What are longer free fatty acids bound to for transport in the blood?
How many FAs per unit of this transport molecule?
- 10 FAs per albumin monomer
How does transport of shorter chain fatty acids differ from longer?
SCFAs are more water-soluble and exist in unionized or anion forms
What is the first step of catabolism of a free fatty acid?
What is special about this step energetically?
Fatty Acid Activation
- with CoA and ATP via acyl-CoA synthetase
- it is the ONLY step of FA oxidation which uses ATP
What is the enzyme which "activates" fatty acids for oxidation and where is it found (4 locations)?
- in the ER
- in peroxisomes
- in mitochondria
- on mitochondrial outer membrane
What is the overal reaction of FFA activation?
Include the enzyme.
FFA + CoA + ATP
---- acyl-CoA synthetase ---->
acyl-CoA + PPi + AMP
What happens to the PPi formed from cleaved ATP during fatty acid activation and why?
it is hydrolyzed by inorganic pyrophosphatase
- to ensure that the reaction is carried out fully and is irreversible in vivo
What is the site of fatty acid activation?
the outer mitochondrial membrane
(where acyl-CoA synthetase is found)
What happens to acyl-CoA in the intermembrane space?
(before it can enter the mitochondrial matrix)
(or Carnitine Acyltransferase-I)
- catalyzes transfer of acyl group from CoA to carnitine to form acylcarnitine
How does acylcarnitine penetrate the inner mitochondrial membrane?
via Carnitine-Acylcarnitine Translocase
- exchanges carnitine for acylcarnitine across the membrane
What happens to acylcarnitine once it is inside the mitochondrial matrix?
Start with the enzyme, then describe the process.
(or Carnitine Acyltransferase-II)
- transfers acyl group to CoA reforming Acyl-CoA and liberating carnitine
Where is Carnitine Palmitoyltransferase-I located?
across the outer mitochondrial membrane
Where is Carnitine-AcylCarnitine Translocase located?
across the inner mitochondrial membrane
Where is Carnitine Palmitoyltransferase-II located?
on the inside of the inner mitochondrial membrane
Why is β-oxidation called β-oxidation?
because it is a cycle of successive cleavages of Acyl-CoA molecules at...
the C-C bond between the α(2) and β(3) carbons
(2nd and 3rd Cs from the -COOH end)
What is the collective name for the enzymes which perform β-oxidation?
And where are they found?
Fatty Acid Oxidase
- found in the mitochondrial matrix and inner mitochondrial membrane
(adjacent to to the respiratory chain)
Energetically, what are the important products (3) of β-oxidation?
How are they used?
FADH2 - oxidative phosphorylation > ATP
NADH - oxidative phosphorylation > ATP
Acetyl-CoA - citric acid cycle > ATP + NADH + FADH2
What is the first step of β-oxidation?
Removal of one hydrogen each from α and β carbons...
Reactants: Acyl-CoA + FAD
Enzyme: Acyl-CoA Dehydrogenase
Products: Δ2-trans-Enoyl-CoA + FADH2
What is the 2nd step of β-oxidation?
Water is added to saturate the double bond...
Reactants: Δ2-trans-Enoyl-CoA + H2O
Enzyme: Δ2-Enoyl-CoA Hydratase
What is the 3rd step of β-oxidation?
What is special about the enzyme?
Further dehydrogenation of the 3-carbon...
Reactants: L-β-Hydroxyacyl-CoA + NAD+
Enzyme: β-Hydroxacyl-CoA Dehydrogenase
Product: β-Ketoacyl-CoA + NADH + H+
The enzyme is stereospecific for the L-isomer.
What is the 4th step of β-oxidation?
Enzyme (2 names)?
How is one of the end products different from what entered β-oxidation?
Cleavage at the 2,3 position...
Reactants: β-Ketoacyl-CoA + CoA-SH
Enzyme: Thiolase (or Acyl-CoA Acetyltransferase)
Products: Acetyl-CoA + Acyl-CoA
Acyl-CoA product here is 2 carbons shorter than acyl-CoA which entered the cycle.
How does a fatty acid chain's length affect how it is transported into the mitochondria?
> 12C - with carnitine
< 12 C - without carnitine, activated in mitoch.
Which β-oxidation enzyme has 3 different isoforms?
What are they?
Which one is frequently deficient?
Acyl-CoA Dehydrogenase (the 1st step)
- for different lengths of fatty acids
- LCFAs (C 12-18)
- MCFAs (C 4-14) - frequently deficient (MCAD)
- SCFAs (C 4-8)
How many ATP are ultimately formed per NADH produced in β-oxidation?
NADH - 2.5 ATP
FADH2 - 1.5 ATP
Where are > 12 C FAs oxidized?
And < 12 C?
> 12 C - on the inner mitochondrial membrane
< 12 C - via soluble enzymes in the mitochondrial matrix
What is special about the last 3 enzymes of β-oxidation?
And what are the 3 enzymes?
they are a tightly associated trifunctional protein
- enoyl-CoA hydratase
- β-hydroxyacyl-CoA dehydrogenase
What results from the breakdown of an odd-chain fatty acid?
Where can this go and what can it become?
The remaining 3C residue is...
...which is converted to succinyl-CoA and enters the citric acid cycle
- in this way, it is the only glucogenic part of any fatty acid
How are very long chain fatty acids oxidized?
What products result from this?
VLCFAs (C20/22) are oxidized in peroxisomes
- forming acetyl-CoA and H2O2
- BUT this β-oxidation sequence ends at Octanoyl-CoA and is continued in mitochondria
What is the first step of glycerol conversion to a glycolysis intermediate in the liver?
Enzyme + product + special reactant
Phosphorylation of glycerol...
Reactants: Glycerol + ATP
Enzyme: Glycerol Kinase
Products: Glycerol-3-phosphate + ADP
What is the 2nd step of glycerol conversion to a glycolysis intermediate in the liver?
(Enzyme + products + special reactants)
Dehydrogenation of G-3-P...
Reactants: G-3-P + NAD+
Enzyme: Glycerol-3-phosphate Dehydrogenase
Products: DHAP + NADH + H+
What two hormones induce increased fatty acid oxidation in the fasting/low-glucose state?
Epinephrine/Adrenaline + Glucagon
Induce increased oxidation via:
- Phosphorylation/Inhibition of Perilipin (lipid droplet "protecting" protein)
- Activation of Hormone-sensitive Lipase