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SMP - MNE Exam 2 > Lecture 31: Urea Cycle, Metabolic Priorities, and Diabetes > Flashcards

Lecture 31: Urea Cycle, Metabolic Priorities, and Diabetes Flashcards

1
Q

What is the purpose of the urea cycle?

A

To dispose of excess Nitrogen in the form of urea?

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2
Q

What is urea?

A

H2N-C-NH2
||
O

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3
Q

What is the only organ that can perform the urea cycle?

A

Liver

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4
Q

What is ornithine?

A

A 5C nonstandard AA: not used in protein synthesis, intermediate or UC

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5
Q

Is ornithine expended in the UC?

A

No it’s used and then regenerated

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6
Q

Urea Cycle Step 1: Enzyme?

A

CPS I: carbamoyl phosphate synthetase I

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7
Q

Urea Cycle Step 1: Location?

A

Mitosol

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8
Q

What is the first committed step of the urea cycle?

A

Step 1

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9
Q

What is the main regulatory step of the urea cycle?

A

Step 1

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10
Q

Ureal Cycle Step 1a: Reactants/Products?

A

HCO3- + ATP => Carbonic-phosphoric acid anhydride + ADP

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11
Q

Ureal Cycle Step 1b: Reactants/Products?

A

Carbonic-phosphoric acid anhydride + NH4+ => carbamate + Pi

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12
Q

Ureal Cycle Step 1c: Reactants/Products?

A

Carbamate + ATP => carbamoyl phosphate + ADP

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13
Q

What is the purpose of the 2 phosphorylations occurring in Step 1 of the UC?

A

They prepare the substrates for nucleophilic attacks

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14
Q

Where does the nitrogen used in step 1 of the UC come from?

A

Glutamate dehydrogenase: Glutamate + H2O + NADP/NAD+ => alpha-ketoglutarate + NADPH/NADH + NH4+

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15
Q

What is the center of nitrogen metabolism?

A

The mito

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16
Q

What regulates CPS I? How? Why?

A

N-acetylglutamate by allosteric regulation because high levels represent high levels of glutamate, which mean:

  1. Low gluconeogenesis because glutamate is not being used (high levels of Nitrogen in the body)
  2. High alpha-ketoglutarate levels = high rate of TCA cycle

=> LOW GLUCONEOGENESIS FROM AAs

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17
Q

How is N-acetylglutamate formed?

A

N-acetylglutamate synthase: acetyl-CoA + glutamate => N-acetylglutamate

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18
Q

Urea Cycle Step 2: Enzyme?

A

Ornithine transcarbamoylase

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19
Q

Urea Cycle Step 2: Location?

A

Mitosol

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20
Q

Ureal Cycle Step 2: Reactants/Products?

A

Carbamoyl phosphate + ornithine = citrulline + Pi

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21
Q

Net reaction of UC step 1?

A

HCO3- + 2 ATP + NH3 = carbamoyl phosphate + 2 ADP + Pi

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22
Q

How does the UC happen in both the mitosol and the cytosol?

A

Ornithine and citrulline can cross the mito membrane via transporters

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23
Q

Urea Cycle Step 3: Enzyme?

A

Argininosuccinate synthetase

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24
Q

Urea Cycle Step 3: Location?

A

Cytosol

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25
Q

Urea Cycle Step 3: Reactants/Products?

A

Citrulline + aspartate + ATP = arginino-succinate + AMP + PPi

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26
Q

Urea Cycle Step 4: Enzyme?

A

Argininosuccinase

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27
Q

Urea Cycle Step 4: Location?

A

Cytosol

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28
Q

Urea Cycle Step 4: Reactants/Products?

A

Arginino-succinate => fumarate + arginine

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29
Q

Urea Cycle Step 5: Enzyme?

A

Arginase

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30
Q

Urea Cycle Step 5: Location?

A

Cytosol

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31
Q

Urea Cycle Step 5: Reactants/Products?

A

Arginine + H2O => ornithine + urea

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32
Q

What happens to the ornithine regenerated in the 5th step of the UC?

A

Goes back in the mito for another round

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33
Q

How does the urea cycle reinforce the second metabolic priority?

A

When levels or arginine and ornithine are low it means that gluconeogenesis is high (arginine is glucogenic and ornithine is made from glutamate which is glucogenic), so you want the urea cycle to be slowed down to prevent protein catabolism

34
Q

What does the rate of the urea cycle depend on?

A

Levels of:

  1. Ornithine
  2. Aspartate

=> LEVEL OF TCA INTERMEDIATES

35
Q

Is the urea cycle energetically expensive?

A

No because it generates NADH:

  1. The first NH4+ added comes from this reaction: Glutamate + H2O + NADP/NAD+ => alpha-ketoglutarate + NADPH/NADH + NH4+
  2. Fumarate enters TCA after being formed in step 4 of UC and is converted to malate, forming NADH

TOTAL: 2 NADH formed = 5 ATP

Energy used: 4 high energy bonds = 2 ATP broken down into 2 ADP + 1 ATP broken down into AMP (2)

36
Q

Where does the aspartate used in step 3 of the urea cycle come from?

A

Oxaloacetate + glutamate = aspartate + alpha-ketoglutarate

37
Q

What are the 2 fates of the fumarate formed in step 4 of the urea cycle?

A
  1. Well-fed: enters mitosol to enter TCA to be converted to malate and continues through the TCA
  2. Starvation: stays in cytosol and is converted to malate => to oxaloacetate => to phosphoenolpyruvate through gluconeogenesis
38
Q

Describe the starvation metabolism. What hormones cause this?

A

High catecholamines AND low insulin =>

  1. TAG breakdown to liberate FFAs
  2. Ketogenesis because TCA intermediates are being used for gluconeogenesis so not enough of them for acetyl-CoA to enter the TCA
  3. Low glucose uptake by muscle and adipocytes
  4. Proteolysis to generate TCA cycle intermediates to be used in gluconeogenesis
39
Q

How is the pH drop from ketogenesis balanced out? 3 mechanisms

A
  1. Kidney released NH4+ since it can perform gluconeo but not urea cycle
  2. Other organs release K+
  3. Kussmaul breathing
40
Q

What is the most dangerous effect of ketoacidosis?

A

Neurons release their K+ to counter balance the pH drop which messes up their RMP

41
Q

What is nonketotic hyperosmolar coma? To what patients does this happen?

A

Hyperglycemia => water sucked out of cells => excretion of many critical solutes => coma

DIABETICS

42
Q

What is the lipostat theory? Describe the mechanism.

A

Adipose tissue is an endocrine organ secreting leptin which feeds back on the hypo to inhibit appetite, stimulate FA beta oxidation, and increase insulin sensitivity

  1. Leptin secreted binds to hypo
  2. Hypo stimulates sympathetic nervous outflow to release norepi on adipocytes
  3. Norepi binds to beta-adrenergic receptors: Gs cascade activating PKA:
  • PKA phosphorylates hormone sensitive lipase and perilipin = phosphorylates perilipin = TAGs available for HSL to break them down
  • PKA upregulates the expression of uncoupling proteins so fatty acid beta oxidation is increased cause energy is being waster through thermogenesis
43
Q

What 2 experiments confirm the lipostat theory?

A
  1. (ob/ob) knockout mice (double knockout of the leptin gene) become obese and insulin resistant
  2. (db/db) knockout mice (double knockout for the leptin receptor gene) become obese and insulin resistant
44
Q

Why are leptin knockout mice unable to stay warm?

A

They are unable to do this:

  1. Leptin secreted binds to hypo
  2. Hypo stimulates sympathetic nervous outflow to release norepi on adipocytes
  3. Norepi binds to beta-adrenergic receptors: Gs cascade activating PKA
  4. PKA upregulates expression of uncoupling proteins for brown fat to create heat
45
Q

How does leptin increase the sensitivity to insulin?

A
  1. Leptin’s receptor is also a protein kinase and helps insulin phosphorylate IRS-2 which then activates PI-3K
  2. Leptin activates AMP-dependent protein kinase (AMPK) which phosphorylates similar substrates as the insulin receptor (eg: PKB)
46
Q

How is leptin secreted in obese peeps?

A

The hormonal activity of the adipose tissue is dysfunctional and leptin is not secreted as well

47
Q

What is the role of adiponectin? What is it secreted by? For who is this hormone important?

A

Produced and released by adipose tissue and also activates AMPK

48
Q

What effects does AMPK have on the muscles and liver? What is its overall goal?

A

Muscles:

  1. Helps muscle take up glucose and FAs
  2. Promotes FA beta oxidation especially during exercise

Liver:
3. Inhibits FA synthesis in the liver

=> SAVE ATP

49
Q

Other than leptin and adiponectin, what else stimulates AMPK in cells? How does this work?

A

EXERCISE! ATP is used up = AMP is produced = AMPK is activated

50
Q

Why is it important to preserve proteins during starvation?

A

You want to avoid wasting away enzymes needed for catalysis

51
Q

What is the predominant source for gluconeogenesis during starvation?

A

Glycerol for TAGs

52
Q

Difference between CPS-I and II?

A

CPS-I: uses glutamate in the mitosol

CPS-II: uses glutamine in the cytosol

53
Q

Where do the 2 nitrogens in the urea cycle come from?

A
  1. Glutamate

2. Aspartate

54
Q

Describe the mechanism in Step 3 of the Urea Cycle.

A

AMP is attached to citrulline, and then Nu substitution of AMP and aspartate

55
Q

What exactly happens in Step 4 of the Urea Cycle?

A

The carbon skeleton of aspartate is reduced and released = fumarate

56
Q

What is citrulline?

A

A 6C nonstandard AA: not used in protein synthesis, intermediate of UC

57
Q

What does dearth mean?

A

Lack of something/low levels of something

58
Q

What do low amounts of TCA intermediates mean?

A

Low levels of glucogenic AAs, meaning they are being used for gluconeogenesis

59
Q

What is the main hormone of starvation?

A

CATECHOLAMINES

60
Q

What happens to the excess nitrogen in the kidney during starvation, since this organ can perform gluconeogenesis but not the urea cycle?

A

Secreted to balance out the drop in pH due to ketogenesis

61
Q

What is ammonium?

A

NH4+

62
Q

What are levels of acetyl-CoA in the mitochondria representative of?

A

Pretty much nothing

63
Q

What are the 2 ways in which adipose tissue regulates itself?

A

LEPTIN

  1. Decrease appetite
  2. Increase fatty acid beta oxidation by increasing uncoupling proteins
64
Q

What are the 2 ways in which AMPK can be activated in diabetics?

A
  1. Exercise

2. Thiazolidinediones drugs (Avandia and Actos) which increase adiponectin in adipose tissue

65
Q

What are the 3 side effects of thiazolidinediones?

A

Increased risk of:

  1. Stroke
  2. Heart attacks
  3. Bladder cancer
66
Q

On what hypothalamic nucleus does leptin act?

A

Arcuate nucleus

67
Q

Where does the hyperglycemia come from in ketoacidosis?

A

Liver gluconeogenesis

68
Q

Why does DKA not cause the same symptoms as lactic acidosis?

A

Lactic acid will be converted to glucose again in the liver or lactic acid will fill up the TCA cycle and be used to catabolize fatty acids in the liver, so it does not cause as many problems

69
Q

What causes lactic acidosis?

A

Exercise and being out of breath most of the time

70
Q

What often causes DKA in diabetics?

A

Stress which increases energy needs and cortisol and cathecholamines powerfully stimulate gluconeogenesis causing excess ketogenesis

71
Q

Why could it be dangerous to only inject insulin in a patient with diabetic DKA? What else should be injected with insulin?

A

As we inject insulin, the blood pH will begin to rise. This will then lead to potassium being transported back into the cells causing an extremely low levels of potassium in the extracellular matrix.

K+ should also be injected

72
Q

What organ regulates Kussmaul breathing?

A

Adrenal medulla

73
Q

What is the normal range of blood bicarbonate?

A

24-28 mEq/L

74
Q

What is the normal blood [K+]?

A

3.5-5.0 mEq/L = 50 mEq/kg

75
Q

What is the normal BUN range?

A

10-20 mg/dL

76
Q

What is the normal BUN range?

A

10-20 mg/dL

77
Q

What is pancreatitis? Symptom? Patients at risk?

A

Pancreatic enzymes get processed too soon and start digesting the pancreas

Upper abdominal pain that extends through the back

Happens in diabetes and digestive disorders

78
Q

What is alcohol ketoacidosis?

A

Alcohol consumption => liver needs to oxidize ethanol to detoxify it generating a lot of NADH => not enough NAD+ to drive gluconeogenesis nor convert alpha-ketoglutarate to glutamate so glucoenogenesis using AAs is inhibited => not enough energy fuel after a night of binge drinking => high levels of ketones

79
Q

Why can heavy drinking cause hyperglycemia?

A

Many alcoholic beverages have a lot of sugar

80
Q

What are the symptoms of DKA? Explain each.

A

• Hyperglycemia: Over 300 mg/dL glucose (this is very elevated glucose) due to gluconeogenesis lack of insulin
• Low bicarbonate: Less than 15 mEq/L: used in gluconeogenesis and to buffer low blood pH
• Acidosis: pH is less than 7.30: low bicarbonate and high ketone bodies
• Ketonemia and Ketonuria: high blood and urine levels of ketone bodies. Ketone bodies are not just metabolic fuel but a mechanism of getting rid of excess levels of Acetyl-CoA in the liver.
• Water deficit: increased urine output with high spill off of glucose and ketones + lots of hydrolyses reactions H2O is being consumed rapidly by the cells.
• Total body potassium deficit (deficit of 3-5 mEq/kg body weight with normal being 55
mEq/kg): K+ used to counter balance the low pH of blood (the potassium levels in the blood are normal or can even be elevated, but the total body potassium is low because excreted in urine)
• High blood urea nitrogen: the body is in starvation mode, thus fat and protein breakdown leads
to urea build up

81
Q

What is normal blood pH?

A

7.35-7.45

SMP - MNE Exam 2 (17 decks)

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