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DEMS > Metabolism > Flashcards

Metabolism Flashcards

1
Q

What are the products of the HMP pathway?

A

NADPH (for energy) and ribose sugars (for purines, pyrimidines, acetyl CoA, etc.)

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2
Q

What are the two transporters that take up glucose into cells and what are the differences between them?

A

Glut2 and Glut4

Glut4 = insulin sensitive (skeletal muscle)

Glut2 = not insulin sensitive (brain, liver)

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3
Q

Hexokinase

A

Regulates the first key step in glycolysis: adding a phosphate to glucose to make it glucose 6-p

Hexokinase is located everywhere but the liver; it has a much lower Km (concentration of glucose at which the rxn is half maximal) and Vmax (max rate of the enzyme) than glucokinase

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4
Q

Glucokinase

A

Regulates the first key step in glycolysis: adding a phosphate to glucose to make it glucose 6-p

Located in the liver. Has a higher Km and Vmax than hexokinase. Reason: when your blood sugar is low, you want it to go to the peripheral tissues! Thus, at low concentrations, hexokinase is more active than glucokinase. However, if you have a lot of glucose, you want to direct it to the liver to be stored as glycogen.

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5
Q

Phosphofructokinase-1 (PFK-1)

A

Regulates a key step in glycolysis: turning fructose 6-P into fructose 1,6-bisphosphate

Has both allosteric and covalent modification

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6
Q

Which molecules downregulate PFK-1?

A

ATP and citrate

If there’s a lot of ATP, you have enough energy and you don’t need glycolysis. If there’s a lot of citrate, TCA cycle is running (it’s an intermediate) and you don’t need energy/glycolysis.

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7
Q

Which molecules upregulate PFK-1?

A

AMP and fructose 2,6-bisP

If AMP is high = there’s no energy = you need glycolysis. F2,6bisP is a sign that insulin is high and glucagon is low; i.e., there’s glucose around and glycolysis needs to start.

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8
Q

Insulin generally does what?

A

Dephosphorylates

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9
Q

Glucagon generally does what?

A

Phosphorylates

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10
Q

What are the 3 key regulated steps in glycolysis?

A

1) glucose –> glucose 6-P
2) fructose 6-p –> fructose 1,6-bisP
3) phosphoenolpyruvate –> pyruvate

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11
Q

What is the deal with the whole PFK-2/FBP-2 + fructose 2,6-bisP thing?

A

High insulin –> dephosphorylation of the PFK-2/FBP-2 complex –> PFK-2 is active –> favors formation of fructose 2,6bisP

Fructose 2,6-bisP activates PFK-1, which leads to an increased rate of glycolysis

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12
Q

Pyruvate kinase

A

Turns phosphoenolpyruvate –> pyruvate in glycolysis

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13
Q

How do insulin and glucagon regulate pyruvate kinase?

A

Glucagon phosphorylates and inactivates it

Insulin dephosphorylates and activates it

We want glycolysis to go when we have lots of glucose in the blood

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14
Q

What are the net results of glycolysis?

A

2 ATP and 2 NADH

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15
Q

Lactate dehydrogenase

A

Facilitates interconversion of pyruvate lactate

This enzyme can go either way ;). Both molecules have similar levels of energy.

Driven by ratio of NADH to NAD. A cell w/ a lot of NADH (e.g., cell is running glycolysis, generating pyruvate and NADH is in excess) —> rxn will run more towards lactate

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16
Q

When pyruvate turns into acetyl CoA, what is lost?

A

CO2

Pyruvate = 3 carbons
Acetyl CoA = 2 carbons

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17
Q

Pyruvate dehydrogenase complex (PDH)

A

Turns pyruvate into acetyl CoA
Key regulated step!

This process takes place in the mitochondria

This enzyme requires a THIAMINE COFACTOR. Produces NADH

Regulated via end-product inhibition. If you have a lot of acetyl CoA or NADH, you don’t need this process, and it’s inhibited via allosteric regulation

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18
Q

Where does the TCA cycle happen?

A

In the mitochondrial matrix

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19
Q

Where does electron transport happen?

A

In the inner mitochondrial membrane and intermembranous space

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20
Q

Citrate

A

Substrate in the TCA cycle

Also the precursor to acetyl CoA in fatty acid synthesis

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21
Q

Citrate synthase

A

Enzyme in the TCA cycle. Forms citrate from acetyl CoA and/or oxaloacetate

Most commonly measured mitochondrial enzyme

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22
Q

Oxaloacetate

A

Substrate in the TCA cycle and gluconeogenesis. Last step of TCA cycle.

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23
Q

α-ketoglutarate

A

Substrate in the TCA cycle

This is also the entry point into the TCA cycle for turning amino acids into glucose via gluconeogenesis

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24
Q

Succinate dehydrogenase

A

Enzyme in the TCA cycle. Converts succinate into fumarate.

Converts FAD to FADH2. Takes place at the inner mitochondrial membrane; really part of the ETC

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25
Q

What are the products of the TCA cycle?

A

2 CO2 molecules (all carbons from glucose are gone)

3 NADH

Also FADH2, GTP

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26
Q

Malate dehydrogenase

A

Enzyme in the TCA cycle. Converts malate into oxaloacetate.

Malate (precursor to oxaloacetate) is also involved in gluconeogenesis

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27
Q

Coenzyme Q (CoQ)

A

Part of the electron transport chain. Shuttles electrons from one part to the next

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28
Q

How is overnutrition/obesity an oxidative stress?

A

If you’re generating a bunch of electrons but not generating ATP because you have enough already, that electron can go onto an oxygen species and create an oxygen radical :(

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29
Q

How do RBCs get energy?

A

They don’t have mitochondria, so they burn glucose and get lactate (anaerobic respiration)

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30
Q

What are potential sources of carbon skeletons that the liver can use for gluconeogenesis?

A

Lactate, glycerol (from adipose), and amino acids

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31
Q

When fat is oxidized, what does it turn into, and where?

A

Acetyl CoA in the liver

FAT CANNOT TURN INTO GLUCOSE

32
Q

What is the Cori cycle?

A

Glucose made by the liver goes out to the tissues, is metabolized into lactate, lactate goes back to the liver, gets turned back into glucose via gluconeogenesis.

33
Q

What is the first key regulated step of gluconeogenesis?

A

Pyruvate inside the mitochondria turns into oxaloacetate

Enzyme: pyruvate carboxylase

34
Q

Pyruvate carboxylase

A

Enzyme that converts pyruvate into oxaloacetate as part of gluconeogenesis

Key regulated step!

The enzyme fixes CO2 and sticks it on pyruvate = 3C to 4C.

Allosterically regulated - acetyl CoA stimulates this. Acetyl CoA comes from fat oxidation.

35
Q

What is the second key regulated step of gluconeogenesis?

A

PEPCK turns (cytosolic) oxaloacetate into phosphoenolpyruvate.

(After oxaloacetate is created in the mitochondria, it gets converted into malate, malate gets transported into the cytosol, and then gets reoxidized to oxaloacetate)

This rxn produces a CO2 molecule

36
Q

PEP carboxykinase (PEPCK)

A

Enzyme in gluconeogenesis. Turns cytosolic oxaloacetate into phosphoenolpyruvate. Produces a CO2 molecule.

This enzyme is transcriptionally regulated by glucagon. When glucagon is high, we’re fasting, we make more PEPCK, and so we run the pathway in this direction.

37
Q

Fructose 1,6 bisphosphatase

A

Enzyme in gluconeogenesis. Converts fructose 1,6 bisphosphate into fructose 6-phosphate

Key regulated step!

38
Q

Glucose 6-phosphatase

A

Enzyme in gluconeogenesis. Converts glucose 6-phosphate back into glucose. Glucose can then exit the cell.

39
Q

What enzyme is only found in the liver and kidneys?

A

Glucose 6-phosphatase

Only about 20% of gluconeogenesis occurs in the kidney

40
Q

What is glycogen used for and where is it in our bodies?

A

Rapidly available form of glucose

Found in muscle and liver

The glycogen in muscle is primarily for its own use. The glycogen in liver is for the whole body. Thus, the regulation of glycogen breakdown in these tissues is slightly different.

41
Q

What is the structure of glycogen?

A

Branched glucose molecules, like a tree. Allows for more rapid pruning; rapid mobilization and storage of glucose.

The linear chains are 1,4 bonds and the branches are 1,6 bonds

SIX = STICKS (branches)

42
Q

Glycogenin

A

The protein anchor that takes the very first glucose to build the glycogen molecule

43
Q

Glycogen synthase

A

Synthesizes glycogen :)

Only synthesizes the 1,4 bond linear chains

44
Q

Branching enzyme

A

Synthesizes the 1,6 bonds of the glycogen molecule

45
Q

Glycogen phosphorylase

A

Sequentially removes 1 glucose 1-P molecule at a time from a glycogen molecule

Stops 4 residues away from a branch point

46
Q

Debranching enzyme

A

2 activities:

1) transferase - takes 4 remaining residues in a branch, transfers 3 to the end of a linear chain
2) glucosidase - removes the 1 remaining branched residue at the 1,6 bond

47
Q

What causes glycogen breakdown in muscle?

A

Ca2+ and AMP.
When you start exercising, AMP goes up (you’re using energy) and Ca2+ goes up (it’s muscle). These signal for the breakdown of glycogen for more energy.

Thus, obviously, G6P and ATP inhibit the breakdown of glycogen, and G6P actually promotes the creation of glycogen.

48
Q

Hemolytic anemia, a/w drugs, in a woman from Africa

A

G6PD deficiency

49
Q

Glucose 6-phosphate dehydrogenase

A

Key enzyme in HMP pathway

Important for the synthesis of lipids; maintaining redox balance

50
Q

What does NADPH do?

A

1) it’s an energy source - important for the synthesis of lipids
2) it protects against oxidant stress!

If you get oxidant stresses (like sulfa drugs), normally you protect against them with glutathione; you need NADPH

If there’s a deficiency in G6PD, you won’t have any NADPH –> increased susceptibility to oxidant stresses like medications, possibly leading to hemolytic anemias

51
Q

What is the proportion of resting energy expenditure in a sedentary person?

A

75% of total energy expenditure

52
Q

Is cortisol water- or lipid-soluble?

A

Lipid-soluble

53
Q

Describe the structure of insulin from the moment it comes off the ribosome to its final form

A

Insulin comes off the ribosome as pre-pro-insulin

After a signal peptide is cut off = pro-insulin. That structure folds, acquires disulfide bonds = 3D structure

C-peptide gets cut off. Afterwards = insulin

Thus, C-peptide is a measure of endogenous insulin production

54
Q

Biphasic insulin release

A

When glucose arrives in the bloodstream, there is an initial burst of insulin = first phase

Later, there is a more sustained, slower release = second phase

Diabetics lose the first phase of insulin release

55
Q

Mechanism of insulin secretion

A

Glucose enters a beta cell via glut-2 transporters (can’t be insulin sensitive transporters, as there is no insulin in the blood!)

Once in the cell, glucose undergoes glycolysis –> produces pyruvate, ATP, and NADH. An increase in the latter 2 causes the closing of voltage-gated K+ channels –> cell depolarizes –> Ca2+ channels open, Ca2+ enters the cell –> causes vesicles full of insulin to bind to cell membrane and expel their contents

56
Q

What happens when free insulin binds to its cell membrane-bound receptor?

A

It phosphorylates amino acids inside the the intracellular domain of the receptor

This attracts other proteins to the receptor = insulin receptor substrates

Downstream effects, etc. etc.

57
Q

What are the two main downstream pathways of insulin we have to know about?

A

1) PI3K pathway - SUGAR! This pathway mediates some of the glucose effects of insulin
2) MAP kinase/ERK - mitogenesis, growth, etc. Ppl with diabetes/obesity get more cancer, probably because this pathway does not become insulin insensitive & gets a lot of stimulation from the chronic hyperinsulinemia

58
Q

What is the downstream effect of PI3K?

A

When PI3K is activated, the vesicles with glut 4 transporters dock at the cell membrane –> more glucose transporters get inserted into membrane –> more glucose gets taken up into cells

This is short-term. If the insulin goes away and glucagon goes up, these receptors get endocytosed

59
Q

Why do type 2 diabetics have high levels of glucagon?

A

There is a receptor on the glucagon-containing cells that is insulin sensitive. Since a T2DM individual is insulin resistant, that receptor doesn’t receive any signaling. Thus, there is no suppression of glucagon in the fed state, and blood sugar levels continue to rise

60
Q

Incretin effect

A

If there’s food in the intestine, rather than waiting for blood sugar to rise, the body will signal to the pancreas to increase insulin levels

Thus, glucose taken PO will cause a much higher rise in insulin than glucose given IV

Important hormone involved in this: GLP-1

61
Q

DPP-4

A

Enzyme that inactivates GLP-1

Blocking this enzyme = diabetic tx!

62
Q

What is the criteria for diabetes?

A

Fasting glucose >=126
Oral glucose tolerance test >=200
HgA1c >=6.5%

Impaired (“pre-diabetes”):
Fasting glucose = 100-125
GTT = 140-199
HgA1c = 5.7-6.4

63
Q

What are the four autoantibodies present in Type 1 diabetes?

A

Insulin, IA-2, GAD65, and ZnT8

64
Q

Maturity onset diabetes of the young (MODY)

A

AD

Familial diabetes presenting in youth that is neither Type 1 nor Type 2

Characterized by impaired insulin secretion with no defects in insulin action

Can be treated with sulfonylureas

65
Q

Humalog (Lispro)
Novolog (Aspart)
Glulisine (Apidra)

A

Rapid-acting insulins

Onset 5-15 min, peak 1-1.5 hrs, duration 3-5 hrs

Given just prior to a meal

66
Q

Afrezza

A

Inhaled rapid-acting insulin

Onset 5 min, peak 1 hour, duration 2 hours

Given just prior to a meal

67
Q

Humulin R

Novolin R

A

Short-acting regular insulin

Onset 30-60 min, peak 2 hrs, duration 6-8 hrs

Inject 30 min before eating

68
Q

NPH (Humulin N, Novolin N)

A

Intermediate-acting insulin

Onset 1-3 hours, peak 6-8 hours, duration 12-16 hours

SQ injection only

Acts as basal coverage

69
Q

Glargine (Lantus)

Detemir (Levemir)

A

Long-acting insulin

Onset 1-1.5 hours, no peak

Duration 24 hrs (glargine) or 12-20 hrs (detemir)

SQ injection. Cannot be mixed in the same syringe with any other insulins

70
Q

Sulfonylureas

A

Cause release of insulin from beta cells; address beta cell dysfxn

Pros:

  • inexpensive
  • combo pills available

Cons:

  • weight gain
  • hypoglycemia
  • lose effectiveness with longer duration of diabetes
71
Q

Metformin

A

Potentiates the suppressive effect of insulin on hepatic glucose production

Pros:

  • no hypoglycemia
  • inexpensive
  • no weight gain
  • combo pills available

Cons:

  • GI SE: N/D
  • risk of lactic acidosis with HF, renal insuff.
72
Q

Thiazolidinediones (TZDs)

A

Increase insulin sensitivity

Pros:
- mechanism of action

Cons:

  • WORSENING OF CHF
  • $$
73
Q

GLP-1

A

Potentiates the action of glucose. Does not, by itself, cause insulin secretion.

If you have an increase in glucose + GLP-1, you get more insulin out into circulation than just with either alone.

Also inhibits glucagon release! Also decreases appetite! Also slows down stomach emptying!

If you give someone GLP-1 and their blood sugar is normal, insulin doesn’t come out. Only comes out if glucose is high.
If you give someone GLP-1 and their blood sugar is high, it’ll lower blood sugars, but it won’t make them hypoglycemic :)

74
Q

GLP-1 agonists

A

Pros:

  • multiple mechanisms to lower postprandial glucose
  • effects are insulin-dependent
  • weight loss

Cons:

  • SQ injections
  • SE
  • $$
75
Q

DPP-4 inhibitors

A

Pros:

  • multiple MOAs
  • oral
  • once daily
  • weight neutral
  • combo pill w/ metformin available

Cons:

  • Less potent
  • SE
  • $$
76
Q

SGLT-2 inhibitors

A

Block glucose reuptake in the kidney

Result: any blood sugar over 100 gets peed out

Pros:

  • novel mechanism that doesn’t depend on pancreatic fxn
  • weight loss
  • pill
  • combo pill w/ metformin available

Cons:

  • risk for UTI and GU infections
  • risk for low K
  • $$
  • long-term safety??

See Glucose Lost via Tinkling

DEMS (4 decks)

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