Disposal of Amino Acid Nitrogen: the Urea Cycle

Question 1

In the fed state, amino acids are absorbed and transfered via the ____ to the ____

Answer 1

In the fed state, amino acids are absorbed and transfered via the portal vein to the liver

Question 2

In the liver, nitrogen from many excess amino acids is converted into water soluble non-toxic ____ to be excreted

Answer 2

In the liver, nitrogen from many excess amino acids is converted into water soluble non-toxic urea to be excreted

Question 3

Significant amounts of ammonia released via intestinal bacteria travel to the liver via the portal vein and are converted to either ____ or ____

Answer 3

Significant amounts of ammonia released via intestinal bacteria travel to the liver via the portal vein and are converted to either urea or glutamate

Question 4

Carbon skeletons from excess amino acids may be used for ____ or ____ synthesis, or converted to ____

Answer 4

Carbon skeletons from excess amino acids may be used for fatty acid or TAG synthesis, or converted to glucose

Question 5

Low ____ in the fasting state causes breakdown and release of amino acids which go to the liver to be used to make ____, ____, and ____

Answer 5

Low insulin in the fasting state causes breakdown and release of amino acids which go to the liver to be used to make ketones, glucose, and urea

Question 6

Excretion of nitrogen in the form of urea in the fed and fasting state

Answer 6

Question 7

The first step in amino acid catabolism is the removal of the ____ and this poses a serious biochemical problem because ____ is toxic

Answer 7

The first step in amino acid catabolism is the removal of the amino group and this poses a serious biochemical problem because ammonia is toxic

Question 8

The ____ and other neural tissues are particularly sensitive to ammonia. Damage from excess ammonia can cause (4 examples)

Answer 8

The brain and other neural tissues are particularly sensitive to ammonia. Damage from excess ammonia can cause:

• Ataxia
• Epileptic seizures
• Cognitive impairment
• Brain swelling that may lead to coma and death

Question 9

In the blood, about ____% of ammonia is in the protonated form (NH₄+) which cannot diffuse across memranes.

The small amount of uncharged NH₃ can diffuse across membranes, including the blood-brain barrier, allowing it to enter cells, where much of it becomes protonated and can accumulate inside cells as NH₄+

Answer 9

In the blood, about 99% of ammonia is in the protonated form (NH₄+) which cannot diffuse across memranes.

The small amount of uncharged NH₃ can diffuse across membranes, including the blood-brain barrier, allowing it to enter cells, where much of it becomes protonated and can accumulate inside cells as NH₄+

Question 10

Nitrogen from amino acids can be converted to ____ (which is toxic) and ____, which can then both enter the urea cycle and be converted into ____ (which is non-toxic)

Answer 10

Nitrogen from amino acids can be converted to ammonia (which is toxic) and aspartate, which can then both enter the urea cycle and be converted into urea (which is non-toxic)

Question 11

____ catalyze the transfer of the amino group from an amino acid to an a-keto acid, forming a new amino acid and the a-keto acid corresponding to the donor amino acid

Answer 11

Transaminases catalyze the transfer of the amino group from an amino acid to an a-keto acid, forming a new amino acid and the a-keto acid corresponding to the donor amino acid

Question 12

ALT (Alanine Aminotransferase) catalyzes the conversion between ____ and ____

This reaction also catalyzes the conversion between ____ and ____

This reaction requires the coenzyme ____

Answer 12

ALT (Alanine Aminotransferase) catalyzes the conversion between Alanine and Pyruvate

This reaction also catalyzes the conversion between a-Ketogluturate and Glutamate

This reaction requires the coenzyme PLP (Pyridoxal Phosphate)

Question 13

AST (Aspertate Aminotransferase) catalyzes the conversion between ____ and ____

This reaction also catalyzes the conversion between ____ and ____

This reaction requires the coenzyme ____

Answer 13

AST (Aspertate Aminotransferase) catalyzes the conversion between Aspartate and Oxaloacetate

This reaction also catalyzes the conversion between a-Ketogluterate and Glutamate

This reaction requires the coenzyme PLP (Pyridoxal Phosphate)

Question 14

PLP (Pyridoxal Phosphate) is derived from ____

Answer 14

PLP (Pyridoxal Phosphate) is derived from Vitamin B6 (Pyroxidine)

Question 15

All amino acids except ____ and ____ have the ability to undergo transamination reactions

Answer 15

All amino acids except lysine and threonine have the ability to undergo transamination reactions

Question 16

What are the three categories of liver injury?

Answer 16

• Hepatocellular: primary injury is to the hepatocytes
• Cholestatic: primary injury is to the bile ducts
• Infiltrative: includes sarcoidosis, other types of granulomatous diseases, or unsuspected metastasis of cancer to the liver

Question 17

Blood levels of ____ and ____ are two very useful measures of possible liver cell injury

Answer 17

Blood levels of ALT and AST are two very useful measures of possible liver cell injury

Note: AST is less liver specific than ALT, as elevated AST may also be seen in acute injury to cardiac or skeletal muscle

Question 18

Diseases that primarily affect hepatocytes, such as Alcoholic Liver Disease, Viral Hepatitis (A,B,C), Fatty Liver, and some Metabolic Liver Diseases (e.g. MCAD deficiency and some glycogen storage diseases), will cause elevations in the blood ____ and ____

Answer 18

Diseases that primarily affect hepatocytes, such as Alcoholic Liver Disease, Viral Hepatitis (A,B,C), Fatty Liver, and some Metabolic Liver Diseases (e.g. MCAD deficiency and some glycogen storage diseases), will cause elevations in the blood AST and ALT

Question 19

How is ALT measured?

Answer 19

Question 20

Glutamate is NOT an ____ amino acids, as it can be formed from a-ketogluterate removed from the TCA cycle

The Glutamate Dehydrogenase (GDH) reversible reaction occurs in the ____ of most cells and releases ____ from glutamate, which can then enter the urea cycle

Answer 20

Glutamate is NOT an essential amino acids, as it can be formed from a-ketogluterate removed from the TCA cycle

The Glutamate Dehydrogenase (GDH) reversible reaction occurs in the mitochondria of most cells and releases ammonia from glutamate, which can then enter the urea cycle

Question 21

____ is the key player in transferring nitrogen to the urea cycle

Answer 21

Glutamate is the key player in transferring nitrogen to the urea cycle

Question 22

Because ammonia is toxic (particularly to neural tissues) the formation of ____ from glutamate and NH₄+ by ____ provides a means of removing ammonia in the brain and other tissues

____ catalyzes the reverse reaction in which ammonia is releases from ____. This reaction is inhibited by high [ammonia]

Answer 22

Because ammonia is toxic (particularly to neural tissues) the formation of glutamine from glutamate and NH₄+ by glutamine synthetase provides a means of removing ammonia in the brain and other tissues

Glutaminase catalyzes the reverse reaction in which ammonia is releases from glutamine. This reaction is inhibited by high [ammonia]

Question 23

Glutamine in the blood serves many important metabolic functions (3 examples)

Answer 23

Glutamine in the blood serves many important functions:

• Protein synthesis
• Ammoniagenesis for proton excretion
• Nitrogen donor for synthesis of:
  
  • Purines/Pyrimidines
  • NAD+
  • Amino Sugars
  • Asparagine
  • And many other compounds

Question 24

____ such as epinephrine and norepinephrine can be converted to ammonia via ____

Answer 24

Catecholamines such as epinephrine and norepinephrine can be converted to ammonia via MAD (Mono Amine Oxidase)

Question 25

The net effect of the Purine Nucleotide Cycle is the deamination of ____ to ____, which can feed into and replenish the TCA cycle in the muscles and brain

Answer 25

The net effect of the Purine Nucleotide Cycle is the deamination of aspartate to fumarate, which can feed into and replenish the TCA cycle in the muscles and brain

Question 26

The complete set of urea cycle reactions occurs exclusively in the ____

Answer 26

The complete set of urea cycle reactions occurs exclusively in the liver

Question 27

The urea cycle contains 5 reactions. The first 2 reactions occur in the ____ and the last 3 occur in the ____

Answer 27

The urea cycle contains 5 reactions. The first 2 reactions occur in the mitochondria and the last 3 occur in the cytoplasm

Question 28

1st reaction of the urea cycle

Involves the combination of ____ and ____ to form ____

Catalyzed by the enzyme ____

Answer 28

1st reaction of the urea cycle

Involves the combination of bicarbonate ion (HCO3-) and ammonia (NH4+) to form carbamoyl phosphate

Catalyzed by the enzyme Carbamoyl phosphate synthetase I (CPSI)

Question 29

2nd reaction of the urea cycle

Carbamoyl phosphate is covterted to ____

During this reaction ____ is also converted into ____

This reaction is catalyzed by ____

Answer 29

2nd reaction of the urea cycle

Carbamoyl phosphate is covterted to Pi

During this reaction ornithine is also converted into citrulline

This reaction is catalyzed by Ornithine transcarbamoylase (OTC)

Question 30

3rd reaction of the urea cycle

Citrulline is combined with ____ to form ____

This reaction is catalyzed by ____

Answer 30

3rd reaction of the urea cycle

Citrulline is combined with aspartate to form arginosuccinate

This reaction is catalyzed by Arginosuccinate synthetase (ASS)

Question 31

4th reaction of the urea cycle

Arginosuccinate is converted into ____ and ____

This reaction is catalyzed by ____

Answer 31

4th reaction of the urea cycle

Arginosuccinate is converted into arginine and fumarate

This reaction is catalyzed by Arginosuccinate lyase (ASL)

Question 32

5th reaction of the urea cycle

Arginine is converted into ____ and ____

This reaction is catalyzed by ____

Answer 32

5th reaction of the urea cycle

Arginine is converted into urea and ornithine

This reaction is catalyzed by Arginase (Arg1)

Note: urea can then be exreted in the urine and ornithine can be transported into the mitochondria for reaction 2 of the urea cycle

Question 33

Arginine is synthesized from ____ via the urea cycle

Although adults synthesize sufficient arginine, the amount is not enough to support growth; thus, arginine is ____

Answer 33

Arginine is synthesized from glutamate via the urea cycle

Although adults synthesize sufficient arginine, the amount is not enough to support growth; thus, arginine is conditionally essential

Question 34

The Krebs Bi-Cycle

Reaction 4 of the urea cycle produces ____ which can be fed into the TCA cycle which involves production of ____ which can be converted via AST to aspartate which can then feed back into the urea cycle at reaction 3

Answer 34

The Krebs Bi-Cycle

Reaction 4 of the urea cycle produces fumarate which can be fed into the TCA cycle which involves production of oxaloacetate which can be converted via AST to aspartate which can then feed back into the urea cycle at reaction 3

Question 35

The genes for all 5 urea cycle enzymes are transcribed at higher rates during the ____ state

Answer 35

The genes for all 5 urea cycle enzymes are transcribed at higher rates during the fasting state

Question 36

The urea cycle is regulated in a ____ mannor, such that when amino acid degradation is occuring, the rate of the cycle is ____

Arginine stimulates ____, which produces ____, which stimulates ____

Answer 36

The urea cycle is regulated in a feed-foward mannor, such that when amino acid degradation is occuring, the rate of the cycle is increased

Arginine stimulates NAGS (N-acetylglutamate synthase), which produces NAG (N-acetylglutamate), which stimulates CPSI (Carbamoyl phosphate synthetase)

Question 37

Severe deficiencies of CPSI, OTC, ASS, or ASL in the urea cycle (reactions 1-4), or the cofactor producer NAGS, results in ____ 1-3 days following birth

Patient with partial deficiencies may present later in life when a ____ event occurs (infection, illness, stress)

The ____ is much more susceptible to the deleterious effects of prolonged ____ in childhood than in adults

Answer 37

Severe deficiencies of CPSI, OTC, ASS, or ASL in the urea cycle (reactions 1-4), or the cofactor producer NAGS, results in hyperammonemia 1-3 days following birth

Patient with partial deficiencies may present later in life when a triggering event occurs (infection, illness, stress)

The brain is much more susceptible to the deleterious effects of prolonged hyperammonemia in childhood than in adults

Question 38

Common presentation of hyperammonemia shows increased blood ____ and decreased blood ____

Mild hyperammonemia symptoms include (5 examples)

Severe hyperammonemia symptoms include (4 examples)

Answer 38

Common presentation of hyperammonemia shows increased blood glutamine and decreased blood urea nitrogen (BUN)

Mild hyperammonemia symptoms include: agitation, headache, vomiting, lethargy, confusion

Severe hyperammonemia symptoms include: seizures, ataxia, encephalopathy, coma

Question 39

Hyperammonemia with moderate citrulline concentrations and plasma arginosuccinate would indicate a ____ deficiency

Answer 39

Hyperammonemia with moderate citrulline concentrations and plasma arginosuccinate would indicate a ASL deficiency

Question 40

Hyperammonemia with high citruline concentrations would indicate a ____ or ____ deficiency

Answer 40

Hyperammonemia with high citruline concentrations would indicate a ASS or CTLN2 deficiency

Question 41

Hyperammonemia with absent/low blood citrulline and absent/low urine orotic acid indicates a ____ or ____ deficiency

Answer 41

Hyperammonemia with absent/low blood citrulline and absent/low urine orotic acid indicates a CPSI or NAGS deficiency

Question 42

Hyperammonemia with absent/low blood citrulline and high urine orotoic acid indicates a ____ deficiency

When ____ is deficient, carbamoyl phosphate accumulates and enters the pyrimidine synthesis pathway which creates orotic acid which is excreted in the urine

Answer 42

Hyperammonemia with absent/low blood citrulline and high urine orotoic acid indicates a OTC deficiency

When OTC is deficient, carbamoyl phosphate accumulates and enters the pyrimidine synthesis pathway which creates orotic acid which is excreted in the urine

Question 43

Treatment of neonates with possible urea cycle disorders should not be delayed in order to avoid ____

The rapid removal of ____ should be the immediate therapeutic goal in neonatal hyperammonemia

In cases of severe hyperammonemia, ____ should be started promtly for hyperammonemia which does not correct rapidly

IV ____ is essential to reverse/prevent catabolsim (along with careful use of ____)

Answer 43

Treatment of neonates with possible urea cycle disorders should not be delayed in order to avoid permanent brain damage!

The rapid removal of NH4+ should be the immediate therapeutic goal in neonatal hyperammonemia

In cases of severe hyperammonemia, hemodialysis should be started promtly for hyperammonemia which does not correct rapidly

IV glucose is essential to reverse/prevent catabolsim (along with careful use of insuline)

Note: Can treat while waiting for molecular genetic or screen tests results to reach a final diagnosis

Question 44

____ transplantation is the only known cure for severe urea cycle disorders and is best performed between age three months and one year to decrease neurological complications and improve survival

Answer 44

Liver transplantation is the only known cure for severe urea cycle disorders and is best performed between age three months and one year to decrease neurological complications and improve survival

Question 45

____ restriction is the cornerstone of urea cycle disorder therapy

Answer 45

Protein restriction is the cornerstone of urea cycle disorder therapy

Question 46

Large doses of ____ are given for arginosuccinate synthetase (ASS) and arginosuccinatelyase (ASL) deficiencies

Answer 46

Large doses of arginine (Arg) are given for arginosuccinate synthetase (ASS) and arginosuccinatelyase (ASL) deficiencies

Question 47

Large doses of ____ are given for carbamylphosphate synthetase I (CPSI) and OTC deficiencies

Answer 47

Large doses of citrulline are given for carbamylphosphate synthetase I (CPSI) and OTC deficiencies

Question 48

NAGS deficiency is effectively treated with a compound that mimics N-acetylglutamte (NAG) called ____, as well as administration of IV ____ and/or ____ as nitrogen scavenging drugs

Answer 48

NAGS deficiency is effectively treated with a compound that mimics N-acetylglutamte (NAG) called N-carbamylglutamate, as well as administration of IV sodium benzoate and/or phenylacetate that allow for an alternative pathway to the urea cycle for excess nitrogen to be excreted

Question 49

Hyperammonemia leads to brain ____ in part due to an ____ imbalance caused by high levels of both ammonia and glutamine in astrocytes

Answer 49

Hyperammonemia leads to brain swelling (cerebral edema) in part due to an osmotic imbalance caused by high levels of both ammonia and glutamine in astrocytes

Question 50

Hyperammonemia rapidly lowers ____ levels by increasing glutamine levels via the glutamine synthetase reaction

Answer 50

Hyperammonemia rapidly lowers glutamate levels by increasing glutamine levels via the glutamine synthetase reaction

Question 51

Glutamate is a ____ neurotransmitter. In hyperammonemia glutamatergic neurotransmission is impaired, leading to lethargy and reduced nervous system activity

Answer 51

Glutamate is a excitatory neurotransmitter. In hyperammonemia glutamatergic neurotransmission is impaired, leading to lethargy and reduced nervous system activity

Question 52

Hyperammonemia depletes ____ from the TCA cycle by increasing glutamate and glutamine synthesis (by glutamate dehydrogenase and glutamine synthetase respectively), depreving the ____ of enegry

Answer 52

Hyperammonemia depletes a-ketogluterate from the TCA cycle by increasing glutamate and glutamine synthesis (by glutamate dehydrogenase and glutamine synthetase respectively), depreving the brain of enegry

Question 53

Primary hyperammonemia is due to _____ or ____ defects in the ____

Answer 53

Primary hyperammonemia is due to enzyme or transporter defects in the urea cycle

Example deficiencies:

• Urea cycle enzyme deficiencies
• NAGS deficiencies
• Transporter deficiencies (ORNT1, CTLN2)

Question 54

Secondary hyperammonemia occurs when the function of the urea cycle is inhibited by ________ or ________

Answer 54

Secondary hyperammonemia occurs when the function of the urea cycle is inhibited by toxic metabolites or substrate deficiencies

Question 55

Acquired hyperammonemia (3 main examples)

Answer 55

Acquired hyperammonemia example causes:

• Acute or chronic liver failure
• Urease-producing organisms
• L-asparaginase drugs or other chemotherpeutic agents
• Total parenteral nutrition (TPN) with relative arginine deficiency
• Valproic acid treatment
• Portosynstemic shunting

Question 56

Nitrogen from amino acid catabolism travels in the blood mainly as alanine and glutamine. Glutamine aids in the excretion of ____ by the kidneys and alanine is used by the liver for ____

Answer 56

Nitrogen from amino acid catabolism travels in the blood mainly as alanine and glutamine. Glutamine aids in the excretion of metabolic acids by the kidneys and alanine is used by the liver for gluconeogenesis

Question 57

Excess nitrogen is converted into ____ in the liver. ____ then travels to the kidneys and exits the body in the urine.

Answer 57

Excess nitrogen is converted into non-toxic urea in the liver. Urea then travels to the kidneys and exits the body in the urine.

Question 58

Fatty acid oxidation defects may result in ____ hyperammonemia

Answer 58

Fatty acid oxidation defects may result in secondary hyperammonemia

Question 59

LCAD and MCAD deficiencies cause a lack of ____ and decrease production of N-acetylglutmate which is absolutely required as a positive alosteric activator of ____

Long chain fatty ____ (specifically ____), which accumulates in LCAD deficiency, may cause fatty acylation of an active site of cysteine residue of ____ which inhibits its activity

Answer 59

LCAD and MCAD deficiencies cause a lack of Acyl-CoAs and decrease production of N-acetylglutmate which is absolutely required as a positive alosteric activator of CPSI (carbamoyl phosphate synthetase)

Long chain fatty acyl-CoAs (specifically palmitoyl-CoA), which accumulates in LCAD deficiency, may cause fatty acylation of an active site of cysteine residue of CPS1 which inhibits its activity

Question 60

Carnitine cycle defects may result in ____ hyperammonemia caused by a lack of ____

Answer 60

Carnitine cycle defects may result in secondary hyperammonemia caused by a lack of acetyl-CoA

Question 61

Carnitine is an essential co-factor in the metabolsim of ________ and is required as the carrier that transports activated ________ across the inner mitochondrial membrane

Answer 61

Carnitine is an essential co-factor in the metabolsim of long-chain fatty acids and is required as the carrier that transports activated long-chain fatty acyl groups across the inner mitochondrial membrane

Question 62

Both Carnitine Palmitoyltransferase II (CPT II) and Carnitine-Acylcarnitine Translocase (CACT) deficiencies may cause a lack of mitochondrial ____, inhibiting NAG production reduced activity of ____, leading to secondary hyperammonemia

Answer 62

Both Carnitine Palmitoyltransferase II (CPT II) and Carnitine-Acylcarnitine Translocase (CACT) deficiencies may cause a lack of mitochondrial acetyl-CoA, inhibiting NAG production reduced activity of CPS1 leading to secondary hyperammonemia

Question 63

Secondary hyperammonemia can also be caused by ____, ____, and ____ acidurias

Answer 63

Secondary hyperammonemia can also be caused by methylmalonic, proprionic, and isolvaleric acidurias

Question 64

____ is a metabolically stable analogue of N-acetylglutamate (NAG) and is used to treat neonate hyperammonemia caused by NAG synthase deficiency

Answer 64

N-carbamylglutamate (NCG) is a metabolically stable analogue of N-acetylglutamate (NAG) and is used to treat neonate hyperammonemia caused by NAG synthase deficiency

Question 65

________ deficiency inhibits the urea cycle by limiting aspartate, causing secondary hyperammonemia

Answer 65

Pyruvate carboxylase deficiency inhibits the urea cycle by limiting aspartate, causing secondary hyperammonemia

Question 66

____ and ____ are the two sources of nitrogen in the urea cycle

Answer 66

Ammonia and Aspartate are the two sources of nitrogen in the urea cycle