Chapter 16 part 2
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Chapter 16 (Part 2). 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

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Chapter 16 (Part 2)

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Chapter 16 part 2

Chapter 16 (Part 2)

Fatty acid Catabolism

(b-oxidation)


Chapter 16 part 2

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

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

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


Chapter 16 part 2

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

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 oxidation1

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


Chapter 16 part 2

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.


Chapter 16 part 2

Acyl-CoA Dehydrogenase


Chapter 16 part 2

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, withcis D2 substrate forms D-isomer.

  • Normal reaction converts trans-enoyl-CoA to L--hydroxyacyl-CoA


Chapter 16 part 2

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


Chapter 16 part 2

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

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 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

b-oxidation of fatty acids with even numbered double bonds


Chapter 16 part 2

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!


Chapter 16 part 2

Re-utilization of

ketone bodies

Formation of

ketone bodies


Ketone bodies and diabetes

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.


Chapter 16 part 2

The Glyoxylate Cycle

  • A variant of TCA for plants and bacteria

  • Acetate-based growth - net synthesis of carbohydrates and other intermediates from acetate - is not possible with TCA

  • Glyoxylate cycle offers a solution for plants and some bacteria and algae

  • The CO2-evolving steps are bypassed and an extra acetate is utilized

  • Isocitrate lyase and malate synthase are the short-circuiting enzymes


Chapter 16 part 2

Glyoxylate Cycle

  • Rxns occur in specialized organelles (glycoxysomes)

  • Plants store carbon in seeds as oil

  • The glyoxylate cycle allows plants to use acetyl-CoA derived from B-oxidation of fatty acids for carbohydrate synthesis

  • Animals can not do this! Acetyl-CoA is totally oxidized to CO2

  • Malate used in gluconeogenesis


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