Dr Kevin Ahern of Oregon State University lectures on (Beta) fatty acid oxidation. Course notes:
1. Fats are broken down to fatty acids and glycerol by enzymes known as lipases. One of these, hormone sensitive triacylglycerol lipase, is the only regulated enzyme of fat or fatty acid breakdown. It is located in fat-storing cells called adipocytes.
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. Glycerol, is the only part of a fat that can be made into glucose (via gluconeogenesis). Fatty acids travel in the bloodstream carried by serum albumin.
4. 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.
5. Steps in fatty acid oxidation include dehydrogenation, hydration, oxidation, and thiolytic cleavage. The dehydrogenation and oxidation reactions yield reduced electron carriers (FADH2 and NADH). The double bond formed in the first dehydrogenation reaction is in the trans form. The hydration yields a hydroxyl group on the third carbon from CoA end in the "L" configuration. Thiolytic cleavage is catalyzed by the enzyme called thiolase. Two enzymes you should know include acyl-CoA dehydrogenase, which come in three forms (specialized for long, medium, and short chain fatty acyl-CoAs) and thiolase, which catalyzes the thiolytic cleavage to release acetyl-CoA.
6. The first reaction of fatty acid oxidation involves a set of enzymes know as 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.
7. The long chain acyl dehydrogenases are found in peroxisomes and this is where oxidation of long chain fatty acids (longer than 16 carbons) begins (not in the mitochondrial matrix). Oxidation here involves transfer of electrons to oxygen to make hydrogen peroxide, instead of FADH2. Peroxisomal fatty acid oxidation is therefore LESS efficient than mitochondrial beta oxidation.
8. 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. The last step is catalyzed by the enzyme thiolase.
9. The reactions of beta oxidation up to the thiolase reaction chemically mirror the reactions of the oxidation of succinate up to oxaloacetate.
10. Seven cycles of beta oxidation of palmitoyl-CoA in the matrix yield 8 acetyl-CoAs.
11. 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.
12. Enoyl-CoA-isomerase converts cis or trans bonds between carbons 3 and 4 to trans bonds between carbons 2 and 3. Since beta oxidation normally has trans bonded intermediates between carbons 2 and 3, this enzyme is sufficient for conversion of many naturally occurring fatty acids to be oxidized.
13. 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. Enoyl-CoA-isomerase then can convert this intermediate to one with a trans double bond between carbons 2-3, thus allowing beta oxidation to continue.
