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MFM > Nitrogen Metabolism and Urea Cycle > Flashcards

Nitrogen Metabolism and Urea Cycle Flashcards

1
Q

what is aspartate converted to during aspartate transamination

A

OAA

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2
Q

what is alpha ketoglutarate converted to during aspartate transamination

A

glutamate

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3
Q

what enzyme is needed for transamination of aspartate?

A

AST (aspartate aminotransferase) aka SGOT (serum glutamate oxaloacetate aminotransferase)

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4
Q

what cofactor is needed for transamination of aspartate

A

PLP, pyridoxal phosphate aka B6

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5
Q

why do alcoholics have a hard time mobilizing AA?

A

they usually lack or have a deficiency in B6, so transamination cannot occur.

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6
Q

where is AST found?

A

liver, heart, skeletal muscle, kidney, brain, RBC

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7
Q

what is alanine converted to during alanine transamination

A

pyruvate

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8
Q

what is alpha ketoglutarate converted to during alanine transamination

A

glutamate

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9
Q

what enzyme is needed for transamination of alanine

A

ALT (alanine aminotransferase) aka SGPT (glutamate pyruvate transaminase)

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10
Q

what cofactor is needed for transamination of alanine

A

B6 aka PLP

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11
Q

where is ALT found?

A

high concentration in the liver, relatively high in muscle

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12
Q

what are 2 first products in amino acid breakdown?

A

nitrogen and carbon

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13
Q

what are the nitrogen products in amino acid breakdown and where are they sent?

A

aspartate and a free Nitrogen from ammonia

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14
Q

what is the use of carbon from the breakdown of amino acids?

A

carbons are used for either storage or energy, giving off CO2 and H2O

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15
Q

what makes up urea?

A

a carbonyl carbon with 2 nitrogens that came from aspartate and ammonia

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16
Q

what is the significance of urea production?

A

sequesters free, toxic ammonia in the liver and then travels to the blood to be excreted by the kidney

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17
Q

what occurs if there is a blockage in the urea cycle?

A

increased free N as ammonia and decreased BUN (blood urea nitrogen)

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18
Q

how is pyridoxal phosphate used in transamination?

A
  1. pyridoxal phosphate that is bound to its enzyme binds the first amino acid at its 1st nitrogen. this causes the amino terminal of the amino acid to be transferred to the enzyme, and the enzyme is disconnected. 2. the 1st amino acid is hydrated, and leaves PLP as the 1st alpha keto acid. this leaves the PLP with an amino group from the 1st amino acid where the 1st amino acid was bonded. 3. a 2nd alpha keto acid binds at the amino group on the PLP. 4. a hydrogen is added to the 2nd alpha keto acid and the enzyme with the amino group attached attacks the nitrogen on the PLP, separating the newly made 2nd amino acid from the PLP, and donates 2 hydrogens, completing its amino group. 5. at the end, the 2nd amino acid has the 1st amino acid’s nitrogen. TLDR: PLP holds the 1st amino acid’s nitrogen while it is converted to the 1st alpha keto acid and then puts that nitrogen on a 2nd alpha keto acid that is made into a 2nd AA.
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19
Q

what is the extracellular of Nitrogen and why?

A

Alanine. when AA are broken down, you expect to see an equal amount of different types of AA. but we see increased alanine in the bloodstream.

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20
Q

what is the intracellular carrier of nitrogen and why?

A

Glutamate. it is high intracellularly during periods of protein degradation.

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21
Q

what enzyme transdeaminates glutamate and what does this produce?

A

glutamate dehydrogenase, provides a free ammonium ion for the urea cycle and alpha ketoglutarate

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22
Q

7 central roles of transdeaminations

A
  1. digestion and absorption of dietary protein
  2. protein degradation in tissues (endogenous protein)
  3. protein synthesis
  4. oxidation of oxoacid (makes CO2 and H2O)
  5. gluconeogenesis or glyconeogenesis (oxoacid gives a glucose)
  6. lipid synthesis (oxoacid gives acetyl CoA for backbone)
  7. glycolysis (glucose made into oxoacid)
23
Q

what is the intracellular and extracellular carrier of nitrogen

A

glutamine, carries 2 N in the tissues, and can transport into the blood to the intestine to give off ammonia and glutamate

24
Q

describe transamination in the muscle cells

A
  1. amino acids and alpha ketoglutarate transaminated to glutamate and alpha keto acids via B6.
  2. glutamate and pyruvate transaminase to produce alpha ketoglutarate and alanine via ALT/B6.
  3. alanine is released into the bloodstream as the extracellular N carrier.
  4. alanine taken up into the liver cells.
  5. alanine and alpha ketoglutarate transaminated to pyruvate and glutamate via ALT/B6.
  6. glutamate to alpha ketoglutarate by glutamate dehydrogenase and NAD, giving off ammonia, ammonia goes to urea cycle.
  7. glutamate and OAA transaminate to alpha ketoglutarate and aspartate via AST/B6, aspartate goes to urea cycle.
  8. ammonia sequestered in liver as urea, transported to blood, then kidney, then urine.
25
Q

describe transamination in most other tissues

A
  1. glutamate, the intracellular carrier of 1 N, made into glutamine (intra and extracellular carrier of 2 N) by glutamine synthase (adds 1 more N)
  2. glutamine goes to the blood and goes to the kidney and intestine.
  3. in the intestine, glutaminase breaks glutamine down to glutamate, releasing 1 N via ammonia into the portal blood, and to the liver. ammonia enters urea cycle.
  4. in the kidney, glutaminase breaks glutamine into glutamate, releasing 1 ammonia, which is detoxified by adding 1 H, making ammonium, which is excreted in urine.
26
Q

describe transamination in the liver

A
  1. liver receives alanine from muscle tissue and ammonia from intestine (portal blood).
  2. alanine and alpha ketoglutarate transaminate to pyruvate and glutamate via ALT/B6.
  3. glutamate and oxaloacetate transaminate to alpha ketoglutarate and aspartate via AST/B6.
  4. glutamate broken down to alpha ketoglutarate via glutamate dehydrogenase, releasing ammonia.
  5. aspartate and ammonia from glutamate and intestine (which is from glutamine) enter urea cycle.
  6. urea sent to kidney through the blood.
  7. excreted as urine.
27
Q

what does glutaminase do?

A

glutamine to glutamate + ammonia, metabolic function

28
Q

what does asparaginase do

A

asparagine to aspartate + ammonia, no metabolic function, only used to make AA

29
Q

what does glutamine synthetase do?

A

glutamate + ammonia + ATP —> glutamine + ADP + Pi

(glutamate has 1 N, intracellular carrier)

(glutamine has 2 N, intra and extracellular carrier)

30
Q

what does L-amino acid oxidase do, AND WHERE

A

L-amino acid + H2O+FMN(flavin mononucleotide, B2) —> alpha keto acid + ammonium + hydrogen peroxide + FMNH2

IN THE PEROXISOMES OF HUMANS

31
Q

what does D amino acid oxidase do and where?

A

D amino acid + H2O + FAD —> alpha keto acid + ammonium + FADH2 + hydrogen peroxide

IN PEROXISOMES OF BACTERIA

32
Q

rationale of the cahill (glucose alanine) cycle?

A

conserving glucose and ridding the body of toxic ammonia.

conserve glucose to send it to the brain and RBC, but if it goes to the muscle cells, it can be converted to pyruvate and combined with ammonia to make alanine (before PDH makes it into acetyl CoA), send alanine to the liver to make pyruvate and glucose again.

33
Q

what is normal ammonium ion blood level?

A

0.5mg/L

34
Q

why is ammonia toxic?

A

due to its pK=9.3, it has a high affinity for H+, and is reactive, easily making ammonium. the increased level of ammonium shifts glutamate dehydrogenase reaction to alpha ketoglutarate making glutamate. alpha ketoglutarate (key intermediate in TCA) is then depleted in the mitochondria, reducing TCA activity, reducing ATP.

35
Q

what constitutes ammonia toxicity?

A

ammonia level greater than 10micrograms/L is TOXIC

36
Q

what occurs if there is a complete block in the urea cycle?

A

any complete block is incompatible with life

37
Q

what occurs in defects of the urea cycle?

A

decreased BUN, increased ammonia, leading to ammonemia, leading to ammonia intoxication, which crosses BBB.

38
Q

what are signs of defects of the urea cycle?

A
  1. early onset
  2. intolerant to protein ingestion
  3. hyperammonemia
  4. mental and CNS deficiency
39
Q

how are defects in urea cycle treated?

A
  1. low protein diet
  2. alpha ketoglutarate - because can be transaminated to increased glutamate (stick N on there to decrease ammonia concentration)
40
Q

what activates carbamoyl phosphate synthetase I?

A

N acetylglutamate (product of glutamate + acetyl coa) (means there is an increase in glutamate aka nitrogen levels bc glutamate intracellular n carrier)

41
Q

what activates the production of N acetylglutamate?

A

increased arginine

42
Q

what does carbamoyl phosphate synthetase I do?

A

enzyme in mitochondria, first step in urea cycle, converts HCO3 and ammonium (from glutamate dehydrogenase) to carbamoyl phosphate (which is half a urea)

HCO3+NH4+2ATP —> carbamoyl phosphate+2ADP+2Pi

43
Q

what does ornitine transcarbamoylase do??

A

takes carbamoyl phosphate and ornithine and makes citrulline and pi

carbamoyl phosphate + ornithine –> citrulline + pi

44
Q

what occurs in the mitochondria once citrulline is made?

A

it is transported out of the mitochondria to the cytosol and combined with aspartate to make arginosuccinate, which then gives off fumarate and arginine. arginine gives off urea and ornithine. ornithine transported back to the mitochondria to assist with ornithine transcarbamoylase again.

45
Q

what are the urea precursors?

A

aspartate from the muscles, NH4 from intestine and other tissues. NH4 then is made into carbamoyl phosphate, which combines with ornithine to make citrulline and then enters cytosol to make urea and ornithine again.

46
Q

what enzyme is deficient in hyperammonemia I?

A

CPS I

47
Q

what enzyme is deficient in hyperammonemia II?

A

ornithine transcarbamoylase

48
Q

what occurs if CPSI is defective?

A

ammonia from glutamate dehydrogenase cannot be made into carbamoyl phosphate by CPSI (rate limiting step), so ammonia increases, BUN decreases, and blood glutamine increases (trying to sequester ammonia)

49
Q

symptoms of CPSI deficiency?

A

hyperammonemia

increased blood glutamine

decreased BUN

NO increase in orotic acid or uracil

cerebral edema

lethargy, convulsions, coma, death

50
Q

what occurs if ornithine transcarbamoylase is deficient?

A

carbamoyl phosphate cannot be made into citrulline, so carbamoyl phosphate is shunted to pyrimidine synthesis (combines with aspartate to eventually make orotate, which then makes uracil)

51
Q

symptoms of ornithine transcarbamoylase deficiency?

A

hyperammonemia

increased blood glutamine

decreased BUN

increased orotic acid and uracil in blood and urine

cerebral edema

lethargy, convulsions, coma, death

52
Q

differentiate between UMP synthase deficiency, CPSI deficiency, and OTC deficiency

A

UMP synthase: see increased orotic acid but no increase in ammonia

OTC: increase in orotic acid and hyperammonemia

CPSI: no increase in orotic acid but hyperammonemia

53
Q

how to treat OTC or CPSI deficiencies

A

low protein diet, sodium benzoate, phenylpyruvate

54
Q

5 enzymes that can cause hyperammonemia

A
  1. carbamoyl phosphate synthase I
  2. ornithine transcarbamoylase
  3. arginosuccinate synthase
  4. arginosuccinate lyase
  5. arginase

MFM (39 decks)

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