Fatty Acid Oxidation

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fatty acid oxidation

Text of Fatty Acid Oxidation

  • Fatty Acid Oxidation

    Molecular Biochemistry II

  • A 16-C fatty acid with numbering conventions is shown.

    Most naturally occurring fatty acids have an even number of carbon atoms.

    The pathway for catabolism of fatty acids is referred to as the b-oxidation pathway, because oxidation occurs at the b-carbon (C-3).

    C

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    g

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    g

    EMBED ChemDraw.Document.4.5

    fatty acid with a cis-9

    double bond

    _1008576813.cdx_1008576919.cdx_965825676.cdx
  • Triacylglycerols (triglycerides) are the most abundant dietary lipids. They are the form in which we store reduced C for energy.

    Each triacylglycerol has a glycerol backbone to which are esterified 3 fatty acids

    Most triacylglycerols are mixed. The 3 fatty acids differ in chain length & number of double bonds.

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    glycerol fatty acid triacylglycerol

    EMBED ChemDraw.Document.4.5

    _977227313.cdx_977227727.cdx_1008575693.cdx_977227399.cdx_977163222.cdx
  • Lipid digestion, absorption, transport will be covered separately.

    Lipases hydrolyze triacylglycerols, releasing 1 fatty acid at a time, yielding diacylglycerols, & eventually glycerol.

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    glycerol fatty acid triacylglycerol

    EMBED ChemDraw.Document.4.5

    _977227313.cdx_977227727.cdx_1008575693.cdx_977227399.cdx_977163222.cdx
  • Glycerol, arising from hydrolysis of triacylglycerols, is converted to the Glycolysis intermediate dihydroxyacetone phosphate, by reactions catalyzed by:

    1 Glycerol Kinase

    2 Glycerol Phosphate Dehydrogenase.

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    glycerol glycerol-3-P dihydroxyacetone-P

    EMBED ChemDraw.Document.4.5

    ATP ADP

    H+ +

    NAD+ NADH

    1

    2

    _977171398.cdx
  • Free fatty acids, which in solution have detergent properties, are transported in the blood bound to albumin, a serum protein produced by the liver.

    Several proteins have been identified that facilitate transport of long chain fatty acids into cells, including the plasma membrane protein CD36.

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    EMBED ChemDraw.Document.4.5

    fatty acid with a cis-9

    double bond

    _1008576813.cdx_1008576919.cdx_965825676.cdx
  • Fatty acid activation:

    Fatty acids must be esterified to Coenzyme A before they can undergo oxidative degradation, be utilized for synthesis of complex lipids, or be attached to proteins as lipid anchors.

    Acyl-CoA Synthases (Thiokinases) of ER & outer mitochondrial membranes catalyze activation of long chain fatty acids, esterifying them to coenzyme A.

    This process is ATP-dependent, & occurs in 2 steps.

    There are different Acyl-CoA Synthases for fatty acids of different chain lengths.

  • Acyl-CoA Synthases

    Exergonic PPi (P~P) hydrolysis, catalyzed by Pyrophosphatase, makes the coupled reaction spontaneous.

    2 ~P bonds of ATP are cleaved.

    The acyl-CoA product includes one "~" thioester linkage.

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    Fatty acid activation

    EMBED ChemDraw.Document.4.5

    fatty acid

    ATP

    acyl-

    adenylate

    acyl-CoA

    _1104392193.cdx
  • Summary of fatty aid activation:

    fatty acid + ATP acyladenylate + PPi

    PPi 2 Pi

    acyladenylate + HS-CoA acyl-CoA + AMP

    Overall:

    fatty acid + ATP + HS-CoA acyl-CoA + AMP + 2 Pi

  • For most steps of the pathway there are multiple enzymes specific for particular fatty acid chain lengths.

    b-Oxidation pathway:

    Fatty acids are degraded in the mitochondrial matrix via the b-Oxidation Pathway.

    Fatty acyl-CoA formed in cytosol by enzymes of outer mitochondrial membrane & ER

    inner

    membrane

    -Oxidation pathway in matrix

    Mitochondrion

  • Fatty acyl-CoA formed outside can pass through the outer mitochondrial membrane (which has large VDAC channels), but cannot penetrate the inner membrane.

    Many of the constituent enzymes are soluble proteins located in the mitochondrial matrix.

    But enzymes specific for very long chain fatty acids are associated with the inner membrane, facing the matrix.

    Fatty acyl-CoA formed in cytosol by enzymes of outer mitochondrial membrane & ER

    inner

    membrane

    -Oxidation pathway in matrix

    Mitochondrion

  • Carnitine Palmitoyl Transferases catalyzes transfer of a fatty acid between the thiol of Coenzyme A and the hydroxyl on carnitine.

    Transfer of the fatty acid moiety across the mitochondrial inner membrane involves carnitine.

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    EMBED ChemDraw.Document.4.5

    carnitine

    fatty acyl carnitine

    Carnitine Palmitoyl Transferase

    _1008786327.cdx
  • Carnitine-mediated transfer of the fatty acyl moiety into the mitochondrial matrix is a 3-step process:

    1. Carnitine Palmitoyl Transferase I, an enzyme on the cytosolic surface of the outer mitochondrial membrane, transfers a fatty acid from CoA to the OH on carnitine.

    2. An antiporter in the inner mitochondrial