Transcript Lecture Slides for Fatty Acid 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
• 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 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!!!
Regulation
(ACC = Acetyl CoA 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 CoA
Dehydrogenase
Acyl CoA
Oxidase
Catalase
Glucose
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.
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 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