ketoacids provides the carbon skeleton for an amino acid capable of carrying 2 atoms of nitrogen per molecule from other tissues to the liver and kidney via the blood?
A) acetoacetate
B) a-ketoglutarate
C) a-ketoisocaproic acid
D) oxaloacetate
E) pyruvate

Accepted Answer

Alpha-ketoglutarate is the ketoacid that provides the carbon skeleton for glutamate, which can be converted to glutamine. Glutamine carries two nitrogen atoms and transports them from peripheral tissues to the liver and kidneys.  α-Ketoglutarate is capable of accepting 2 moles of ammonia, first via the action of glutamate dehydrogenase yielding glutamate and then via glutamine synthetase yielding glutamaine. Glutamate plays the central role in mammalian nitrogen flow, serving as both a nitrogen donor and nitrogen acceptor. Glutamine is the nitrogen repository found in the circulatory system. Its role there is to carry ammonia to and from various tissues but principally from peripheral tissues to the kidney.

Quiz 29: Nitrogen: Nitrogen Homeostasis and Disposal Via Urea

The waste nitrogen from skeletal amino acid catabolism is diverted to the liver for incorporation into urea in which of the following compounds?

When the body becomes acidotic the liver and the kidneys play central roles in reactions designed to reduce the pH of the blood. Which of the following constitutes the primary critical hepatic reaction occurring during periods of acidosis?

Which of the following represents the major compound of the circulation responsible for transport of nitrogen?

Under acidotic conditions the liver will divert which of the following compounds to the kidneys as a means to increase the pH?

An individual harboring a mutation in OTC would be expected to exhibit which of the following measurable abnormalities?

Neonatal urea cycle defects are usually misdiagnosed because of a failure to assess which of the following?

Which of the following would most likely be associated with a negative nitrogen balance?

Which of the following vitamins is critically important in the overall process of nitrogen transfer from a-amino acids to a-keto acids?

Under which of the following conditions would you most likely expect the glutamate dehydrogenase reaction to proceed in the direction of glutamate synthesis?

The most abundant end product of nitrogen metabolism in humans is which of the following?

Which of the following ketoacids provides the carbon skeleton for an amino acid capable of carrying 2 atoms of nitrogen per molecule from other tissues to the liver and kidney via the blood?