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Lipid Catabolism

Lipid Catabolism. CH339K. Fats are stored in lipid droplets. Lipid droplets in a rat adipocyte. Glucagon Epinephrine. 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

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Lipid Catabolism

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  1. Lipid Catabolism CH339K

  2. Fats are stored in lipid droplets Lipid droplets in a rat adipocyte

  3. Glucagon Epinephrine

  4. 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

  5. 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.

  6. Fate of Glycerol • Not wasted • Shuttled to liver in blood • Catabolized there Glycolysis Gluconeogenesis

  7. Activation of Fatty Acids Overall: Keq = 535,000 Keq = 1589 Keq = 337

  8. Transport into the Mitochondrion (Carnitine-Acylcarnitine Translocase)

  9. b-oxidation • Mitochondrial matrix • Oxidizes fatty acyl CoA’s at the b carbon • Sequentially cleaves off acetyl CoAs • Acetyl CoA is processed through Krebs and ETC

  10. 2 Systems for b-oxidation • ≥ 12 carbons: • TFP – last 3 enzymes in multienzyme complex • < 12 carbons • 4 soluble matrix enzymes

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

  12. Monounstaurated • Fatty Acids • Need one extra enzyme • Converts double bond 1

  13. Polyunsaturated Fatty Acids • Need two extra enzymes • Reduce conjugated double bonds to a single double bond 1 2 1

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

  15. 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 (1920’s) 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.)

  16. Liver Juice! Ummm!!!

  17. Regulation (ACC = Acetyl CoA Carboxylase)

  18. 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)

  19. Acyl CoA Oxidase Acyl CoA Dehydrogenase Catalase Glucose

  20. 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.

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

  22. Plants don’t store much fat, but seeds often do.

  23. Ω-Oxidation • ER of vertebrates • Medium chain FAs

  24. 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.

  25. a-oxidation • (Peroxisomes) • Phytanates have b-methylgroups • Can’t do b-oxidation • Dietary phytanates • Dairy • Fish • Animal fats

  26. Refsum’s 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

  27. Refsum’s sign

  28. Ketone Body Generation • During fasting or carbohydrate starvation, oxaloacetate in the liver is used for gluconeogenesis. • Acetyl-CoA then doesn’t 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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