CHEM 3303'02 Biochemistry

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CHEM 3303.02 Biochemistry

• Chapter 17
• Fatty Acid Catabolism

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Knowledge/ skills

• Entire chapter-
• Digestion, mobilization and transport of fats
• Oxidation of fatty acids
• Ketone bodies

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The fates of fatty acids

• Oxidation of long chain fatty acids to
  acetyl-CoA is a central energy yielding pathway
• The acetyl-CoA produced can be completely
  oxidized in the citric acid cycle, and the
  removed electrons passed down through the
  respiratory chain to make ATP
• The mechanism is in a 4 step process called
  b-oxidation where carbon is removed two units at
  a time
• In mammalian heart and liver, it provides up to
  80 of the energetic needs under all
  physiological circumstances
• the acetyl-CoA may have other biosynthetic fates
• Acetyl-CoA may be used to produce ketone bodies
  in the liver

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Fatty acid sources

• There are three sources
• 1. fats consumed in the diet
• 2. fats stored in cells as lipid droplets
• 3. fats synthesized in one organ for export to
  another.
• Triacylglycerols provide more than half the
  energy requirements of liver, heart and resting
  skeletal muscle
• They are the sole source of energy in hibernating
  animals and migrating birds
• Germinating seeds use fats as a source of energy

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In vertebrates

• Ingested triacylglycerols must be converted from
  macroscopic insoluble particles to finely
  dispersed microscopic micelles
• After ingestion of a fatty acid meal, bile salts
  (amphipathic compounds e.g. taurocholic acid,
  synthesized from cholesterol in liver and stored
  in the gall bladder) is released to form mixed
  micelles to increase the accessibility of lipid
  molecules to water soluble lipases in the
  intestine
• Lipase converts triacylglycerols to
  monoglycerols, diglycerols, free fatty acids and
  glycerol

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Lipoprotein aggregates

• Smaller products diffuse across the epithelial
  cells of the intestinal lining
• In the epithelial cells, products are reconverted
  to triacylglycerols and packaged with dietary
  cholesterol and specific proteins into
  lipoprotein aggregates.
• These specific proteins are called
  apolipoproteins
• The aggregates contain a surface layer of
  phospholipid with triacylglycerols (about 80 of
  the mass) in the interior
• Combinations of lipid an proteins produce
  particles of different densities ranging from
  chylomicrons and very low-density lipoproteins
  (VLDL) to very high density lipoproteins (VHDL)

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Delivery of lipids to target tissues

• Protein moieties of lipoproteins are recognized
  by receptors on cell surfaces. For example,
  chylomicrons contain apolipoprotein C-II, move
  from the intestinal mucosa into the lymphatic
  system, then enter blood which goes to muscle and
  adipose tissue. In the capillaries of these
  tissues, extracellular lipoprotein lipase
  activated by the apolipoprotein C-II hydrolyses
  the triacylglycerols to fatty acids and glycerol
  which are taken up by the cells of the target
  tissue. In adipose tissue, they are re-esterified
  for storage as triacylglycerol

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Chylomicron remnants

• Chylomicrons that have been depleted of their
  triacylglycerols (still containing cholesterol
  and apolipoproteins) stay in the blood and are
  removed in the liver
• Receptors in liver cause them to be taken up by
  endocytosis that was mediated by the
  apolipoprotein
• Remaining triacylglycerols may be oxidized for
  energy production or may be used for biosynthesis
  of ketone bodies
• When excess fatty acids are taken up, the liver
  converts them to triacylglycerols which are
  packaged with specific apolipoproteins into VLDL
  that are transported in the blood to adipose
  tissue where they are removed and stored as lipid
  droplets in the adipocytes and in steroid
  synthesizing cells of the adrenal cortex, ovary
  and testes

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Classification by density

• Listed in order from larger and less dense (more
  fat than protein) to smaller and more dense
• Chlyomicrons- carry triacylglycerol from
  intestines to liver and adipose tissue
• VLDL- very low density lipoproteins- carry newly
  synthesized triacylglycerol from liver to adipose
  tissue and muscle tissue
• LDL- low density lipoproteins carry cholesterol
  from liver to body cells- bad cholesterol. Caused
  by extraction of lipids from VLDL
• HDL- High density lipoproteins- collect excess
  cholesterol from body tissues and bring it back
  to the liver- good cholesterol

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Lipid storage in cells

• In storage tissue, triacylglycerols form lipid
  droplets with a core of sterol esters surrounded
  by a monolayer of phospholipids called perilipins
• Perilipins restrict access to lipid droplets
  until a hormone signals the need to use the
  triacylglycerols for energy

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Glucagon triggered release of fatty acids

• Glucagon binds to its hormone receptor on the
  membrane of the adipocyte and triggers a series
  of events

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Fatty acids are oxidized in the mitochondria

• Fatty acids with a chain length of 12 or fewer
  carbons enter the mitochondria directly
• Longer chain fatty acids need the help of a
  transport system called the carnitine shuttle
• The carnitine shuttle is a 3 enzyme system
• The first step is catalyzed by the acyl-CoA
  synthetases- a family of isozymes, specific for
  short, intermediate or long carbon chains present
  on the outer mitochondrial membrane
• Reaction is fatty acid CoA ATP ? fatty
  acyl-CoA AMP PPi

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The mitochondrion

• Double membrane
• Readily permeable to small ltMr 5,000 molecules
  and ions moving through integral membrane porins
• Inner membrane is impermeable to most small
  molecules and ions including H. Specific
  transporters allow molecules/ions to pass

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Acyl-CoA synthetase reaction

• Overall reaction is fatty acid CoA ATP ?
  fatty acyl-CoA AMP 2Pi
• ?Gº is -34kJ/mol

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Transport of fatty acid into mitochondria

• Fatty acyl-CoA formed at the cytosolic side of
  the outer mitochondrial membrane can be
  transported into the mitochondrion or used in the
  cytosol to form membrane lipids
• Second reaction in the shuttle is formation of
  fatty acyl-carnitine I

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Overview of fatty acid oxidation

• Stage 1 b oxidation- long chain fatty acid is
  oxidized to yield acetyl residues in the form of
  acetyl-CoA
• The process starts at the carboxyl end
• Formation of each acetyl-CoA requires removal of
  4 hydrogen atoms (4 electrons and 4H) by
  dehydrogenases

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• 4 step process

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Step 1- dehydrogenation of C skeleton
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Step 2- hydration of the trans double bond
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Step 3- dehydrogenation to form a ketone
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Step 4 thiolysis
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• Trifunctional protein, a membrane bound multi
  subunit protein degrades carbon chains till they
  are down to C12
• When they are 12 or fewer C, 4 soluble enzymes of
  the mitochondrial matrix do the job

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• The overall reaction is
• Palmitoyl-CoA CoA FAD NAD H2O ?
  myristoyl CoA acetyl-CoA FADH2 NADH H
• When electrons are donated from FADH2 and NADH, 4
  ATP are generated (1.5 from FADH2 and 2.5 from
  NADH). Water is also generated from transfer of
  two electrons to oxygen via the reaction NADH
  H ½ O2? NAD H2O
• Palmitoyl is a 16-C, while myristoyl is a 14-C
• Overall reaction to break down the entire 16-C is
  
• Palmitoyl-CoA 7CoA 7FAD 7NAD 7H2O ? 8
  acetyl-CoA 7 FADH2 7 NADH 7H
• Or Palmitoyl-CoA 7CoA 7O2 28Pi 28ADP ? 8
  acetyl-CoA 7H2O 28ATP

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Complete oxidation of a fatty acid

• Acetyl-CoA can be fed into the TCA cycle and
  electrons so formed can be transferred down the
  respiratory chain to form more ATP
• Overall oxidation from TCA and into the
  respiratory chain is
• 8 Acetyl-CoA 16O2 80Pi 80ADP ? 8CoA
  16H2O 80ATP 16 CO2
• Combining the b-oxidation and acetyl-CoA
  oxidation
• Palmitoyl-CoA 23O2 108Pi 108ADP ? CoA
  23H2O 108ATP 16 CO2

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Steps in oxidation with cis double bonds

• Acetyl- CoA is generated till just before the
  double bond. Because the enoyl-CoA hydratase
  recognises only trans double bond, need a ?3,
  ?2, -enoyl-CoA isomerase to change the bond from
  cis to trans

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Steps in oxidation of two cis double bonds

• Need two enzymes, an enoyl-CoA isomerase and
  2,4-dienoyl-CoA reductase to change the double
  bonds to trans

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Odd number fatty acids leaves a 3C propionyl-CoA

• Propionyl-CoA is converted to succinyl-CoA that
  can enter the TCA cycle. One molecule of ATP is
  converted to ADP to power the reaction

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Fatty acid oxidation is regulated
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Fatty acid oxidation can occur in two
organelles, the mitochondria or in peroxisomes

• In plants, fatty acid oxidation occurs primarily
  in peroxisomes in leaf tissue and in glyoxysomes
  in germinating seeds

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w oxidation of fatty acids- normally minor

• In b oxidation, cleavage occurs at the carboxyl
  end of the fatty acid.
• w oxidation starts furthermost away from the
  carboxylic acid.
• Occurs in the endoplasmic reticulum of liver and
  kidney
• Preferred substrate of 10 or 12 carbon atoms

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Presence of a methyl group makes b oxidation
impossible

• Use a oxidation to remove the methyl group

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Ketone bodies

• Acetyl-CoA converted to ketones- acetone,
  acetoacetate and D-b-hyroxybutyrate
• All are soluble in blood and urine.
• Acetone is exhaled
• Acetoacetate and D-b-hyroxybutyrate are
  transported to extrahepatic tissues where they
  are converted to acetyl-CoA and oxidized by the
  TCA cycle

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Use of ketone bodies as fuel
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