Lipid Catabolism CH 339 K Fats are stored
Lipid Catabolism CH 339 K
Fats are stored in lipid droplets Lipid droplets in a rat adipocyte
Glucagon Epinephrine
Human Serum Albumin • 30 -50 g/l of blood • 67 k. Dal • 585 amino acids • Can bind up to 10 fatty acids • Different binding sites have different affinities • Also binds thyroid hormones
FADL – An E. coli Fatty Acid Transporter 1) 2) 3) 4) b-Barrel Transmembrane Protein 14 Antiparallel b-sheets N-terminal “hatch” domain Conformational change on substrate binding opens hatch a) Ribbon drawing of intact protein b) “Hatch” domain c) Cutaway view to show hatch in central channel d) Cytoplasmic space-filling view to show hatch plugging channel van den Berg, B. (2005) Current Opinion in Structural Biology 15(4): 401 -407.
Fate of Glycerol • Not wasted • Shuttled to liver in blood • Catabolized there Glycolysis Gluconeogenesis
Activation of Fatty Acids Overall: Keq = 1589 Keq = 337 Keq = 535, 000
Transport into the Mitochondrion (Carnitine-Acylcarnitine Translocase)
b-oxidation • Mitochondrial matrix • Oxidizes fatty acyl Co. A’s at the b carbon • Sequentially cleaves off acetyl Co. As • Acetyl Co. A is processed through Krebs and ETC
2 Systems for b-oxidation • ≥ 12 carbons: • TFP – last 3 enzymes in multienzyme complex • < 12 carbons • 4 soluble matrix enzymes
• Palmitate weighs ~256 g/mol (about 42% more than glucose) • Oxidation yields 108 ATPs, versus 32 ish for glucose (about 340% more)
Monounstaurated Fatty Acids • Need one extra enzyme • Converts double bond 1
Polyunsaturated Fatty Acids • Need two extra enzymes • Reduce conjugated double bonds to a single double bond 1 2 1
Odd-numbered Fatty Acids • • Left with 3 carbons Add inorganic carbon Convert to succinate Throw into Krebs Cycle
Pernicious Anemia • B 12 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 B 12 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 • B 12 isolated in 1948, synthesized in 1973 • Now treated with large doses (several mg) B 12 • Sources: fish, meat, poultry, eggs, milk, especially liver and mollusks (clams, oysters, etc. )
Liver Juice! Ummm!!!
Regulation (ACC = Acetyl Co. A Carboxylase)
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)
Acyl Co. A Dehydrogenase Acyl Co. A Oxidase Catalase Glucose
Catalases • Once again, a heme-containing enzyme • Overall reaction: 2 H 2 O 2 ⇄ O 2 + 2 H 2 O • First step: produces porphyrin cation radical • Second step: HOOH acts as electron donor to produce O 2 and return enzyme to resting state.
Catalase is a fun enzyme to assay • Mr. Bubble of the enzyme world Staphylococcus aureus
Plants don’t store much fat, but seeds often do.
Ω-Oxidation • ER of vertebrates • Medium chain FAs
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.
a-oxidation (Peroxisomes) Phytanates have bmethyl groups Can’t do b-oxidation Dietary phytanates • Dairy • Fish • Animal fats
Refsum’s Disease • Phytanoyl Co. A 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
Refsum’s sign
Ketone Body Generation • During fasting or carbohydrate starvation, oxaloacetate in the liver is used for gluconeogenesis. • Acetyl-Co. A then doesn’t enter Krebs cycle. • Acetyl-Co. A converted in mitochondria to ketone bodies, • Ketone bodies are transported in the blood to other cells • Converted back to acetyl-Co. A for catabolism in Krebs cycle, to generate ATP.
b-oxidation in reverse
Diabetic Ketoacidosis • Primarily in Type 1 (insulin-dependent) • Low insulin = low glucose transport into cells • Liver thinks it’s starving • Ketone body production ramps up • Blood p. H drops into danger zone
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