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Biochemistry II > FA metabolism > Flashcards

FA metabolism Flashcards

1
Q

What is the general function of triacylglycerols?

Where are they stored and metabolized?

A

major energy reserve of the body (9 kcal/g), stored in adipose tissue

→ lipolysis, released into blood stream and transported to effector organs

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2
Q

As a review…

List the most important saturated, mono-, polyunsaturated fatty acids.

A
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3
Q

Differentiate btw the 3 types of lipases found in adipocytes.

A
  • adipocyte triglyceride lipase (ATGL): activated once CGI binds to it after detaching from perilipin
    TAG → DAG + FA
  • hormone-sensitive lipase (HSL): activated in response to phosphorylation by PKA
    DAG → MAG + FA
  • monoacylglycerol lipase (MSL):
    MAG → G + FA
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4
Q

What is the function of perilipins?

A

cover lipid droplets

  • prevent unregulated lipolysis (when dephosphorylated)
  • CGI detaches in response to phosphorylation
    → activation of ATGL
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5
Q

Describe the 5 step process of lipolysis.

A
  1. hormonal response to low blood glucose (glucagon, adrenalin, ACTH)
  2. activates adenylyl cyclase cascade → PKA
  3. PKA phosphorylates
    • perilipins → lipase can access TG
    • hormone-sensitive lipase activated
  4. CGI dissociates from perilipin, associates with adipocyte triglyceride lipase → activation
  5. lipolysis
    • ATGL: TAG → DAG + fatty acid
    • HSL: DAG → MAG + fatty acid
    • MGL: MAG → G + fatty acid

⇒ transported into blood stream as FFAs

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6
Q

Since glycerol is also an product of lipolysis…

Where and how is it metabolized?

Reaction + structures.

A

first ATP used to convert glycerol to glycerol-3P

  • in liver: converted to DHAP
    → used for glycolysis, gluconeogenesis
  • in intestinal mucosa: mainly used for resynthesis of TAGs for transport

ALSO: in kidney + lactating mammary glands

(cf. figure for details)

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7
Q

In which form are FAs transported in the blood?

A

as free (unesterified) fatty acids (FFA)

  • long chain FFAs bind to
    • in plasma: albumin (10 FFAs/monomer)
    • in cell: FA binding protein
  • short chain FFAs exist as unionized acid or FA anion
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8
Q

Once FAs enter the target tissue something else must happen before they can be degraded to yield energy.

What and how?

A

activation by acyl-CoA synthetase
2 step reaction

  1. FA + ATP → acyl adenylate + PPi
  2. acyl adenylate + CoA → AMP + acyl-CoA

REMEMBER: only step of FA degradation that requires energy from ATP

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9
Q

Where can acyl-CoA synthetase be found in the cell?

A

in outer mitochondrial membrane

→ activates long chain FFs (> 12C)

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10
Q

Where does β-oxidation take place?

What must happen in order to shuttle acyl-CoAs there?
Explain.

A

happens in mitochondria
→ carnitine transport system necessary for acyl-CoA > 12C

  1. carnitine palmityltransferase I: in outer mit. membrane
    acyl-CoA + carnitine → acylcarnitine + CoA-SH
  2. carnitine-acylcarnitine translocase: in inner mit. membrane
    exchanges carnitine w/ acylcarnitine
  3. ​carnitine palmityltransferase II: in inner mit. membrane
    acylcarnitine + CoA-SH → acyl-CoA + carnitine
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11
Q

What is the importance of the carnitine transport system?

Since it only applies to FAs > 12C, what happens to the ones < 12C?

A

CPT 1 catalyzes rate-limiting step of β oxidation

BUT: FAs < 12C diffuse through membrane + are also activated in mitochondria

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12
Q

What is an inhibitor of CPT I?

A

malonyl-CoA

= in high conc. during fatty acid synthesis

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13
Q

What happens with the acyl-CoA (even #C) once it entered the mitochondrium?

Under which conditions does it happen?

A

enters β-oxidation
acyl-CoA is stepwise cleaved to produce acetyl-CoA, 1 FADH2, 1 NADH

  • acetyl CoA → citrate cycle
  • FADH2, NADH: oxidative phosphorylation

BUT: only under aerobic conditions, otherwise no reoxidation to NAD+, FAD

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14
Q

Which enzyme catalyzes the 1st step of β-oxidation?

Reaction + structures.

A

acyl-CoA dehydrogenase
1st oxidation

acyl CoA + FAD
→ trans-Δ2-enoyl-CoA + FADH2

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15
Q

Which enzyme catalyzes the conversion of trans-Δ2-enoyl-CoA during β-oxidation?

Reaction + structures.

A

enoyl-CoA hydratase

trans-Δ2-enoyl-CoA + H2O
→ L-β-hydroxyacyl-CoA

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16
Q

Which enzyme catalyzes the conversion of L-hydroxyacyl-CoA during β-oxidation?

Reaction + structures.

A

β-hydroxyacyl-CoA dehydrogenase
2nd oxidation

L-hydroxyacyl-CoA + NAD+
→ β-ketoacyl-CoA + NADH

stereospecific

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17
Q

Which enzyme catalyzes the conversion of β-ketoacyl-CoA during β-oxidation?

Reaction + structures.

What happens in case of odd #C FAs?

A

thiolase (acyl-CoA acetyltransferase)

β-ketoacyl-CoA + CoA-SH
→ acyl-CoA (-2C) + acetyl-CoA

⇒ can enter β-oxidation again

NOTE: odd #C FAs produce propionyl-CoA in their last cycle

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18
Q

Which enzymes involved in β-oxidation have isoenzymes?

Where are they located?

A

3 isoenzymes for acyl-CoA dehydrogenase:

  • long chain FAs: on inner mit. membr.
  • medium, short chain FAs: in matrix

isoenzymes for 2nd - 4th step:

  • long chain FAs: trifunctional enzyme (1 enzyme for all 3 reactions), on inner mit. membr.
  • medium & short chain FAs: individual enzymes, in matrix
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19
Q

How is β-oxidation of odd #C acyl-CoAs different from the “normal” one?

A

proprionyl CoA (3C) formed
(instead of last acetyl CoA (2C) in last cycle of β-oxidation

⇒ converted to succinyl-CoA in 3 steps, then enters TCA cycle (glucogenic!)

NOTE: requires biotin + 1 ATP

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20
Q

How would you calculate the energy gain of any complete β-oxidation?

ex: palmitic acid

A
  • each complete β-oxidation: 1 NADH + 1 FADH2 produced ⇒ 4 ATP/cycle
  • each acetyl-CoA oxidized: 3 NADH + 1 FADH2 + 1 GTP produced ⇒ 10 ATP/acetyl-CoA
  • -2 ATP for activation of FA

​e.g. palmitic acid (16C): 7 cycles, 8 acetyl-CoA
⇒ 7x4 + 8x10 = 108 [ATP] formed
⇒ BUT: 106 ATP net gain

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21
Q

What is the function of β-oxidation in peroxisomes?

How is it different from that in mitochondria?

A
  • shortens VLCFAs > 20C → ends at octanoyl-CoA
  • FADH2 oxidized to produce H2O2

acyl-CoA + O2 → Δ2-trans enyol-CoA + H2O2

further differences:

  • no carnitine-dependent transport
  • NAD+ cannot be regenerated inside peroxisome
  • no enzymes for TCA cycle in peroxisome
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22
Q

What increases the rate of β-oxidation?

A
  • thyroid hormones → induce expression of CPT
  • PPAR-α
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23
Q

What decreases the rate of β-oxidation on the level of inhibition?

A
  • malonyl-CoA → inhibition of CPT I
  • NADH → inhibition of L-hydroxyacyl-CoA dehydrogenase (product inhibition)
  • acetyl-CoA → inhibition of thiolase (product inhibition)
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24
Q

Explain the general effect of PPAR-α.

When is it activated?

A

transcription factor that enhances fat utilization

activated in response to energy demand (fasting, btw-meal periods, exercise)

<em>in neonates: </em>causes metabolic transition from E generation from glucose/lactate to FAs

25
Q

Which genes are induced/repressed by PPAR-α?

A

represses

  • apo CIII

induces:

  • apo AI, AII
  • lipoprotein lipase
  • acyl-CoA synthetase
  • CPT I, II
  • enzymes of peroxisomal FA oxidation
26
Q

What are fibrates?

When are they administered?

A

PPAR-α agonists = enhance fat utilization, e.g. in case of hyperlipidemia

27
Q

What is the most common deficiency in β-oxidation?

Symptoms, therapy.

A

medium-chain acyl-CoA dehydrogenase (MCAD) deficiency

  • symptoms:
    • hypoglycemia + decr. ketogenesis (due to decr. FA oxidation + gluconeogenesis)
    • accumulation of lipids in the liver
    • vomiting, drowsiness
  • therapy: frequent carb-rich meals + carnitine supplementation
28
Q

What can be symptoms/consequences of carnitine deficiency?

How is it treated?

A

muscle, kidney, heart cannot use FAs anymore for energy generation

  • leading to muscle cramps, weakness, can lead to death
  • therapy: carnitine supplementation
29
Q

What can lead to a CPT deficiency?

Symptoms.

A

CPT II gene mutation → partial loss of enzyme activity

causes muscle weakness, when more serious: hypoglycemia w/ decr. ketogenesis

30
Q

What is ketogenesis?

When and where does it occur?

A

formation of ketone bodies from acetyl-CoA​
esp. during high rate of β-oxidation due to high levels of FFAs

  • fasting (↑ gluconeogenesis)
  • untreated diabetes (low insulin)

⇒ synthesized in mitochondria of liver

31
Q

At what concentration can ketone bodies be found in the blood?

A

incr. concentration after depletion of glycogen + incr. β-oxidation

  • after overnight fast: 0.05 mM
  • after 2 days starvation: 2 mM (40-fold incr.)
  • after 40 days: 7 mM

⇒ measurement of ketonemia rather than ketonuria to assess severity of ketosis

32
Q

What are the 3 common steps of ketogenesis?

Enzymes + reactions.

A
  1. thiolase
    2 acetyl-CoA → acetoacetyl-CoA
  2. HMG-CoA synthase
    … + acetyl-CoA → β-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA)
  3. HMC-CoA lyase
    … → acetoacetate + acetyl-CoA
33
Q

List the 3 ketone bodies.

A
  • acetone
  • acetoacetate
  • β-hydroxybutyrate, predominant ketone body in blood
34
Q

How is acetone formed?

Enzyme + reaction.

A

acetoacetate decarboxylase

acetoacetate → acetone + CO2

⇒ acetone then exhaled

reason why you smell bad in the morning

35
Q

How is β-hydroxybutyrate formed?

Enzyme + reaction.

A

β-hydroxybutyrate dehydrogenase

acetoacetate + NADH ⇔ β-hydroxybutyrate + NAD+

36
Q

Where are ketone bodies utilized?

What has to happen first though?

A

important sources of energy

  • heart, muscle, renal cortex (preference to glucose)
    NOTE: renal medulla is glucose dependent
  • brain: glucose is major fuel, but during starvation or diabetes acetoacetate can used

BUT:​ require activation

37
Q

Explain how ketone bodies are oxidized (activated).

Enzymes + structures.

A

D-β-hydroxybutyrate → acetoacetate, then

β-ketoacyl-CoA transferase

acetoacetate + succinyl-CoA
→ acetoacetyl-CoA + succinate

⇒ acetoacetyl-CoA enters β-oxidation

NOTE: acetone only exhaled, cannot be used

38
Q

What happens in FA synthesis?

Enzyme?

Where does it happen?

A

fatty acid synthase
malonyl-CoA stepwise addedto acetyl-CoA primer, uses NADPH

  • 2 steps to charge FA synthase w/ acetyl- and malonyl-CoA
  • cycle of 5 steps to elongate growing FA chain

in cytosol of liver, adipose tissue, lactating mammary gland

39
Q

Differentiate btw FA synthesis and β-oxidation w/r/t

  • site
  • intermediates bound to
  • enzymes
  • reducing equivalents
  • units
  • 3-hydroxyacyl derivative
A
40
Q

Which enzyme catalyzes the rate-limiting step of lipogenesis?

Reaction.

A

acetyl-CoA carboxylase

acetyl-CoA + HCO3- + ATP
↓
malonyl-CoA + ADP + Pi

41
Q

What is the prosthetic group of acetyl-CoA carboxylase.

Explain the reaction mechanism in detail.

A

3 activities in 1 single polypeptide chain,
BUT: biotin = prosthetic group

  1. ATP-dependent transfer of carboxyl group to biotin
  2. activated CO2 moved from biotin carboxylase region to transcarboxylase active site
  3. transfer of activated carboxyl from biotin to acetyl-CoA → malonyl-CoA + enzyme
42
Q

Describe the structure of FA synthase.

A

dimeric multifunctional enzyme, 7 different domains each
2 -SH groups carry intermediates during synthesis

  • ACP = acyl-carrier protein: central SH- group, carries growing FA chain
  • KS = β-ketoacyl-ACP synthase: peripheral SH- group in condensing domain, carries malonyl-CoA
  • MAT = malonyl/acetyl transferase
  • KR = β-ketoacyl-ACP reductase
  • DH = β-hydroxyl-ACP dehydratase
  • ER = enoyl-ACP reductase
  • TE = thioesterase
43
Q

What is the prostethic group of FA synthase?

In which domain is it located?

Structure.

A

4’ phosphopanteine in ACP

44
Q

How and when is FA synthesis terminated?

A

terminated as FA reaches 16-18C
e.g. palmitate (C16) after 7 cycles
(acetyl-CoA + 7 malonyl)

→ then hydrolyzed from ACP by TE (thioesterase)

45
Q

What is the overall equation of FA synthesis?

Example: palmitate.

A

palmitate = 16C, per cycle

  • 1 malonyl-CoA (from acetyl-CoA) + 1 acetyl-CoA primer
  • 2 NADPH used
  • 1 H20 produced (but -1 H20 for hydrolyzation)

→ 7 cycles

46
Q

How are C atoms provided for FA synthesis?

List the basic steps.

A

C from acetyl-CoA,
BUT: produced in mitochondria by PDC, hence needs to be exported

  1. citrate synthase (TCA cycle) uses OXA to form citrate
  2. citrate exported into cytosol
  3. citrate converted back to OXA, gives off acetyl-CoA
  4. OXA converted to malate
  5. 2 options:
    • malate transported into mitochondrium
      → converted back to OXA
    • malate converted to pyruvate, then transported into mitochondrium again
47
Q

What is the function of the tricarboxylate carrier?

How is it inhibited?

A

malate transported into mitochondrium

citrate + H+ transported out of mitochondrium

inhibited by: acyl-CoA

48
Q

Which enzyme catalyzes the cytosolic conversion of citrate for subsequent FA synthesis?

Reaciton.

A

ATP:citrate lyase

ATP + citrate + CoA-SH
→ OXA + acetyl-CoA + ADP + Pi

49
Q

Which enzyme catalyzes the cytosolic conversion of OXA for subsequent import into the mitochondrium?

Reaction.

A

malate dehydrogenase

OXA + NADH ⇔ malate + NAD+

50
Q

Which enzyme catalyzes the cytosolic conversion of malate for subsequent import into the mitochondrium?

Reaction.

Cofactor?

A

malic enzyme

malate + NADP+ → NADPH + CO2 + pyruvate

requires Mg2+

51
Q

How is NADPH provided for FA synthesis?

Where?

A

in cytosol, produced

  • by malic enzyme
  • in PPP
52
Q

How are FAs elongated if more than just 16 - 18C are needed?

A

by microsomal system in ER

→ continues FA synthesis, same mechanism, but fatty acid elongase system needed
(single E for each step, only step 3-6)

53
Q

Which enzymes are regulated to incr. or decr. the rate of lipogenesis?

A

regulation of

  • acetyl-CoA carboxylase: provides malonyl-CoA, catalyzes rate-limiting step
  • pyruvate dehydrogenase: provides acetyl-CoA
  • fatty acid synthase: uses those 2 to synthesize the FA
54
Q

How is the activity of acetyl-CoA carboxylase regulated?

When is it considered to be active or inactive?

A
  • inactive:* in monom. form or phosph.
  • active:* in polym. form and dephosph.

enh. activity: in well-fed state, esp. carb rich

  • [citrate] → polymerization
  • glucose + insulin → induction + insulin dephosphorylation

decr. activity:

  • acyl-CoA → repression
  • catecholamines, glucagon → phosphorylation
55
Q

How is the activity of PDC regulated?

When is it considered to be active or inactive?

A
  • *inactive:** phosphorylated
  • *active:** dephosphorylated

activation: in well-fed state, esp. after carbs

  • ↑ insulin → ↑ glycolysis/pyruvate + dephosphorylation

inhibition:

  • acetyl-CoA, NADH (product inhibition)
56
Q

How is the activity of FA synthase regulated?

A

only induced, repressed

inducers:

  • glucose + insulin: plenty of food, we want to get fat

repressors:

  • catecholamines + glucagon: starvation/stress
  • long chain PUFAs: healthy food keeps us slim
57
Q

As a summary…

How does insulin regulate FA synthesis?

Directly and indirectly.

A
  • ↑ acetyl-CoA carboxylase act.: by induction + dephosphorylation
  • ↑ PDC acti.: by phosphorylation (only in adipose tissue, not liver)
  • ↑ FA synthase act.: by induction
  • ↑ transport of glucose into cell:
    • glucose → induction of acetyl-CoA carboxylase
    • ↑ pyruvate → more substrate for PDC
58
Q

As a summary…

How does glucagon regulate FA synthesis?

A

↑[cAMP] → activation of PKA

  • acetyl-CoA carboxylase: phosphorylation → inactivation
  • FA synthase: repression
59
Q

Explain how different macronutritional diets regulate the lipid metabolism.

A
  • low fat, high carb
    ↑ acetyl-CoA carboxylase + FA synthase
  • fasting + high fat
    ↑ acetyl-CoA carboxylase
  • high fat, low carb = Atkins, etc.
    FA mobilization + ketogenesis (excreted via urine)

Biochemistry II (16 decks)

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