Fatty acid Catabolism (b-oxidation)

Beta Oxidation of Fatty Acids Process by which fatty acids are degraded by removal of 2-C units b-oxidation occurs in the mitochondria matrix The 2-C units are released as acetyl-CoA, not free acetate The process begins with oxidation of the carbon that is "beta" to the carboxyl carbon, so the process is called"beta-oxidation"

Fatty 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 PPi Formation of a CoA ester is expensive energetically Reaction just barely breaks even with ATP hydrolysis DGo’ATP hydroysis = -32.3 kJ/mol, DGo’ Acyl-CoA synthesis +31.5 kJ/mol. But subsequent hydrolysis of PPi drives the reaction strongly forward (DGo’ –33.6 kJ/mol)

Import of acyl-CoA into mitochondria b-oxidation occurs in the mitochondria, requires import of long chain acyl-CoAs Acyl-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 cytosol Acyl-carnitine is then converted back to acyl-CoA in the matrix

Deficiencies of carnitine or carnitine transferase or translocator activity are related to disease state Symptons 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 source People with this disease supplement diet with medium chain fatty acids that do not require carnitine shuttle to enter mitochondria.

b-oxidation Strategy: create a carbonyl group on the -C First 3 reactions do that; fourth cleaves the "-keto ester" in a reverse Claisen condensation Products: an acetyl-CoA and a fatty acid two carbons shorter

b-oxidation B-oxidation of palmitate (C16:0) yields 106 molecules of ATP C 16:0-CoA + 7 FAD + 7 NAD+ + 7 H20 + 7 CoA  8 acetyl-CoA + 7 FADH2 + 7 NADH + 7 H+ 2.5 ATPs per NADH = 17.5 1.5 ATPs per FADH2 = 10.5 10 ATPs per acetyl-CoA = 80 Total = 108 ATPs 2 ATP equivalents (ATP AMP + PPi, PPi  2 Pi) consumed during activation of palmitate to acyl-CoA Net yield = 106 ATPs

Acyl-CoA Dehydrogenase Oxidation of the C-C bond Mechanism involves proton abstraction, followed by double bond formation and hydride removal by FAD Electrons are passed to an electron transfer flavoprotein, and then to the electron transport chain.

Acyl-CoA Dehydrogenase

Enoyl-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

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Hydroxyacyl-CoA Dehydrogenase Oxidizes the -Hydroxyl Group to keto group This enzyme is completely specific for L-hydroxyacyl-CoA D-hydroxylacyl-isomers are handled differently Produces one NADH

Thiolase Nucleophillic 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

b-oxidation of odd chain fatty acids Odd chain fatty acids are less common Formed 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-CoA Final Product succinyl-CoA enters TCA cycle

b-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-CoA Now the b-oxidation can continue on w/ the hydration of the trans-D2-enoyl-CoA Odd numbered double bonds handled by isomerase

b-oxidation of fatty acids with even numbered double bonds

Ketone 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 intermediates Some of the acetyl-CoA produced by fatty acid oxidation in liver mitochondria is converted to acetone, acetoacetate and -hydroxybutyrate These are called "ketone bodies" Source of fuel for brain, heart and muscle Major energy source for brain during starvation They are transportable forms of fatty acids!

Formation of ketone bodies Re-utilization of ketone bodies

Ketone Bodies and Diabetes Lack of insulin related to uncontrolled fat breakdown in adipose tissues Excess 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.