T07 - Amino Acid Metabolism Flashcards
Broadly speaking, what happens to amino groups in amino acid degradation?
amino groups (-NH2) either:
converted to ammonia
removed via urea cycle
used to make new AAs
Removal of an amino group from an amino acid leaves behind
a carbon skeleton, usually in the form of a 2-ketoacid
What are the three major fates of amino acids?
storage in protein
conversion to other biomolecules
degradation to produce energy
What is the major mechanism associated with metabolism of AAs?
transamination
What is a transamination reaction?
transaminase transfers amino group from donor AA to acceptor 2-keto acid
Write out an example of a transamination reaction. Identify the amino donors and acceptors.
alanine donates its amino group to become pyruvate
2-ketoglutarate accepts the amino group to become glutamate
Why are plasma transaminase levels used as a marker for liver disease?
transaminases are abundant in liver/muscle
destruction of liver/muscle releases transaminases into blood
What is the cofactor in transamination reactions?
pyridoxal phosphate (activated vitamin B6)
[same as decarboxylation and deamination]
List the three most common transamination reactions. Identify the substrate and resulting amino acid, along with the enzyme that mediates the reaction.
What are the three most common reactions associated with AA metabolism?
transamination reactions
decarboxylation reactions
deamination reactions
The decarboxylation of glutamate yields
γ-aminobutyric acid (GABA, a neurotransmitter in the cerebral cortex)
What is the cofactor in AA decarboxylation reactions?
pyridoxal phosphate (activated vitamin B6)
[same as transamination and deamination]
Tyrosine is decarboxylated to yield
tyramine, an immune mediator
Dioxophenylalanine (DOPA) is decarboxylated to yield
dopamine, a neurotransmitter
5-hydroxytryptophan is decarboxylated to yield
serotonin, a neurotransmitter
Histidine is decarboxylated to yield
histamine, an immune mediator
Serine is decarboxylated to yield
ethanolamine, used in phospholipid and choline synthesis
The decarboxylation of glutamate to GABA is catalyzed by what enzyme?
glutamate decarboxylase (GAD)
Broadly speaking, what happens in deamination reactions?
reactions release ammonia from amino group and leave behind 2-keto acid
AA deamination reactions use what cofactor?
pyridoxal phosphate (activated vitamin B6)
[same as transamination and decarboxylation]
What enzyme catalyzes glutamate deamination?
glutamate dehydrogenase
Write out the glutamate deamination reaction.
Excess glucose is stored in the body as glycogen. What happens to excess amino acids?
excess amino acids (i.e. more than is needed to produce proteins) is degraded via urea cycle
What does it mean for an amino acid to be “glucogenic?”
AAs that can be metabolized into OAA or pyruvate, precursors of glucose (via gluconeogenesis)
What does it mean for an amino acid to be “ketogenic?”
AAs that can be metabolized to produce acetyl-CoA, a precursor for ketone bodies
(T/F) In humans, acetyl-CoA can be converted into glucose.
False.
What are the essential amino acids?
FILTHMVKW
What are the exclusively glucogenic amino acids?
DVENGRASPTH-CMQ
What are the exclusively ketogenic amino acids?
LK
Which amino acids are both glucogenic and ketogenic?
FYIW
What is the functional role of homocysteine? (2)
one-carbon pool
cysteine synthesis
What is the functional role of ornithine? (2)
urea cycle
proline synthesis
What is the functional role of citrulline?
urea cycle
What is the functional role of hydroxyproline?
collagen synthesis
What is the functional role of hydroxylysine?
collagen synthesis
What is the most abundant free amino acid in serum and tissues? What is a consequence of this abundance?
glutamine is most abundant → important carrier of amino groups between organs
What enzyme produces glutamine?
glutamine synthetase
Write out the reaction for glutamine synthesis.
Under what conditions does glutamine accumulate in the body?
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]
How is glutamine converted back to glutamate? Write out the reaction.
What enzyme catalyzes the conversion of glutamine to glutamate?
glutaminase
The glutaminase reaction, which converts glutamine to glutamate, produces ammonia. How is this ammonia used? (2)
used in kidney to neutralize acid in urine
in liver, enters urea cycle
Disorders in metabolic detoxification begin to show symptoms at what stage?
not present in fetus because mother handles ammonia detoxification
symptoms show 24-48 hours after birth
How does hyperammonemia affect ventilation?
hyperammonemia → hyperventilation → respiratory alkalosis
Of all the enzymes associated with AA metabolism, which is most responsible for the generation of ammonia?
glutamate dehydrogenase (glutamate + NADP → α-KG + NADPH + NH3)
(T/F) The glutamate dehydrogenase reaction is reversible.
True. However, because the ammonia produced is rapidly removed, the reaction will normally go in the direction of producing ammonia.
What are the allosteric activators and inhibitors of glutamate dehydrogenase?
allosteric activators: ADP, GDP (signal of low-energy state)
allosteric inhibitors: ATP, GTP (signal of high-energy state)
What is the significance of the deamination of AMP?
deamination of AMP = source of much of NH3 released by muscle during exercise
What are the two primary purposes of the urea cycle?
(1) eliminate nitrogenous waste
(2) arginine synthesis
List the order of enzymes used in the urea cycle. Also denote where in the cell the enzyme is located.
carbamylphosphate synthetase I (CPS I) - mitochondria
ornithine transcarbamylase (OTC) - mitochondria
argininosuccinate synthetase (AS) - cytosol
argininosuccinate lyase (AL) - cytosol
arginase - cytosol
What does carbamylphosphate synthetase I (CPS I) do?
NH3 → carbamyl phosphate
What coreactants/cofactors are required for the carbamylphosphate synthetase I (CPS I) reaction? (2)
CO2 as carbon source
2 ATP
Describe the reversibility of the carbamylphosphate synthetase I (CPS I) reaction.
irreversible (because of the consumption of ATP)
Describe the regulation of carbamylphosphate synthetase I (CPS I). (2)
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
What does ornithine transcarbamylase (OTC) do?
carbamyl phosphate + ornithine → citrulline
Describe the mitochondrial/cytosolic compartmentation of the urea cycle.
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
What does argininosuccinate synthetase (AS) do?
citrulline + aspartate → argininosuccinate
What coreactants/cofactors are used in the argininosuccinate synthetase (AS) reaction?
consumes 1 ATP → AMP, making reaction irreversible
What does argininosuccinate lyase (AL) do?
removal of carbon skeleton of argininosuccinate → produces arginine + fumarate
Describe the reversibility of the argininosuccinate lyase (AL) reaction.
reversible (no energy consumed)
What does arginase, the last enzyme of the urea cycle, do?
hydrolyzes arginine → urea + ornithine
Describe the reversibility of the arginase reaction.
irreversible
Draw out the urea cycle.
Hyperammonemic patients have elevated blood levels of which molecules?
glutamine
alanine
(2-3x higher than normal)
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?
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
What is the clinical finding for argininosuccinate lyase deficiency?
argininosuccinic aciduria (argininosuccinate found in blood or urine), but not very detectable
What is the clinical finding for arginase deficiency?
plasma arginine elevated → argininemia
Arginine is normally a non-essential amino acid. Under what conditions does it become an essential amino acid?
if enzymes of the urea cycle (other than arginase) become defective
Broadly speaking, how are urea cycle disorders treated?
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)
If argininosuccinate accumulates, how is it dealt with?
not retained by kidney but excreted
How is argininosuccinate lyase deficiency treated? (2)
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
How is argininosuccinate synthetase deficiency treated?
give arginine to increase excretion (same concept as in argininosuccinate lyase deficiency)
sodium benzoate-alternative pathway therapy
What is the basis of sodium benzoate-alternative pathway therapy?
sodium benzoate conjugated to glycine → forms hippurate → completely removed from blood in one pass by kidney
What is a common treatment used across most urea cycle disorders?
low protein diet
CPS I and OTC deficiences result in accumulation of which amino acids?
glutamine
alanine
How are CPS I and OTC deficiencies treated?
sodium phenylbutyrate (conjugated to glutamine)-alternative pathway therapy
What is propionic aciduria?
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
What are the clinical findings associated with propionic aciduria? (2)
acidosis
hyperammonemia
How is propionic aciduria treated?
low Ile/Val diet
What is tyrosinemia?
mutation of FAH enzyme that converts tyrosine → fumarate + acetoacetate
What are the clinical findings associated with tyrosinemia?
severe liver damage → can lead to liver cancer
How are tyrosinemia patients treated?
using Nitisinone
Describe the role of asparagine in cancer cells. (2)
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
The catabolism of tyrosine ultimately produces
fumarate + acetoacetate (i.e. it is both ketogenic and glucogenic)
Which tissues comprise the glutamine producers? (2)
lungs
skeletal muscle
Which tissues comprise the glutamine consumers? (4)
liver
kidneys
intestines
immune system
What is phenylketonuria? How is it treated?
defect in phenylalanine hydroxylase, which converts phenylalanine → tyrosine
treated with phenylalanine-restricted diets + tyrosine supplementation
What is the Guthrie test?
test to scan for phenylketonuria
What is the emergency treatment option for patients with severe hyperammonemia?
hemodialysis
How do amino acids regulate insulin secretion?
through glutamate dehydrogenase → GDH activity ultimately promotes insulin secretion, but if GDH can’t turn off, then you get hyperinsulinemia
In terms of metabolic workup, how are plasma AAs useful?
useful to detect urea cycle defects
In terms of metabolic workup, how are plasma acylcarnitines useful?
detects metabolic intermediates from AA and fatty acid oxidation
How is acute metabolic acidosis/hyperammonemia treated?
(1) stop all protein intake
(2) dialysis to remove organic acids and ammonia
(3) IV glucose with insulin to promote anabolism/protein synthesis
What is the rate-limiting enzyme of the urea cycle?
CPS I
What is the most common urea cycle disorder?
OTC deficiency
Describe the role of serine in cancer growth.
serine is synthesized by phosphoglycerate dehydrogenase (PHGDH)
tumors seem to upregulate PHGDH expression
