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HMBP Week 3 > The Urea Cycle (LM 11.4) > Flashcards

The Urea Cycle (LM 11.4) Flashcards

1
Q

what is the only organ that carries out the urea cycle? why?

A

the liver!

only the liver has all of the enzymes required for each of the 5 enzymatic steps that comprise the full urea cycle

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2
Q

what are the 5 enzymatic reactions of the urea cycle?where do they occur?

A

MITOCHONDRIAL MATRIX

  1. HCO3- + NH3 –> carbamoyl phosphate
  2. carbamoyl phosphate + ornithine –> citrulline

CYTOSOL

  1. citrulline + aspartate–> argininosuccinate
  2. argininosuccinate –> arginine + fumarate
  3. arginine + H2O –> urea + ornithine (regenerated)
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3
Q

what are increased and decreased cycle flux?

A

an increase in the overall rate of a cycle either due to increased cycling speed and/or increased numbers of the cycle working concurrently is increased cycle flux

decreased cycle flux is when the overall rate decreases

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4
Q

what’s a major source of the ammonia/ammonium in the body? what happens to the extra?

A

the alpha-amino group from AA undergoing catabolism

the other source is the normal turnover of body protein

some of this ammonia & ammonium are consumed in biosynthesis of nitrogen-containing compounds and the excess is converted to urea in the liver and then the urea is excreted from the body in the urine

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5
Q

why is the urea cycle important?

A

it incorporates excess nitrogen in the body to form urea

this is super important for maintaining nitrogen balance and protecting against hyperammonemia which could be deadly

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6
Q

what is the only purpose of urea? why is it good for this job?

A

to rid the body of excess nitrogen - it’s not used for any other pathway or purpose in the body

it’s good for this job because it’s highly soluble in the blood and urine and because its synthesis incorporates TWO amino groups (double duty)

  1. 1 nitrogen from incoming ammonia molecule
  2. another nitrogen from amino group of aspartate
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7
Q

what NEW compounds are made by the urea cycle?

A

only urea!!

the 4 molecular intermediate (ornithine, citrulline, argininosuccinate and arginine) are all recycled with each turn –> they’re like horses on a carousel that just keep spinning around and around

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8
Q

how much ATP is consumed during the urea cycle?

A

3 ATP

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9
Q

where does the carbon in urea come from?

A

HCO3-

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10
Q

where do the two amino groups in urea come from?

A

one from aspartate and one from ammonia (NH3)

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11
Q

where does the oxygen in urea come from?

A

H2O

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12
Q

are high protein diets bad for the liver?

A

no!!!

no matter how much protein you take in your diet, the liver can safely dispose of ammonia/nitrogen produced from catabolism of AA or other metabolic processes

unless you have liver disease or genetic mutations that result in urea cycle disorder

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13
Q

what are two scenarios where healthy individuals are upping their protein catabolism?

A
  1. paleo diet: most calories are derived from protein
  2. naked and afraid
    individuals are really fit in the beginning so they have very little fat reserved to burn for energy - they find very little to eat so their carbohydrate stores are used up quickly and have to resort to burning their body’s own proteins for energy (like skeletal muscle)
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14
Q

how many AA can be used to give rise to net glucose production?

A

14 out of the 20!

the glucogenic AA

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15
Q

how do the urea cycle and TCA cycle work together?

A

when your body needs energy and starts breaking down proteins, the first step in protein catabolism is removal of the alpha-amino nitrogen group of the AA

this gets safely disposed of in the urea cycle and then the carbon skeleton of the glucogenic AAs are fed into various TCA entry points

carbon skeleton usually gets metabolized and enters the TCA cycle where oxaloacetate can enter gluconeogenesis

so the urea cycle and TCA cycle have to be on the same pace! like gears on a bike

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16
Q

what is the first reaction of the urea cycle?

A

carbamoyl phosphate synthetase-I (CSP-I) catalyzes formation of carbamoyl phosphate from bicarbonate and ammonia

driven by high ammonia concentrations services from glutamate dehydrogenase reaction

rate limiting step of the urea cycle!! and also basically irreversible because it uses 2 ATP

in the mitochondrial matrix

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17
Q

what is the allosteric activator of CPS-1 enzyme?

A

N-acetylglutamate (NAG)

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18
Q

what are the 2 different enzymes in the body that can form carbamoyl phosphate?

A

CPS-I and CPS-II

ONLY CSP-I is used in the urea cycle

CPS-II is used in pyrimidine synthesis pathway, it is NOT used in the urea cycle

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19
Q

what are the characteristic of CPS-I?

A

carbamoyl-phosphate synthetase I

CPS-I is the rate limiting step of the urea cycle and it is the first step of the urea cycle

it’s located in the mitochondrial matrix

it uses NH3 as a nitrogen source for its reaction

NAG is an obligate activator of CPS-activity

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20
Q

what regulates CPS-I?

A

NAG

it is ABSOLUTELY NECESSARY for urea cycle function

21
Q

what are the characteristics of CPS-II?

A

it’s located in the cytoplasm

it uses glutamine in its reaction as the nitrogen source

NAG is not involved in CPS-II action

22
Q

what is the second reaction of the urea cycle?

A

ornithine transcarbamoylase converts carbamoyl phosphate to citrulline

in the mitochondrial matrix

citrulline then exits the mitochondria through a specialized membrane transporter –> this is required because the next step of the urea cycle happens in the cytoplasm!

23
Q

what is the most prevalent genetic disorder of the urea cycle?

A

defects in the OTC gene (OTC deficiency) are the most prevalent genetic disorder of the urea cycle

it’s also the only urea cycle disorder that is x-linked

24
Q

what’s the third reaction of the urea cycle?

A

arginosuccinate synthetase (ASS) acts to form arginosuccinate from citrulline and aspartate

in the cytoplasm!

aspartate hops on the citrulline horse on the merry-go-round then gets off at the next step when fumarate is made but leaves behind it’s hate, aka amino group that is the second amino group in the final urea molecule

25
Q

what is the fourth reaction of the urea cycle?

A

argininosuccinase aka argininosuccinate lyase (ASL) cleaves the argininosuccinate forming arginine and fumarate

the carbon skeleton of aspartate is preserved as fumarate and fumarate can serve as precursor for NET glucose production via TCA cycle

26
Q

what happens to the fumarate generated in the urea cycle?

A

fumarate can give rise to NET glucose production because it’s in the TCA cycle! whether fumarate is directed to the gluconeogenesis pathway depends on the energy status of the cell and the glucose needs of other organs

fumarate can be turned into oxaloacetate which can then be turned into PEP which can go into gluconeogenesis and make glucose

since only the liver has urea cycle enzymes, the production of fumarate via argininosuccinase reaction is exclusive to the liver –> this is helpful since the liver is also the sole site of gluconeogenesis

27
Q

what is the final reaction of the urea cycle?

A

arginase cleaves arginine and releases urea and regenerates ornithine

ornithine is then transported from the cytoplasm back to the mitochondria to restart the cycle

28
Q

what does hydrolysis mean?

A

when a molecule is hydrolyzed, it means water is used to break a bond

29
Q

why can’t the kidney do the urea cycle?

A

it has very very very little aka basically no arginase

which is actually why the kidney is the major site of arginine synthesis!

if the kidney did have arginase then it would cleave arginine into urea and ornithine and therefore destroy arginine

30
Q

how is aspartate used in the urea cycle formed?

A

transamination of oxaloacetate

31
Q

which 2 membrane transport proteins at the inner mitochondrial membrane are required for urea cycle function?

A

ORNT1 (symporter)

Citrin (antiporter)

they are both co-transporters!

32
Q

what does ORNT1 do?

A

membrane transport protein at the inner mitochondrial membrane required for urea cycle function

ORNT1 is the transporter that allows for compartmentalization of the urea cycle into the parts in the cytoplasm vs. mitochondria

33
Q

what does Citrin do?

A

membrane transport protein at the inner mitochondrial membrane required for urea cycle function

this transporter provides for an ongoing supply of aspartate and moves it from the mitochondria to the cytoplasm so that there’s sufficient aspartate supply for the urea cycle

it’s also a part of the malate-aspartate shuttle that passes reducing equivalents across the inner mitochondrial membrane in the TCA cycle and oxidative phosphorylation

34
Q

what is Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH)?

A

Genetic mutation in ORNT1 transporter involved in urea cycle

35
Q

what is Citrullinemia Type II?

A

Citrin transporter doesn’t put aspartate into the cytoplasm where it’s needed for urea cycle

aspartate is needed to feed into the argininosuccinate synthetase reaction where it would combine with citrulline to form argininosuccinate

without enough aspartate in the cytoplasm, this reaction doesn’t happen and citrulline would accumulate in the cells and ultimately the blood

36
Q

when would short term regulation of the urea cycle happen?

A

this would occur following a particularly high protein meal or under short term conditions of negative nitrogen balance

short term negative nitrogen balance would be like catabolic stress due to fever or infection

37
Q

how is the urea cycle regulated short term?

A

short term regulation is mainly by regulation of its rate limiting enzyme, CPS-I

however, CPS-I is NOT directly regulated but instead its regulated through controlling the synthesis of its obligate activator, NAG

38
Q

why would elevated acetyl CoA mean there’s increased need for higher urea cycle activity?

A

if a lot of protein is being catabolized then this probably means that the body likely needs a lot of energy

under these conditions the body is likely also burning glucose and/or FA

the end product of carbohydrate and FA catabolism is the production of acetyl CoA for entry into the TCA cycle

39
Q

why do elevated glutamate levels indicate that high urea cycle flux is needed?

A

we know that when there’s a lot of AA catabolism happening then there would be an increased level of transamination of alpha-ketoglutarate to glutamate from the alpha-amino group that’s removed from the AA undergoing catabolism

if you’re breaking down a lot of AA then it means the urea cycle needs to happen to get rid of the N produced

40
Q

how is the urea cycle regulation long term?

A

this would occur with a prolonged high protein diet or prolonged starvation (when the body is using its own proteins like skeletal muscle for energy and to maintain BG)

under these conditions, genes for the enzymes of the urea cycle are transcriptionally induced!

the transcripts for these genes are translated to make higher levels of the enzymes of the urea cycle

41
Q

how are the first steps of AA nitrogen catabolism and the urea cycle interconnected?

A

the first step in AA catabolism is the removal of their amino group by a transamination reaction

no matter what AA is undergoing this transamination, that amino group that got removed is transferred to alpha-ketoglutarate to form glutamate!!!!!!

so with high AA catabolism, there’s increased glutamate formation –> this promotes NAG synthesis which ensures high activity of CPS-I in the rate limiting step of the urea cycle so that it can keep up with the increased protein catabolism

the glutamate can also donate its amino group to oxaloacetate to form the aspartate that is needed for the argininosuccinate synthase reaction of the urea cycle

HOWEVER, most of the glutamate formed undergoes oxidative deamination by action of glutamate dehydrogenase which provides the free ammonia that gets used in the first reaction of the urea cycle to make carbamoyl phosphate

42
Q

how is the urea cycle inked to the TCA cycle?

A

the production of fumarate by the urea cycle and the conversion of the TCA cycle intermediate oxaloacetate to aspartate are reasons that connect the urea cycle with the TCA cycle

this ensures that TCA cycle flux and urea cycle flux are pretty matched up

43
Q

why is it important that the flux of the TCA cycle and urea cycle be matched up?

A

as carbon skeletons of some of the AA feed into the TCA cycle, the body is also assured that their is sufficient concurrent urea cycle activity to dispose of the amino nitrogen groups of these catabolized AA in a non-toxic manner through the formation of urea

44
Q

which molecules tie the TCA cycle and the urea cycle?

A

fumarate
aspartate
oxaloacetate
malate

45
Q

what does it mean for your TCA cycle and alpha-ketoglutarate if you’re breaking down AA?

A

if you’re breaking down AA then you are super desperate and your glycogen stores are long used up so you’re turning to AA to help meet and maintain correct blood sugar

this also means that your liver needs to be conducting de novo glucose synthesis aka gluconeogenesis

so what happens is that alpha-ketoglutarate is a glucogenic substance –> it can be made from the carbon skeletons of some glucogenic amino acids or by transamination of glutamate

increasing alpha-ketoglutarate derived from glutamate into the TCA cycle contributes to new glucose formation because eventually you’ll get to oxaloacetate which can be used to form pyruvate (the starting point of gluconeogenesis!)

46
Q

what are the two ways you can make alpha-ketoglutarate?

A

from the carbon skeletons of glucogenic AA

OR

transamination of glutamate via glutamate dehydrogenase

47
Q

how is glutamate dehydrogenase regulated?

A

high ADP increases its activity because it means the cell is at a low energy state

ATP is a positive allosteric effector of the REVERSE glutamate dehydrogenase reaction - this happens during biosynthesis of AA

48
Q

how many urea disorders are there?

A

8

any genetic defect that comprises the function of the genes for the 5 Urea Cycle enzymes or the NAG synthetase or the two transporter (ORNT1 and Citrin)

49
Q

what are the 8 urea cycle disorders?

A
  1. argininase deficiency
  2. ornithine transcarbamoylase deficiency
  3. carbamoyl phosphate synthetase deficiency
  4. N-acetylglutamate synthase deficiency
  5. argininosuccinate synthetase deficiency
  6. argininosuccinase deficiency
    +2 transporter disorders

HMBP Week 3 (8 decks)

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