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Genitourinary 1 > Amino Acid Metabolism and Urea Cycle > Flashcards

Amino Acid Metabolism and Urea Cycle Flashcards

1
Q

What happens in amino acid synthesis?

A

the synthesis of non-essential amino acids from metabolic intermediates or essential amino acids

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2
Q

Why is there amino acid synthesis?

A

to provide necessary amino acids for protein synthesis, as well as precursors of many nitrogen-containing compounds (porphyrins, neurotransmitters, hormones, purines, and pyrimidines

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3
Q

Where does amino acid synthesis occur?

A

Cytosol and/or mitochondria depending on the amino acid

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4
Q

How are amino acids synthesized?

A

De novo synthesis - ‘from scratch’

synthesis by transamination of corresponding alpha-keto acids

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5
Q

How are amino acids synthesized de novo?

A

adults can make all but 9 amino acids from scratch

  • tyrosine and cysteine are made from essential amino acids
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6
Q

How are amino acids synthesized by transamination?

A

transamination of alpha-keto acids is the most direct of the amino acid biosynthetic pathways

Pyruvate -> alanine

alpha-Ketoglutarate -> glutamate

Oxaloacetate -> aspartate

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7
Q

What is amino acid catabolism?

A

the breakdown of amino acids by removal of the amino group and the resulting carbon skeletons can be completely degraded to CO2 via the TCA cycle or used to synthesize glucose and/or ketone bodies

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8
Q

Why are amino acids catabolized?

A

Excess amino acids are not stored, so they are degraded to provide energy or synthetic intermediates

The nitrogen from amino acids can also be used for synthesis of nitrogen-containing compounds

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9
Q

Wheare are amino acids catabolized?

A

cytosol and/or mitochondria - depending on their enzyme and tissue

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10
Q

How are amino acids catabolized?

A

two steps: amino group removal/fixation and fate of carbon skeletons

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11
Q

What are the steps of amino acid catabolism?

A
  1. remove amino groups (-NH2) and transfer to alpha-ketoglutarate to make glutamate (via transamination reactions)
  2. the resulting alpha-ketoacids can now be utilized or catabolized via entry into several points along the glycolytic pathway or TCA cycle within the cell
  3. another amino group is usually added to glutamate to make glutamine
  • carries two amino groups for removal
  • is the primary water-soluble, nontoxic, nitrogen-carrying intermediate exported by most cells to the liver
  1. muscle tissue also exports amino groups using alanine (by transamination of pyruvate), which is also a water-soluble, nontoxic nitrogen carrier
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12
Q

What is the overall plan of amino group removal/fixation?

A

Amino group removal/transfer stage - 3 enzymes

  • aminotransferases - in cytosol and mitochondria of all cells
  • glutamate dehydrogenase - in mitochondria; primarily in the liver and kidney
  • amino acid oxidases - play a minor role in amino group removal; L-amino acid oxidases mainly in liver and kidney; D-amino acid oxidases in the liver

Amino group fixation/excretion stage - 2 enzymes + urea cycle

  • glutamine synthetase - a mitochondrial enzyme in many tissues (but in brain, for instance, is cytosolic)
  • glutaminase - in liver and kidney
  • carbamoyl-phosphate synthetase I (first enzyme of urea cycle)
  • urea cycle - urea is produced in the liver
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13
Q

What type of reactions do aminotransferases catalyze? Features?

A

catalyze the transfer of -NH2 group from a DONOR alpha-amino acid to an ACCEPTOR alpha-keto acid (aka transamination reactions)

  • reversible
  • either to make a new amino acid that is needed in the cell OR to make excess glutamate - which is used as an amino group donor or as one of the steps in the excretion of nitrogen
  • in many cases, alpha-ketoglutarate is the acceptor alpha-keto acid
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14
Q

What is the transamination reaction mechanism?

A

enzyme cofactor: pyridoxal-phosphate

  • derivative of vitamin B6
  • Pyridoxal-P acts as a carrier of amino group
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15
Q

What is the nomenclature for aminotransferases?

A

named after the donor amino acid

examples:

  • alanine aminotransferase (ALT)
  • aspartate aminotransferase (AST)
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16
Q

Why are aminotransferases clinically relevant generally?

A

test for serum levels of these aminotransferases

  • low levels of aminotransferases normally found in plasma (represents the release of cellular contents during normal cell turnover)
  • elevated plasma levels indicate damage to cells rich in aminotransferases; physical trauma or disease processes -> cell lysis -> release of intravecllular enzymes into blood
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17
Q

Why are aminotransferases clinically relevant for liver disease?

A

plasma AST and ALT elevated in most liver diseases

liver damage -> elevated levels of ALT and AST

particularly high in conditions that cause extensive cell necrosis (e.g. viral hepatitis, toxic injury, prolonged circulatory collapse)

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18
Q

Why are aminotransferases clinically relevant non-hepatic disease?

A

aminotransferases may be elevated in diseases that cause damage to cardiac or skeletal muscle

these disorders can usually be distinguished clinically from liver disease

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19
Q

What are glutamate dehydrogenases?

A

mitochondrial enzyme

unique because it can use NAD+ or NADP+ as a coenzyme

glutamate + NAD+ + H2O –> alpha-ketoglutarate (to TCA) + NADH (to ETC) + NH4+(to urea cycle)

20
Q

What do glutamate dehydrogenases do in the liver?

A

catalyzes the oxidative deamination of glutamate to:

  • alpha-ketoglutarate - enters the TCA cycle
  • free ammonia (NH4+) - enters the urea cycle (in kidney: NH4+ -> urine)

in this direction, NAD+ is reduced to NADH + H+ -> ETC

the removal of ammonia (into urea cycle) pulls the reaction in this direction

Regulated by:

  • high energy state [ATP, GTP, NADH] = INHIBIT enzyme
  • low energy state [ADP, GDP] = ACTIVATE enzyme
21
Q

What do glutamate dehydrogenases do in peripheral tissues?

A

catalyzes the reductive amination of alpha-ketoglutarate to glutamate

Purpose: to fix nitrogen

in this direction, NADPH + H+ is oxidized to NADP+

22
Q

What are amino acid oxidases?

A

minor route of amino group removal and releases it as free ammonia (NH4+)

FMNH2 (or FADH2) is bound to enzyme and reoxidized using O2 forming H2O2

23
Q

What is glutamine synthetase?

A

major route of ammonia fixation leading to excretion

glutamine - primary water-soluble, nontoxic transport form of ammonia from peripheral tissues to the liver or kidney

glutamine - also a nitrogen donor for synthesis (i.e. NTP, dNTP)

24
Q

What is glutaminase?

A

catalyzes reverse reaction of glutamine synthetase

liver or kidney: glutamine is cleaved to form glutamate and free NH4+

NH4+ goes into the urea cycle in the liver (in kidney: NH4+ -> urine)

glutamate - can have its alpha-amino group removed by glutamate dehydrogenase or used for other amino acid syntheses

25
Q

What are the sources of ammonia?

A

amino acid catabolism

  • breakdown of dietary proteins
  • cellular protein catabolism

nucleotide catabolism

intestinal bacteria (urease)

26
Q

What is carbamoyl phosphate synthetase I (CPS I)?

A

catalyzes the first step of the urea cycle - an essentially irreversible reaction

HCO3- + NH4+ + 2ATP –CPS I –>carbamoyl phosphate + 2(ADP+Pi)

major route of ammonia fixation in the liver

committed step and is regulated

CPS I is a mitochondrial enzyme

27
Q

How is CPS I regulated?

A

positive effector: N-acetyl glutamate

Produced from acetyl CoA and glutamate by N-acetylglutamate synthase

Arignine - activates N-acetylglutamate synthesis (NAGS)

28
Q

Where does the urea cycle occur?

A

occurs in the liver

both mitochondria and cytosol, but begins and ends in the mitochondria

29
Q

What are the steps of the urea cycle?

A
  1. bicarbonate (from CO2) provides the carbon atom of urea
  2. free ammonia provides one of the nitrogen atoms of urea
  3. the enzyme has an absolute requirement of N-acetyl-glutamate, which acts as an allosteric activator
  4. citrulline is synthesized and transported out of the mitochondrion
  5. the amino group of aspartate provides one of the nitrogen atoms of urea
  6. fumarate is hydrated to malate, which is oxidized to oxaloacetate, which is transaminated to aspartate
  7. tissues other than liver use enzymes of this pathway to make arginine
  8. ornithine is regenerated and transported into the mitochondrion
30
Q

What are the five enzymes and transporter used in the urea cycle?

A

Carbamoyl phosphate synthetase I (CPS I)

Ornithine trans-carbamoylase (OTC)

Argininosuccinate synthetase

Argininosuccinate lyase

Arginase

31
Q

What is the overall reaction of the urea cycle?

A

CO2 + NH4+ + 3 ATP + Asp + 2 H2O ->

urea + fumarate + 2 ADP + 2 Pi + AMP + PPi

Net input: NH4+ + CO2 + Asp + energy (ATP)

Net output: urea and fumarate

physiological/clinical significance: converts TOXIC ammonia (NH4+) to NON-TOXIC urea

32
Q

What is urea?

A

major end product of nitrogen metabolism

  • accounts for >85% of N excreted
  • other forms: NH4+, uric acid, creatinine, bile pigment

water-soluble and nontoxic -> transport in blood to kidney for excretion

33
Q

What is BUN?

A

blood urea nitrogen

  • if BUN is high: kidney is not excreting urine properly -> kidney failure/malfunction (though the urea cycle in the liver is operating fine)
    • heart failure, dehydration, or high protein diet could also raise BUN level
  • if BUN is low: could result from liver disease/damage; also can occur normally in the second or third trimester of pregnancy
34
Q

How does urea connect to the TCA cycle?

A

fumarate –fumarase–> malate –malate dehydrogenase–> oxaloacetate + glutamate –transaminase–> aspartate + alpha-ketoglutarate

35
Q

What is hyperammonemia?

A

ammonia toxicity

levels of serum ammonia are normally low

when liver function is compromised (e.g. genetic defects of the urea cycle or liver disease), hyperammonemia can occur

medical emergency because ammonia has a direct neurotoxic effect ont he central nervous system

36
Q

What are the symptoms of hyperammonemia?

A

results in ammonia intoxication:

initially: nausea, vomiting, tremors, slurred speech, blurred vision, mental retardation
later: coma, death

37
Q

What is the mechanism of hyperammonemia?

A

first theory: neurotransmitter deprivation (glutamate)

second theory: energy deprivation in the brain

NH4+ + alpha-KG –GluDH–> glutamate + ATP –glutamine synthetase–> glutamine

  • uses up ATP and limits TCA cycle
  • occurs when NH4+ levels exceed 50micromol/L in adults or 100 micromol/L in newborns (liver disease, genetic defects of the ucrea cycle)
38
Q

What is hereditary hyperammonemia?

A

genetic defects are known in all 5 enzymes of the urea cycle

mostly autosomal recessive

hyperammonemia observed during the first weeks after birth due to failure to synthesize urea

Hyperammonemia I: CPS I deficiency

Hyperammonemia II: OTC deficiency

  • most common of these disorders
  • X-linked
39
Q

What is the treatment for hereditary hyperammonemia?

A

restriction of dietary protein

administration of compound that covalently bind to amino acids to produce nitrogen containing molecules that can be excreted in the urine (e.g. phenylbutyrate)

40
Q

What is acquired hyperammonemia?

A

liver disease is a common cause of hyperammonemia in adults (e.g. caused by viral hepatitis or hepatotoxins such as alcohol)

cirrhosis of the liver may lead to formation of collateral circulation around the liver -> portal blood is shunted directly into the systemic circulation (doesn’t have access to liver) -> conversion of ammonia to urea is severely impaired -> leading to elevated levels of ammonia

41
Q

What is valproate-associated hyperammonemia?

A

valproate used to treat epileptic seizures, psychiatric disorders, and migraine

valproate may cause hyperammonemia (in the absence of liver toxicity)

42
Q

What are the mechanisms of valproate-associated hyperammonemia?

A

metabolites of valproate

  • valproyl-CoA -> inhibits N-acetylglutamate (NAG) synthase -> reduced activation of CPS I -> reduces the flux of urea cycle
  • valproic acid decreases carnitine -> decreases fatty acid oxidation to acetyl-CoA (which is needed for NAG synthesis)
43
Q

What are the treatments for valproate-associated hyperammonemia?

A

the effect is reversible - withdrawal of the drug will restore normal N-acetylglutamate synthase activity and urea cycle function

N-carbamylglutamate administration: N-carbamylglutamate is an analog of NAG -> direct action on CPS I -> reactivation of the urea cycle

carnitine supplementation

44
Q

What is hyperammonemia and how does it relate to hepatic coma?

A

an increase of ammonia in the blood over the normal concentration range may cause coma

loss of consciousness in general may be a consequence of ATP depletion

ammonia crosses the blood brain barrier and might shift glutamate DH equilibrium so alpha-KG becomes limiting for TCA cycle

synthesis of glutamine might also contribute to a decrease in the ATP level

45
Q

What is the cause of hyperammonemia?

A

inability of the patient to form urea at a sufficient rate to maintain tolerable levels of ammonia

ammonia is not cleared from the blood efficiently in cases in which normal blood flow through the liver is reduced

  • cirrhosis of the liver can result in the development of collateral circulation of blood from the portal system to the inferior vena cava, bypassing the liver
46
Q

What can be used as a treatment for hyperammonemia and hepatic coma?

A

careful administration of benzoate and/or phenylacetate can compensate for deficiencies in the urea cycle and in preventing ammonia toxicity

additional treatment: substitute in the diet of alpha-keto analogs of some amino acids to reduce the total intake of nitrogen and to divert amino groups from an excretory fate to the production of essential amino acids for protein synthesis

Genitourinary 1 (17 decks)

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