#37 Biochemistry Fat/Fatty Acid Metabolism I Lecture for Kevin Ahern's BB 451/551
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Highlights -
Fatty Acid Oxidation
1.
Fats are broken down to fatty acids and glycerol by enzymes known as lipases. Hormone sensitive triacylglycerol lipase is the only regulated enzyme of fat or fatty acid breakdown.
2.
Triacylglycerol lipase action cleaves the first fatty acid off of a fat and this step is necessary before the other lipase can act to remove the other fatty acids from a fat.
3.
Fatty acid oxidation occurs in the matrix of the mitochondrion
. In the cell, fatty acids are attached to CoA and then at the mitochondrion, the CoA is replaced by carnitine.
Inside the mitochondrial matrix, the carnitine is replace by CoA again.
4.
Steps in fatty acid oxidation include dehydrogenation, hydration, oxidation, and thiolytic cleavage. The dehydrogenation and oxidation reactions yield reduced electron carriers. Thiolytic cleavage is catalyzed by the enzyme called thiolase.
5. The first reaction of fatty acid oxidation involves acyl dehydrogenases. These are specific for fatty acids with long, medium, or short chains. The medium chain acyl dehydrogenase has been implicated in some instances of sudden infant death syndrome.
6. The long chain acyl dehydrogenases are found in peroxisomes and this is where oxidation of long chain fatty acids (longer than 16 carbons) begins. Oxidation involves transfer of electrons to oxygen to make hydrogen peroxide, instead of
FADH2.
7. The first step of oxidation generates a trans-intermediate plus FADH2. The second step involves addition of water across the trans double bond to create an intermediate in with an OH on carbon 3 in the L configuration. The third step involves oxidation of the hydroxyl intermediate to a ketone on carbon 3. The last step involves cleaving off of an acetyl-CoA and production of a fatty acyl-CoA with two fewer carbons.
8. Oxidation of biologically occurring fatty acids with cis double bonds requires two additional enzymes compared to oxidation of saturated fatty acids. These enzymes are enoyl-CoA-isomerase and 2,4-dienoyl-CoA-reductase.
9. Enoyl-CoA-isomerase converts cis or trans bonds between carbons 3 and 4 to trans bonds between carbons 2 and 3.
10. 2,4-dienoyl-CoA reductase acts on intermediates that have double bonds between carbons 2-3 and 4-5. It uses
NADPH to reduce the two double bonds to one double bond and the resulting double bond is placed in a cis configuration between carbons
3-4.
11. Oxidation of fatty acids with odd numbers of carbons yields a final product of propionyl-CoA, not acetyl-CoA.
12.
Conversion of propionyl-CoA to succinyl-CoA requires three steps. The first is addition of a carboxyl-group to the middle carbon in the molecule.
13.
Ketone bodies are produced by the body when glucose precursors are not available to make glucose. Examples of ketone bodies include acetoacetate and hydroxybutyrate.
Diabetics have problems with glucose metabolism and may produce ketone bodies to provide energy to keep the brain alive. One can detect this by the smell of acetone on their breath.
Fatty Acid Biosynthesis
1. The process occurs similarly to beta-oxidation, though in reverse. Important distinctions are noted below in a-f.
a.
Fatty acid synthesis up to palmitate occurs in the cytoplasm.
b.
Fatty acids are built using an acyl carrier protein (
ACP),.
c. NADPH is used to donate electrons in synthesis.
d. A three carbon molecule, malonyl-ACP donates two carbons to the growing fatty acid chain - a carbon dioxide is lost in the process.
e.
Synthesis of fatty acids longer than 16 carbons occurs in endoplasmic reticulum or mitochondrion.
f. In fatty acid biosynthesis, a D-hydroxyl intermediate is formed at carbon #3.
2.
Acetyl-CoA carboxylase catalyzes the addition of a carboxyl group to acetyl-CoA to form malonyl-CoA.
3. The enzymes of fatty acid synthesis apart from acetyl-CoA carboxylase are contained in a complex known as fatty acid synthase.
4.
Fatty acid synthase produces the saturated 16 carbon fatty acid known as palmitate.