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Tissues > T07 - Amino Acid Metabolism > Flashcards

T07 - Amino Acid Metabolism Flashcards

1
Q

Broadly speaking, what happens to amino groups in amino acid degradation?

A

amino groups (-NH2) either:

converted to ammonia

removed via urea cycle

used to make new AAs

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2
Q

Removal of an amino group from an amino acid leaves behind

A

a carbon skeleton, usually in the form of a 2-ketoacid

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3
Q

What are the three major fates of amino acids?

A

storage in protein

conversion to other biomolecules

degradation to produce energy

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4
Q

What is the major mechanism associated with metabolism of AAs?

A

transamination

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5
Q

What is a transamination reaction?

A

transaminase transfers amino group from donor AA to acceptor 2-keto acid

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6
Q

Write out an example of a transamination reaction. Identify the amino donors and acceptors.

A

alanine donates its amino group to become pyruvate

2-ketoglutarate accepts the amino group to become glutamate

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7
Q

Why are plasma transaminase levels used as a marker for liver disease?

A

transaminases are abundant in liver/muscle

destruction of liver/muscle releases transaminases into blood

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8
Q

What is the cofactor in transamination reactions?

A

pyridoxal phosphate (activated vitamin B6)

[same as decarboxylation and deamination]

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9
Q

List the three most common transamination reactions. Identify the substrate and resulting amino acid, along with the enzyme that mediates the reaction.

A
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10
Q

What are the three most common reactions associated with AA metabolism?

A

transamination reactions

decarboxylation reactions

deamination reactions

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11
Q

The decarboxylation of glutamate yields

A

γ-aminobutyric acid (GABA, a neurotransmitter in the cerebral cortex)

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12
Q

What is the cofactor in AA decarboxylation reactions?

A

pyridoxal phosphate (activated vitamin B6)

[same as transamination and deamination]

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13
Q

Tyrosine is decarboxylated to yield

A

tyramine, an immune mediator

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14
Q

Dioxophenylalanine (DOPA) is decarboxylated to yield

A

dopamine, a neurotransmitter

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15
Q

5-hydroxytryptophan is decarboxylated to yield

A

serotonin, a neurotransmitter

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16
Q

Histidine is decarboxylated to yield

A

histamine, an immune mediator

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17
Q

Serine is decarboxylated to yield

A

ethanolamine, used in phospholipid and choline synthesis

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18
Q

The decarboxylation of glutamate to GABA is catalyzed by what enzyme?

A

glutamate decarboxylase (GAD)

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19
Q

Broadly speaking, what happens in deamination reactions?

A

reactions release ammonia from amino group and leave behind 2-keto acid

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20
Q

AA deamination reactions use what cofactor?

A

pyridoxal phosphate (activated vitamin B6)

[same as transamination and decarboxylation]

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21
Q

What enzyme catalyzes glutamate deamination?

A

glutamate dehydrogenase

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22
Q

Write out the glutamate deamination reaction.

A
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23
Q

Excess glucose is stored in the body as glycogen. What happens to excess amino acids?

A

excess amino acids (i.e. more than is needed to produce proteins) is degraded via urea cycle

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24
Q

What does it mean for an amino acid to be “glucogenic?”

A

AAs that can be metabolized into OAA or pyruvate, precursors of glucose (via gluconeogenesis)

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25
Q

What does it mean for an amino acid to be “ketogenic?”

A

AAs that can be metabolized to produce acetyl-CoA, a precursor for ketone bodies

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26
Q

(T/F) In humans, acetyl-CoA can be converted into glucose.

A

False.

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27
Q

What are the essential amino acids?

A

FILTHMVKW

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28
Q

What are the exclusively glucogenic amino acids?

A

DVENGRASPTH-CMQ

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29
Q

What are the exclusively ketogenic amino acids?

A

LK

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30
Q

Which amino acids are both glucogenic and ketogenic?

A

FYIW

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31
Q

What is the functional role of homocysteine? (2)

A

one-carbon pool

cysteine synthesis

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32
Q

What is the functional role of ornithine? (2)

A

urea cycle

proline synthesis

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33
Q

What is the functional role of citrulline?

A

urea cycle

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34
Q

What is the functional role of hydroxyproline?

A

collagen synthesis

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35
Q

What is the functional role of hydroxylysine?

A

collagen synthesis

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36
Q

What is the most abundant free amino acid in serum and tissues? What is a consequence of this abundance?

A

glutamine is most abundant → important carrier of amino groups between organs

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37
Q

What enzyme produces glutamine?

A

glutamine synthetase

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38
Q

Write out the reaction for glutamine synthesis.

A
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39
Q

Under what conditions does glutamine accumulate in the body?

A

glutamine accumulates when ammonia accumulates, because it acts like a buffer

[tip: remember that ammonia is toxic → glutamine “scavenges” for excess ammonia // and also remember that ammonia is a reactant in the synthesis of glutamine]

40
Q

How is glutamine converted back to glutamate? Write out the reaction.

A
41
Q

What enzyme catalyzes the conversion of glutamine to glutamate?

A

glutaminase

42
Q

The glutaminase reaction, which converts glutamine to glutamate, produces ammonia. How is this ammonia used? (2)

A

used in kidney to neutralize acid in urine

in liver, enters urea cycle

43
Q

Disorders in metabolic detoxification begin to show symptoms at what stage?

A

not present in fetus because mother handles ammonia detoxification

symptoms show 24-48 hours after birth

44
Q

How does hyperammonemia affect ventilation?

A

hyperammonemia → hyperventilation → respiratory alkalosis

45
Q

Of all the enzymes associated with AA metabolism, which is most responsible for the generation of ammonia?

A

glutamate dehydrogenase (glutamate + NADP → α-KG + NADPH + NH3)

46
Q

(T/F) The glutamate dehydrogenase reaction is reversible.

A

True. However, because the ammonia produced is rapidly removed, the reaction will normally go in the direction of producing ammonia.

47
Q

What are the allosteric activators and inhibitors of glutamate dehydrogenase?

A

allosteric activators: ADP, GDP (signal of low-energy state)

allosteric inhibitors: ATP, GTP (signal of high-energy state)

48
Q

What is the significance of the deamination of AMP?

A

deamination of AMP = source of much of NH3 released by muscle during exercise

49
Q

What are the two primary purposes of the urea cycle?

A

(1) eliminate nitrogenous waste
(2) arginine synthesis

50
Q

List the order of enzymes used in the urea cycle. Also denote where in the cell the enzyme is located.

A

carbamylphosphate synthetase I (CPS I) - mitochondria

ornithine transcarbamylase (OTC) - mitochondria

argininosuccinate synthetase (AS) - cytosol

argininosuccinate lyase (AL) - cytosol

arginase - cytosol

51
Q

What does carbamylphosphate synthetase I (CPS I) do?

A

NH3 → carbamyl phosphate

52
Q

What coreactants/cofactors are required for the carbamylphosphate synthetase I (CPS I) reaction? (2)

A

CO2 as carbon source

2 ATP

53
Q

Describe the reversibility of the carbamylphosphate synthetase I (CPS I) reaction.

A

irreversible (because of the consumption of ATP)

54
Q

Describe the regulation of carbamylphosphate synthetase I (CPS I). (2)

A

CPS I requires an allosteric regulator, N-acetylglutamate, derived from glutamate + acetyl CoA via N-acetylglutamate synthetase

so if glutamate and acetyl-CoA are low, N-acetylglutamate is low and then CPS I activity is low → slower urea cycle

55
Q

What does ornithine transcarbamylase (OTC) do?

A

carbamyl phosphate + ornithine → citrulline

56
Q

Describe the mitochondrial/cytosolic compartmentation of the urea cycle.

A

CPS I, NAGS, and OTC enzymes are located in the mitochondria and primarily expressed in liver

everything else located in cytosol and expressed widely throughout body

57
Q

What does argininosuccinate synthetase (AS) do?

A

citrulline + aspartate → argininosuccinate

58
Q

What coreactants/cofactors are used in the argininosuccinate synthetase (AS) reaction?

A

consumes 1 ATP → AMP, making reaction irreversible

59
Q

What does argininosuccinate lyase (AL) do?

A

removal of carbon skeleton of argininosuccinate → produces arginine + fumarate

60
Q

Describe the reversibility of the argininosuccinate lyase (AL) reaction.

A

reversible (no energy consumed)

61
Q

What does arginase, the last enzyme of the urea cycle, do?

A

hydrolyzes arginine → urea + ornithine

62
Q

Describe the reversibility of the arginase reaction.

A

irreversible

63
Q

Draw out the urea cycle.

A
64
Q

Hyperammonemic patients have elevated blood levels of which molecules?

A

glutamine

alanine

(2-3x higher than normal)

65
Q

Elevated levels of glutamine and alanine in a patient’s blood is a non-specific finding, because they can be caused by several metabolic disorders. Elevated levels of which molecule serve as a better indicator for hyperammonemia?

A

citrulline:

normal plasma concentration is low, but if there isn’t any citrulline at all, then CPS I or OTC is defective/deficient

if plasma citrulline is very high, then AS is defective/deficient

66
Q

What is the clinical finding for argininosuccinate lyase deficiency?

A

argininosuccinic aciduria (argininosuccinate found in blood or urine), but not very detectable

67
Q

What is the clinical finding for arginase deficiency?

A

plasma arginine elevated → argininemia

68
Q

Arginine is normally a non-essential amino acid. Under what conditions does it become an essential amino acid?

A

if enzymes of the urea cycle (other than arginase) become defective

69
Q

Broadly speaking, how are urea cycle disorders treated?

A

sufficient protein (i.e. enough protein for growth but no excess) diet

alternative pathway therapy (attach toxic ammonia to a non-toxic molecule that can be excreted)

70
Q

If argininosuccinate accumulates, how is it dealt with?

A

not retained by kidney but excreted

71
Q

How is argininosuccinate lyase deficiency treated? (2)

A

give arginine → makes a turn of the urea cycle, consuming ammonia → more argininosuccinate produced → more is excreted (+ more ammonia excreted)

give citrate supplements to prevent deficiency of Krebs cycle intermediates

72
Q

How is argininosuccinate synthetase deficiency treated?

A

give arginine to increase excretion (same concept as in argininosuccinate lyase deficiency)

sodium benzoate-alternative pathway therapy

73
Q

What is the basis of sodium benzoate-alternative pathway therapy?

A

sodium benzoate conjugated to glycine → forms hippurate → completely removed from blood in one pass by kidney

74
Q

What is a common treatment used across most urea cycle disorders?

A

low protein diet

75
Q

CPS I and OTC deficiences result in accumulation of which amino acids?

A

glutamine

alanine

76
Q

How are CPS I and OTC deficiencies treated?

A

sodium phenylbutyrate (conjugated to glutamine)-alternative pathway therapy

77
Q

What is propionic aciduria?

A

defect in propionyl-CoA carboxylase (PCC), which is found in the following pathway:

I,V,T,M → [degraded] → propionyl-CoA → [PCC] → succinyl-CoA → TCA cycle

78
Q

What are the clinical findings associated with propionic aciduria? (2)

A

acidosis

hyperammonemia

79
Q

How is propionic aciduria treated?

A

low Ile/Val diet

80
Q

What is tyrosinemia?

A

mutation of FAH enzyme that converts tyrosine → fumarate + acetoacetate

81
Q

What are the clinical findings associated with tyrosinemia?

A

severe liver damage → can lead to liver cancer

82
Q

How are tyrosinemia patients treated?

A

using Nitisinone

83
Q

Describe the role of asparagine in cancer cells. (2)

A

asparagine, normally a non-essential AA, becomes an essential AA to meet demands of cancer cell growth

using L-asparaginase, a drug that reduces blood [asparagine], is an effective component of chemotherapy

84
Q

The catabolism of tyrosine ultimately produces

A

fumarate + acetoacetate (i.e. it is both ketogenic and glucogenic)

85
Q

Which tissues comprise the glutamine producers? (2)

A

lungs

skeletal muscle

86
Q

Which tissues comprise the glutamine consumers? (4)

A

liver

kidneys

intestines

immune system

87
Q

What is phenylketonuria? How is it treated?

A

defect in phenylalanine hydroxylase, which converts phenylalanine → tyrosine

treated with phenylalanine-restricted diets + tyrosine supplementation

88
Q

What is the Guthrie test?

A

test to scan for phenylketonuria

89
Q

What is the emergency treatment option for patients with severe hyperammonemia?

A

hemodialysis

90
Q

How do amino acids regulate insulin secretion?

A

through glutamate dehydrogenase → GDH activity ultimately promotes insulin secretion, but if GDH can’t turn off, then you get hyperinsulinemia

91
Q

In terms of metabolic workup, how are plasma AAs useful?

A

useful to detect urea cycle defects

92
Q

In terms of metabolic workup, how are plasma acylcarnitines useful?

A

detects metabolic intermediates from AA and fatty acid oxidation

93
Q

How is acute metabolic acidosis/hyperammonemia treated?

A

(1) stop all protein intake
(2) dialysis to remove organic acids and ammonia
(3) IV glucose with insulin to promote anabolism/protein synthesis

94
Q

What is the rate-limiting enzyme of the urea cycle?

A

CPS I

95
Q

What is the most common urea cycle disorder?

A

OTC deficiency

96
Q

Describe the role of serine in cancer growth.

A

serine is synthesized by phosphoglycerate dehydrogenase (PHGDH)

tumors seem to upregulate PHGDH expression

Tissues (23 decks)

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