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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
Which genes are induced/repressed by PPAR-α?
_represses_ * apo CIII _induces:_ * apo AI, AII * lipoprotein lipase * acyl-CoA synthetase * CPT I, II * enzymes of peroxisomal FA oxidation
26
What are fibrates? When are they administered?
**PPAR-α agonists** = enhance fat utilization, e.g. in case of _hyperlipidemia_
27
What is the most common deficiency in β-oxidation? Symptoms, therapy.
_**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
What can be symptoms/consequences of carnitine deficiency? How is it treated?
_muscle, kidney, heart_ cannot use FAs anymore for energy generation * leading to muscle cramps, weakness, can lead to death * *therapy:* **carnitine supplementation**
29
What can lead to a CPT deficiency? Symptoms.
**CPT II** gene mutation → partial loss of enzyme activity causes muscle weakness, when more serious: **hypoglycemia** w/ **decr. ketogenesis**
30
What is ketogenesis? When and where does it occur?
_**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
At what concentration can ketone bodies be found in the blood?
**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
What are the 3 common steps of ketogenesis? Enzymes + reactions.
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
List the 3 ketone bodies.
* **acetone** * **acetoacetate** * **β-hydroxybutyrate**, predominant ketone body in blood
34
How is acetone formed? Enzyme + reaction.
**_acetoacetate decarboxylase_** **acetoacetate → acetone + CO2** ⇒ acetone then exhaled reason why you smell bad in the morning
35
How is β-hydroxybutyrate formed? Enzyme + reaction.
**_β-hydroxybutyrate dehydrogenase_** ## Footnote **acetoacetate + NADH ⇔ β-hydroxybutyrate + NAD+**
36
Where are ketone bodies utilized? What has to happen first though?
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
Explain how ketone bodies are oxidized (activated). Enzymes + structures.
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
What happens in FA synthesis? Enzyme? Where does it happen?
**_fatty acid synthase_ malonyl-CoA stepwise added****to 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
Differentiate btw FA synthesis and β-oxidation w/r/t * site * intermediates bound to * enzymes * reducing equivalents * units * 3-hydroxyacyl derivative
40
Which enzyme catalyzes the rate-limiting step of lipogenesis? Reaction.
**_acetyl-CoA carboxylase_** **acetyl-CoA + HCO3- + ATP ↓ malonyl-CoA + ADP + Pi**
41
What is the prosthetic group of acetyl-CoA carboxylase. Explain the reaction mechanism in detail.
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
Describe the structure of FA synthase.
_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
What is the prostethic group of FA synthase? In which domain is it located? Structure.
**4' phosphopanteine** in ACP
44
How and when is FA synthesis terminated?
_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
What is the overall equation of FA synthesis? Example: palmitate.
_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
How are C atoms provided for FA synthesis? List the basic steps.
**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
What is the function of the tricarboxylate carrier? How is it inhibited?
**malate** transported into mitochondrium **citrate + H+** transported out of mitochondrium _inhibited by:_ **acyl-CoA**
48
Which enzyme catalyzes the cytosolic conversion of citrate for subsequent FA synthesis? Reaciton.
**_ATP:citrate lyase_** ## Footnote **ATP + citrate + CoA-SH → OXA + acetyl-CoA + ADP + Pi**
49
Which enzyme catalyzes the cytosolic conversion of OXA for subsequent import into the mitochondrium? Reaction.
**_malate dehydrogenase_** **OXA + NADH ⇔ malate + NAD+**
50
Which enzyme catalyzes the cytosolic conversion of malate for subsequent import into the mitochondrium? Reaction. Cofactor?
**_malic enzyme_** **malate + NADP+ → NADPH + CO2 + pyruvate** requires Mg2+
51
How is NADPH provided for FA synthesis? Where?
in cytosol, produced * by **malic enzyme** * in **PPP**
52
How are FAs elongated if more than just 16 - 18C are needed?
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
Which enzymes are regulated to incr. or decr. the rate of lipogenesis?
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
How is the activity of acetyl-CoA carboxylase regulated? When is it considered to be active or inactive?
* 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
How is the activity of PDC regulated? When is it considered to be active or inactive?
* *inactive:** phosphorylated * *active:** dephosphorylated _activation:_ in well-fed state, esp. after carbs * ↑ **insulin** → ↑ glycolysis/pyruvate + dephosphorylation _inhibition:_ * **acetyl-CoA,** **NADH** (product inhibition)
56
How is the activity of FA synthase regulated?
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
As a summary... How does insulin regulate FA synthesis? Directly and indirectly.
* **↑ 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
As a summary... How does glucagon regulate FA synthesis?
↑[cAMP] → activation of PKA * **acetyl-CoA carboxylase:** phosphorylation → inactivation * **FA synthase:** repression
59
Explain how different macronutritional diets regulate the lipid metabolism.
* **_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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