3Beta Oxidation of Fatty Acids Process by which fatty acids are degraded by removal of 2-C unitsb-oxidation occurs in the mitochondria matrixThe 2-C units are released as acetyl-CoA, not free acetateThe process begins with oxidation of the carbon that is "beta" to the carboxyl carbon, so the process is called"beta-oxidation"
4Fatty acids must first be activated by formation of acyl-CoA Acyl-CoA synthetase condenses fatty acids with CoA, with simultaneous hydrolysis of ATP to AMP and PPiFormation of a CoA ester is expensive energeticallyReaction just barely breaks even with ATP hydrolysis DGo’ATP hydroysis = kJ/mol, DGo’ Acyl-CoA synthesis kJ/mol.But subsequent hydrolysis of PPi drives the reaction strongly forward (DGo’ –33.6 kJ/mol)
6Import of acyl-CoA into mitochondria b-oxidation occurs in the mitochondria, requires import of long chain acyl-CoAsAcyl-CoAs are converted to acyl-carnitines by carnitine acyltransferase.A translocator then imports Acyl carnitine into the matrix while simultaneously exporting free carnitine to the cytosolAcyl-carnitine is then converted back to acyl-CoA in the matrix
7Deficiencies of carnitine or carnitine transferase or translocator activity are related to disease stateSymptons include muscle cramping during exercise, severe weakness and death.Affects muscles, kidney, and heart tissues.Muscle weakness related to importance of fatty acids as long term energy sourcePeople with this disease supplement diet with medium chain fatty acids that do not require carnitine shuttle to enter mitochondria.
8b-oxidation Strategy: create a carbonyl group on the -C First 3 reactions do that; fourth cleaves the "-keto ester" in a reverse Claisen condensationProducts: an acetyl-CoA and a fatty acid two carbons shorter
9b-oxidationB-oxidation of palmitate (C16:0) yields 106 molecules of ATPC 16:0-CoA + 7 FAD + 7 NAD+ + 7 H CoA 8 acetyl-CoA + 7 FADH2 + 7 NADH + 7 H+2.5 ATPs per NADH = 17.51.5 ATPs per FADH2 = 10.510 ATPs per acetyl-CoA = 80Total = 108 ATPs2 ATP equivalents (ATP AMP + PPi, PPi 2 Pi) consumed during activation of palmitate to acyl-CoANet yield = 106 ATPs
10Acyl-CoA Dehydrogenase Oxidation of the C-C bondMechanism involves proton abstraction, followed by double bond formation and hydride removal by FADElectrons are passed to an electron transfer flavoprotein, and then to the electron transport chain.
12Enoyl-CoA Hydratase aka crotonases Adds water across the double bond Uses substrates with trans-D2-and cis D2 double bonds (impt in b-oxidation of unsaturated FAs)With trans-D2 substrate forms L-isomer, with cis D2 substrate forms D-isomer.Normal reaction converts trans-enoyl-CoA to L--hydroxyacyl-CoA
14Hydroxyacyl-CoA Dehydrogenase Oxidizes the -Hydroxyl Group to keto groupThis enzyme is completely specific for L-hydroxyacyl-CoAD-hydroxylacyl-isomers are handled differentlyProduces one NADH
15ThiolaseNucleophillic sulfhydryl group of CoA-SH attacks the b-carbonyl carbon of the 3-keto-acyl-CoA.Results in the cleavage of the Ca-Cb bond.Acetyl-CoA and an acyl-CoA (-) 2 carbons are formed
16b-oxidation of odd chain fatty acids Odd chain fatty acids are less commonFormed by some bacteria in the stomachs of rumaniants and the human colon.b-oxidation occurs pretty much as w/ even chain fatty acids until the final thiolase cleavage which results in a 3 carbon acyl-CoA (propionyl-CoA)Special set of 3 enzymes are required to further oxidize propionyl-CoAFinal Product succinyl-CoA enters TCA cycle
17b-oxidation of unsaturated fatty acids b-oxidation occurs normally for 3 rounds until a cis-D3-enoyl-CoA is formed.Acyl-CoA dehydrogenase can not add double bond between the a and b carbons.Enoyl-CoA isomerase converts this to trans- 2 enoly-CoANow the b-oxidation can continue on w/ the hydration of the trans-D2-enoyl-CoAOdd numbered double bonds handled by isomerase
18b-oxidation of fatty acids with even numbered double bonds
19Ketone Bodies A special source of fuel and energy for certain tissues Produced when acetyl-CoA levels exceed the capacity of the TCA cycle (depends on OAA levels)Under starvation conditions no carbos to produced anpleorotic intermediatesSome of the acetyl-CoA produced by fatty acid oxidation in liver mitochondria is converted to acetone, acetoacetate and -hydroxybutyrateThese are called "ketone bodies"Source of fuel for brain, heart and muscleMajor energy source for brain during starvationThey are transportable forms of fatty acids!
21Ketone Bodies and Diabetes Lack of insulin related to uncontrolled fat breakdown in adipose tissuesExcess b-oxidation of fatty acids results in ketone body formation.Can often smell acetone on the breath of diabetics.High levels of ketone bodies leads to condition known as diabetic ketoacidosis.Because ketone bodies are acids, accumulation can lower blood pH.