Transcript
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
Also binds thyroid hormones
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.
Fate of Glycerol
Not wasted
Shuttled to liver in blood
Catabolized there
Glycolysis
Gluconeogenesis
Activation of Fatty Acids
Keq = 337
Keq = 1589
Overall:
Keq = 535,000
Transport into the Mitochondrion
(Carnitine-Acylcarnitine
Translocase)
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
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 32ish 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
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.)
Liver Juice! Ummm!!!
(ACC = Acetyl CoA Carboxylase)
Regulation
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)
Catalase
Glucose
Acyl CoA
Dehydrogenase
Acyl CoA
Oxidase
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.
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.
?-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 b-methyl groups
Can’t do b-oxidation
Dietary phytanates
Dairy
Fish
Animal fats
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
Refsum’s sign
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.
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 pH drops into danger zone
