2.4.3. Oxidation of Fatty Acids II Flashcards
What are the major fatty acid components of diet?
Palmitate (C16:0)
Stearate (C18:0)
Oleate (C18:1)
Linoleate (C18:2)
How are Fatty Acids and Genetics linked?
At least 15 proteins involved with mitochondrial FA metabolism have been implicated in inherited disease
What is the main type of oxidation that occurs with FAs?
β-oxidation
Carnitine Carrier System
Transporter for long-chain fatty acids after they have been activated (forming fatty acyl-CoA) into the mitochondria
Where does Beta-oxidation occur?
Mitochondria
Simplified overview of Beta-oxidation
Four steps produce:
- FADH2 and NADH
- Two carbons are cleaved from fatty acyl-CoA and are released as acetyl-CoA
- Series of steps is repeated until an even-chain FA is completely converted to acetyl-COA
How is ATP obtained during Beta-oxidation?
When FADH2 and NADH interact with the ETC or when acetyl-CoA is oxidized further
What happens to acetyl-CoA in skeletal and heart muscle?
Enters the TCA cycle and is oxidized to CO2 and H20
What happens to acetyl-CoA in the liver?
Converted to ketone bodies
What are they other types of oxidation FAs can undergo?
α and ω (omega) oxidation
Where are long chain FAs activated?
In they cytosol of the cell, long-chain FAs are activated by ATP and coenzyme A, forming fatty acyl-CoA
Where are short chain FAs activated?
Mitochondria
Transport of fatty acyl-CoA from the cytosol into mitochondria
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)
CAT I aka CPT I
Carnitine acyltransferase I
Carnitine palmitoyltransferase I
CAT II
Carnitine acyltransferase II
malonyl-CoA
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
Primary Carnitine deficiency
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
Hypoketotic hypoglycemia
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)
Secondary Carnitine deficiency
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
First step of Beta-Oxidation
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
acyl-CoA dehydrogenase variants
SCAD, MCAD, LCAD, VLCAD
short-chain, medium-chain, long-chain, very long-chain
Genetic deficiency of MCAD
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)
Second step of Beta-Oxidation
Water adds across the double bond, forming a β-hydroxyacyl-CoA
Enzyme: enoyl-CoA hydratase
Third Step of Beta-Oxidation
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
L-3-hydroxyacyl-CoA dehydrogenase specificity
Only reacts with the L-isomer of the β-hydroxyacyl-CoA
Jamaican vomiting sickness
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
Fourth step of Beta-Oxidation
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
How many repetitions of the 4 step B-oxidation process does 16-carbon palmitoyl-CoA undergo?
7
In the last repetition, a 4-carbon fatty acyl-CoA (butyryl-CoA) is cleaved to two acetyl-CoAs
How much energy is generated from one palmitoyl-CoA being oxidized?
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
What does the oxidation of odd-chain fatty acids produce?
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
What can propionyl-CoA be converted to that acetyl-CoA cannot?
glucose
What’s weird about unsaturated FAs?
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
Odd-numbered unsaturated FA
An isomerase will convert the eventual cis-3 to a trans-2 FA
Even-numbered unsaturated FA
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
ATP yield for unsaturated FAs
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
ω (omega) oxidation of FAs
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
Oxidation of very long-chain FAs in peroxisomes
Differences from β-oxidation:
- molecular O2 is used by VLCAD
- H2O2 is formed
- 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
α-oxidation of FAs in peroxisomes
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)
Where does α-oxidation mainly occur?
Brain and nervous tissue
Adrenoleukodystrophy
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)
Symptoms of Adrenoleukodystrophy
Children will experience cognitive deficiencies, nervous system deterioration, seizures, visual impairment, and may develop Addison’s disease (a loss of adrenal gland function)
Zellweger syndrome
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)
Symptoms of Zellweger syndrome
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
Sources of propionate
50% from AA catabolism
25% from odd chain FA
25% from gut bacteria
Use of methylmalonyl-CoA mutase reaction to determine B12 deficiency
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
Where is B12 deficiency most commonly seen?
Geriatric patients
Fates of succinyl-CoA
- Replenish TCA cycle (anaplerotic rxn)
- Provide carbons for gluconeogenesis
- Oxidation to CO2 and H2O for energy
Regulation of LCFA Oxidation
NAD+/NADH ratio
Compartmentalization:
- FA oxidation located in mito matrix
- FA synthesis located in cytosol
- 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)
4 major physiological functions of FAs
- Insulation
- Energy Storage
- Gluconeogenesis
- Phospholipid membranes
What does free FA mean?
Unesterified FAs
Refsum disease
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
Blood Brain Barrier
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
Sources of blood glucose after a meal
Gut: 0-4 hrs
Liver glycogen: 3-24 hrs
Gluconeogenesis: 8+ hrs
How does gluconeogenesis begin?
With muscle protein breaking down (AA converted to alanine, which is moved to the liver)
What produces glucagon?
The α-islet cells of the pancreas
Insulin is produced by the β-islet cells
What are the two ketone bodies that serve as fuels for many tissues?
β-hydroxybutyrate
Acetoacetate
Conditions that cause FA elevation
Fasting
Starvation
High fat-low carb diet
Endurance exercise
Hormonal stimuli for FA increase
Increase in epinephrine
Increase in glucagon
Decrease in insulin
What tissues cannot use ketone bodies and why?
The liver and RBCs
RBCs because ketone bodies are oxidized aerobically
Liver because it lacks the enzyme necessary to convert acetoacetate to acetoacetyl CoA
Protein sparing effect of ketone bodies
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
Hallmark of diabetic emergency
“Fruity breath” (caused by acetone)
Energy yield from 1 mole of Ketone body Mixture
21.5 moles of ATP
Remember Glucose gives you ~32 and acetyl-CoA gives you 10
