Lipid Catabolism

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Lipid Catabolism

• CH339K

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Fats are stored in lipid droplets
Lipid droplets in a rat adipocyte
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Glucagon Epinephrine
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Human Serum Albumin

• 30-50 g/l of blood
• 67 kDal
• 585 amino acids
• Can bind up to 10 fatty acids
• Different binding sites have different
  affinities
• Also binds thyroid hormones

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FADL An E. coli Fatty Acid Transporter

• b-Barrel Transmembrane Protein
• 14 Antiparallel b-sheets
• N-terminal hatch domain
• Conformational change on substrate binding opens
  hatch
• Ribbon drawing of intact protein
• Hatch domain
• Cutaway view to show hatch in central channel
• Cytoplasmic space-filling view to show hatch
  plugging channel
• van den Berg, B. (2005) Current Opinion in
  Structural Biology 15(4) 401-407.

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Fate of Glycerol

• Not wasted
• Shuttled to liver in blood
• Catabolized there

Glycolysis
Gluconeogenesis
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Activation of Fatty Acids
Overall Keq 535,000
Keq 337
Keq 1589
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Transport into the Mitochondrion
(Carnitine-Acylcarnitine Translocase)
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• b-oxidation
• Mitochondrial matrix
• Oxidizes fatty acyl CoAs at the b carbon
• Sequentially cleaves off acetyl CoAs
• Acetyl CoA is processed through Krebs and ETC

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• 2 Systems for b-oxidation
• 12 carbons
• TFP last 3 enzymes in multienzyme complex
• lt 12 carbons
• 4 soluble matrix enzymes

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• Palmitate weighs 256 g/mol (about 42 more than
  glucose)
• Oxidation yields 108 ATPs, versus 32ish for
  glucose (about 340 more)

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• Monounstaurated
• Fatty Acids
• Need one extra enzyme
• Converts double bond

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• Polyunsaturated Fatty Acids
• Need two extra enzymes
• Reduce conjugated double bonds to a single
  double bond

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• Odd-numbered Fatty Acids
• Left with 3 carbons
• Add inorganic carbon
• Convert to succinate
• Throw into Krebs Cycle

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Pernicious Anemia

• B12 is produced only by several genera of
  bacteria, obtained from animal food
• daily requirement is about 2-3 mg/day
• Gastric mucosa produces a protein called
  intrinsic factor
• Lack of intrinsic factor results in impaired B12
  absorption, pernicious anemia, death in 1-3 years
• Original treatment (1920s) was ½ lb. of raw
  liver daily
• Concentrated liver juice (yum) became available
  in 1928
• B12 isolated in 1948, synthesized in 1973
• Now treated with large doses (several mg) B12
• Sources fish, meat, poultry, eggs, milk,
  especially liver and mollusks (clams, oysters,
  etc.)

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Liver Juice! Ummm!!!
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Regulation
(ACC Acetyl CoA Carboxylase)
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Peroxisomes

• b-Oxidation also occurs in peroxisomes (major
  site in plants)
• In critters, peroxisomes are primary organelles
  for oxidation of very long chain and branched
  fatty acids (cerotic acid, phytanic acids)

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Acyl CoA Oxidase
Acyl CoA Dehydrogenase
Catalase
Glucose
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Catalases

• Once again, a heme-containing enzyme
• Overall reaction 2 H2O2 ? O2 2 H2O
• First step produces porphyrin cation radical
• Second step HOOH acts as electron donor to
  produce O2 and return enzyme to resting state.

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• Catalase is a fun enzyme to assay
• Mr. Bubble of the enzyme world

Staphylococcus aureus
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Plants dont store much fat, but seeds often do.
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• O-Oxidation
• ER of vertebrates
• Medium chain FAs

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a-oxidation
Herbivores consume a lot of chlorophyll.
Chlorophylls have a long hydrophobic tail. Those
tails are split off as part of digestion to form
phytanates.
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• a-oxidation
• (Peroxisomes)
• Phytanates have b-methyl groups
• Cant do b-oxidation
• Dietary phytanates
• Dairy
• Fish
• Animal fats

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Refsums Disease

• Phytanoyl CoA Hydroxylase deficiency
• Can also digest phytanic acid by w-oxidation, but
  only 10 mg/day
• Typical diet contains 50 mg
• Builds up in myelin sheath
• Also screws up vitamin A metabolism
• Demyelinating neuropathy, cerebellar ataxia,
  deafness, anosmia, cranial nerve degeneration

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Refsums sign
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Ketone Body Generation

• During fasting or carbohydrate starvation,
  oxaloacetate in the liver is used for
  gluconeogenesis.
• Acetyl-CoA then doesnt enter Krebs cycle.
• Acetyl-CoA converted in mitochondria to ketone
  bodies,
• Ketone bodies are transported in the blood to
  other cells
• Converted back to acetyl-CoA for catabolism in
  Krebs cycle, to generate ATP.

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b-oxidation in reverse
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Diabetic Ketoacidosis

• Primarily in Type 1 (insulin-dependent)
• Low insulin low glucose transport into cells
• Liver thinks its starving
• Ketone body production ramps up
• Blood pH drops into danger zone

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