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MSK Week 4 > 2.4.3. Oxidation of Fatty Acids II > Flashcards

2.4.3. Oxidation of Fatty Acids II Flashcards

1
Q

What are the major fatty acid components of diet?

A

Palmitate (C16:0)
Stearate (C18:0)
Oleate (C18:1)
Linoleate (C18:2)

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2
Q

How are Fatty Acids and Genetics linked?

A

At least 15 proteins involved with mitochondrial FA metabolism have been implicated in inherited disease

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3
Q

What is the main type of oxidation that occurs with FAs?

A

β-oxidation

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4
Q

Carnitine Carrier System

A

Transporter for long-chain fatty acids after they have been activated (forming fatty acyl-CoA) into the mitochondria

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5
Q

Where does Beta-oxidation occur?

A

Mitochondria

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6
Q

Simplified overview of Beta-oxidation

A

Four steps produce:

  1. FADH2 and NADH
  2. Two carbons are cleaved from fatty acyl-CoA and are released as acetyl-CoA
  3. Series of steps is repeated until an even-chain FA is completely converted to acetyl-COA
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7
Q

How is ATP obtained during Beta-oxidation?

A

When FADH2 and NADH interact with the ETC or when acetyl-CoA is oxidized further

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8
Q

What happens to acetyl-CoA in skeletal and heart muscle?

A

Enters the TCA cycle and is oxidized to CO2 and H20

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9
Q

What happens to acetyl-CoA in the liver?

A

Converted to ketone bodies

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10
Q

What are they other types of oxidation FAs can undergo?

A

α and ω (omega) oxidation

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11
Q

Where are long chain FAs activated?

A

In they cytosol of the cell, long-chain FAs are activated by ATP and coenzyme A, forming fatty acyl-CoA

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12
Q

Where are short chain FAs activated?

A

Mitochondria

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13
Q

Transport of fatty acyl-CoA from the cytosol into mitochondria

A

Fatty acyl-CoA reacts with carnitine in the outer mitochondrial membrane, forming fatty acylcarnitine (enzyme is CAT I aka CPT I)

Fatty acylcarnitine passes to the inner membrane, where it re-forms to fatty acyl-CoA, which enters the matrix (this enzyme is CAT II)

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14
Q

CAT I aka CPT I

A

Carnitine acyltransferase I

Carnitine palmitoyltransferase I

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15
Q

CAT II

A

Carnitine acyltransferase II

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16
Q

malonyl-CoA

A

When fatty acids are being synthesized in the cytosol, malonyl-CoA inhibits their transport into mitochondria and, thus, prevents a futile cycle (synthesis followed by immediate degradation)

malonyl-CoA is an intermediate in FA synthesis

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17
Q

Primary Carnitine deficiency

A

Results from an inability to transport carnitine into the cells that need it (i.e., liver and muscle)

Results in reduced FA oxidation, and in the case of muscle, exercise intolerance and muscle damage during exercise occurs, leading to myobloginuria

In the liver, lack of FA oxidation can lead to hypoketotic hypoglycemia

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18
Q

Hypoketotic hypoglycemia

A

Low blood glucose levels (due to the deficiency in FA oxidation) couple with below normal levels of ketone bodies (due to the deficiency in FA oxidation)

The major organs and systems involved include the cardiac muscle (cardiomyopathy), the CNS (not enough fuel), and the skeletal muscle (muscle damage)

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19
Q

Secondary Carnitine deficiency

A

Caused by other metabolic disorders (such as CAT II mutation, or FA oxidation disorders)

The accumulation of long-chain acylcarnitines it toxic, and can lead to a sudden cardiac arrest

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20
Q

First step of Beta-Oxidation

A

FAD accepts hydrogens from a fatty acyl-CoA, a double bond is produced between the alpha and beta carbons, and an enoyl-CoA is formed

FADH2 that is produced interacts with the ETC, generating ATP

Enzyme: acyl-CoA dehydrogenase

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21
Q

acyl-CoA dehydrogenase variants

A

SCAD, MCAD, LCAD, VLCAD

short-chain, medium-chain, long-chain, very long-chain

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22
Q

Genetic deficiency of MCAD

A

Autosomal recessive disease (1/15,000 live births)

Prevents normal use of FAs as fuels. Fasting hypoglycemia results, and dicarboxylic acids, produced by w-oxidation, are excreted in the urine

Glycines will conjugate with dicarboxylic acids to aid in their excretion (acylglycines)

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23
Q

Second step of Beta-Oxidation

A

Water adds across the double bond, forming a β-hydroxyacyl-CoA

Enzyme: enoyl-CoA hydratase

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24
Q

Third Step of Beta-Oxidation

A

β-hydroxyacyl-CoA is oxidized by NAD+ to a β-ketoacyl-CoA

The NADH that is produced interacts with the ETC, generating ATP

Enzyme: L-3-hydroxyacyl-CoA dehydrogenase

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25
Q

L-3-hydroxyacyl-CoA dehydrogenase specificity

A

Only reacts with the L-isomer of the β-hydroxyacyl-CoA

26
Q

Jamaican vomiting sickness

A

Caused by a toxin (hypoglycin) from the unripe fruit of the akee tree

This toxin inhibits an acyl-CoA dehydrogenase of β-oxidation; consequently, more glucose must be oxidized to compensate for the decreased ability to use FA as a fuel, and severe hypoglycemia can occur

w-oxidation of FA is increased, and dicarboxylic acids are excreted in the urine

27
Q

Fourth step of Beta-Oxidation

A

The bond between the alpha and beta carbons of the β-ketoacyl-CoA is cleaved by a thiolase that requires coenzyme A

Acetyl-CoA is produced from the two carbons at the carboxyl end of the original fatty acyl-CoA and the remaining carbons form a fatty acyl-CoA that is two carbons shorter than the original

Enzyme: β-ketothiolase

28
Q

How many repetitions of the 4 step B-oxidation process does 16-carbon palmitoyl-CoA undergo?

A

7

In the last repetition, a 4-carbon fatty acyl-CoA (butyryl-CoA) is cleaved to two acetyl-CoAs

29
Q

How much energy is generated from one palmitoyl-CoA being oxidized?

A

A net total of 106 ATP are produced (2 ATP used to undergo activation before it can be oxidized) from the oxidation of palmitoyl-CoA to CO2 and H2O

7 FADH2 (10.5 ATP)
7 NADH (17.5 ATP)
8 acetyl-CoA (each produces 10 ATP)
Total of 108 ATP

30
Q

What does the oxidation of odd-chain fatty acids produce?

A

Acetyl-CoA and propionyl-CoA

FAs repeat the four steps of the β-oxidation spiral, producing acetyl-CoA until the last cleavage when the three remaining carbons are released as propionyl-CoA

31
Q

What can propionyl-CoA be converted to that acetyl-CoA cannot?

A

glucose

32
Q

What’s weird about unsaturated FAs?

A

They require enzymes in addition to the four that catalyze the repetitive steps of the β-oxidation spiral

The rxn pathway differs depending on whether the double bond is at an even- or odd-number carbon position

33
Q

Odd-numbered unsaturated FA

A

An isomerase will convert the eventual cis-3 to a trans-2 FA

34
Q

Even-numbered unsaturated FA

A

The eventual trans-2, cis-4 FA will be reduced by a 2,4-dienoyl-CoA reductase

This requires NADPH and generates a trans-3-acyl-CoA and NADP+

The isomerase will convert the trans-3 fatty acyl-CoA to a trans-2 fatty acyl-CoA to allow β-oxidation to continue

35
Q

ATP yield for unsaturated FAs

A

Odd carbon = 1.5 less ATP for each unsaturation due to one less FADH2

Even carbon = 2.5 less ATP due to the use of NADPH in the step catalyzed by the 2,4-dienoyl-CoA reductase

36
Q

ω (omega) oxidation of FAs

A

the ω-carbon (the methyl carbon) of FAs is oxidized to a carboxyl group in the ER

β-oxidation can then occur in mitochondria at this end of the FA as well as from the original carboxyl end

Dicarboxylic acids are produced

37
Q

Oxidation of very long-chain FAs in peroxisomes

A

Differences from β-oxidation:

  1. molecular O2 is used by VLCAD
  2. H2O2 is formed
  3. FADH2 is not generated at the first step

The shorter-chain FAs that are produced travel to mitochondria, where they undergo β-oxidation, generating ATP

38
Q

α-oxidation of FAs in peroxisomes

A

Branched chain FAs are oxidized at the α-carbon and the carboxyl carbon is released as CO2

Branches can interfere with the normal β-oxidation pathway, most often at the acyl-CoA dehydrogenase step

The FA is degraded by one carbon initially, and then two carbons at a time (both acetyl-CoA and propionyl-CoA are products if the branches are methyl groups)

39
Q

Where does α-oxidation mainly occur?

A

Brain and nervous tissue

40
Q

Adrenoleukodystrophy

A

X-linked peroxisomal disorder that affects the transport of very long-chain FAs into the peroxisomes for initial oxidation events

Very long-chain FAs accumulate and target the adrenal glands and the myelin sheath for destruction (via incorporation into the membrane lipids surrounding those structures)

41
Q

Symptoms of Adrenoleukodystrophy

A

Children will experience cognitive deficiencies, nervous system deterioration, seizures, visual impairment, and may develop Addison’s disease (a loss of adrenal gland function)

42
Q

Zellweger syndrome

A

Peroxisome biogenesis disorder. The lack of peroxisomes leads to the buildup of very long-chain FAs, an inability to degrade branched FAs, and gives rise to Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile refsum disease

Myelin structure is altered owing to the accumulation of these FAs (particularly phytanic acid)

43
Q

Symptoms of Zellweger syndrome

A

Enlarged liver, mental retardation, and seizures

Infants with Zellweger syndrome lack appropriate muscle strength and may be unable to move or suck because of their weakened muscles

44
Q

Sources of propionate

A

50% from AA catabolism
25% from odd chain FA
25% from gut bacteria

45
Q

Use of methylmalonyl-CoA mutase reaction to determine B12 deficiency

A

L-methylmalonyl CoA is unable to be converted to succinyl CoA. Instead, it is converted to methylmalonic acid (MMA)

MMA accumulates in the blood and can be detected

46
Q

Where is B12 deficiency most commonly seen?

A

Geriatric patients

47
Q

Fates of succinyl-CoA

A
  1. Replenish TCA cycle (anaplerotic rxn)
  2. Provide carbons for gluconeogenesis
  3. Oxidation to CO2 and H2O for energy
48
Q

Regulation of LCFA Oxidation

A

NAD+/NADH ratio

Compartmentalization:

  1. FA oxidation located in mito matrix
  2. FA synthesis located in cytosol
  3. CPT I is blocked by malonyl CoA, a key intermediate in FA synthesis

End result: we want FA oxidized during exercise or while we are fasting (i.e., ATP is produced when the energy charge of the cell is going down)

49
Q

4 major physiological functions of FAs

A
  1. Insulation
  2. Energy Storage
  3. Gluconeogenesis
  4. Phospholipid membranes
50
Q

What does free FA mean?

A

Unesterified FAs

51
Q

Refsum disease

A

α-hydroxylase deficiency

Autosomal recessive (rare)

Phytanic acid (from plants) accumulates in tissues (on average, adults consume 50-100 mg/day)

Symptom: mainly neurologic
Treatment: dietary restriction

52
Q

Blood Brain Barrier

A

BBB does not allow for normal, long-chained FAs to get into the brain (way of protecting itself from noxious materials that are “FA-like”)

Ketone bodies can reduce glucose demand by 75% in starvation

53
Q

Sources of blood glucose after a meal

A

Gut: 0-4 hrs
Liver glycogen: 3-24 hrs
Gluconeogenesis: 8+ hrs

54
Q

How does gluconeogenesis begin?

A

With muscle protein breaking down (AA converted to alanine, which is moved to the liver)

55
Q

What produces glucagon?

A

The α-islet cells of the pancreas

Insulin is produced by the β-islet cells

56
Q

What are the two ketone bodies that serve as fuels for many tissues?

A

β-hydroxybutyrate

Acetoacetate

57
Q

Conditions that cause FA elevation

A

Fasting
Starvation
High fat-low carb diet
Endurance exercise

58
Q

Hormonal stimuli for FA increase

A

Increase in epinephrine
Increase in glucagon
Decrease in insulin

59
Q

What tissues cannot use ketone bodies and why?

A

The liver and RBCs

RBCs because ketone bodies are oxidized aerobically

Liver because it lacks the enzyme necessary to convert acetoacetate to acetoacetyl CoA

60
Q

Protein sparing effect of ketone bodies

A

Rise in blood ketones = more ketones taken up by brain = less need for glucose = less gluconeogenesis = less need for alanine = less need for muscle proteolysis = less muscle wasting

61
Q

Hallmark of diabetic emergency

A

“Fruity breath” (caused by acetone)

62
Q

Energy yield from 1 mole of Ketone body Mixture

A

21.5 moles of ATP

Remember Glucose gives you ~32 and acetyl-CoA gives you 10

MSK Week 4 (11 decks)

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