week 11-lipi
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BiokimiaTRANSCRIPT
LIPID METABOLISMWeek 11
FATE OF GLYCEROL
� From action of lipoprotein lipase
and hormone-sensitive lipase
�Glycerol is converted to the
Glycolysis/ gluconeogenesis Glycolysis/ gluconeogenesis
intermediate-- dihydroxyacetone
phosphate
Glycerol is converted to dihydroxyacetone phosphate,
by reactions catalyzed by:
1 Glycerol Kinase
2 Glycerol Phosphate Dehydrogenase.
Martius & Knoop (1902) fed dogs even- and odd-carbon fatty acids labelled with a benzene ring in place of the terminal methyl group.
ββββ-Oxidation of fatty acids
Fatty acid oxidation occurs by removal of 2-C
units at a time with oxidation at the β-carbon
of the fatty acid
Fatty Acid β-Oxidation
�All cells except for RBCs and brain can use
fatty acids for energy.
� β-Oxidation occurs in Mitochondria
�Three Steps� A.activation
B.transport into mitochondria� B.transport into mitochondria
� C.oxidation
A.Fatty acid
activation
Acyl-CoA
Synthetase of
ER & outer
mitochondrial
membranes,
catalyzes fatty catalyzes fatty
acid activation
FATTY ACID ACTIVATION
� fatty acid + ATP � acyladenylate + PPiPPi � 2 Pi
� acyladenylate + HS-CoA � acyl-CoA + AMP
Overall: Overall: fatty acid + ATP + HS-CoA � acyl-CoA + AMP + 2 Pi
Exergonic hydrolysis of PPi (P~P), catalyzed by Pyrophosphatase, makes the coupled reaction spontaneous.
Fatty acids are linked to CoA in the cytosol. Enzymes of the b-Oxidation Pathway are in the mitochondrial matrix.
Transfer of the fatty acid across the inner membrane involves carnitine
� The transfers long-chain fatty acyl CoA from the
cytosol into the mitochondria C
arn
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1.Acyl-CoA Dehydrogenase
catalyzes oxidation of the
fatty acyl-CoA, to form a
C2 to C3 double bond.
• FAD is the e−
acceptor for Acyl-CoA Dehydrogenase.
• FADH is reoxidized • FADH2 is reoxidized by transfer of 2 e− to an electron transfer flavoprotein (ETF), which passes 2 e− to coenzyme Q of the respiratory chain.
2.Enoyl-CoA Hydratase
catalyzes hydration of the
trans double bond, yielding L-
hydroxyacyl-Coenzyme A.
3.Hydroxyacyl-CoA
Dehydrogenase
catalyzes oxidation of
the hydroxyl in the βposition (C3) to a ketone.position (C3) to a ketone.
NAD+ is the electron
acceptor.
Process similar to
succinate oxidation in
the Citric Acid Cycle
(dehydrogenation,
hydration,
dehydrogenation)
4. β4. β4. β4. β-Ketothiolasecatalyzes thiolytic
cleavage yielding fatty
acyl-CoA (2 C shorter)
and releasing Acetyl-CoA.
� The β oxidation
pathway is cyclic. The
product, 2 C shorter, is
the input to another
round of the pathway
� Products: an acetyl-
CoA and a fatty acid
two carbons shorter, two carbons shorter,
FADH2, NADH
� If the fatty acid
contains an even
number of C atoms,
Final cleavage product
is acetyl CoA.
� If the number is
odd,final cleavage
product is propionyl
CoA
one round of the β-oxidation pathway:
fatty acyl-CoA + FAD + NAD+ + HS-CoA
����
fatty acyl-CoA (2 C less) + FADH + fatty acyl-CoA (2 C less) + FADH2 +
NADH + H+ + acetyl-CoA
Acetyl-CoA can enter Krebs cycle, yielding
additional NADH, FADH2, and GTP
Complete β- oxidation of 1 mol palmitic acid yields 106 mol ATP
How many cycles occurred in the oxidation of
palmitic acid? (#C/2) – 1 (16/2) –1 = 7
14 ATP per cycle 7 * 14 = 98
the last 2 carbons + 10
Subtract 2 for the initial activation –2Subtract 2 for the initial activation –2
Net ATP formed 106
Fatty acid oxidation is a major source of cell ATP
It also produces large amounts of metabolic
water( 130 H2O per palmitoyl-CoA).
“The ship of the desert” sails on its own metabolic
water.
β-Oxidation of Unsaturated and Odd Chain Fatty Acids
�Variations on β-Oxidation - extra enzymes required
�Unsaturated FA (C18:1, C18:2, C18:3 and others)others)� require two extra enzymes to get double bonds in the right place for enzymes of β-oxidation to work(cis-trans isomerase, reductase)
� skip one or more oxidation steps -Slightly less Energy derived as these molecules are slightly more oxidized to begin with
ββββ−−−− Oxidation of Odd-Chain Fatty Acids
• Odd-chain fatty acids occur in plants and
microorganisms
• Final cleavage product is propionyl CoA
rather than acetyl CoA
• Three enzymes convert propionyl CoA to
succinyl CoA (citric acid cycle intermediate)
Conversion of propionyl CoA to
succinyl CoA
Succinyl CoA --> oxalacetate--> glucose
(gluconeogenesis)
During CHO starvation, oxaloacetate in liver is depleted due to
gluconeogenesis. This impedes acetyl-CoA entry to Krebs cycle.
Acetyl-CoA in liver mitochondria is converted then to ketone
bodies.
KETONE BODIES FORMATION
METABOLISM OF KETONE BODIES
� Acetone, Acetoacetate, β- hydroxybutyrate are
called ketone bodies.
� Produced in liver,Diffuse out of the liver into
the blood .Acetone is exhaled by the lungs,
Acetoacetate and beta hydroxybutyrate are Acetoacetate and beta hydroxybutyrate are
taken up by extrahepatic tissues and
catabolized for energy.
�Fuel molecules
�derived from excess acetyl CoA
�Water solubleWater soluble
�readily and quickly transported to
other tissues for energy
�Major source of energy for brain in starvation
(skeletal muscle and kidney, also)
KETONE BODIES OXIDIZED IN
MITOCHONDRIA OF EXTRAHEPATIC TISSUES
FATTY ACID BIOSYNTHESIS
� Not exactly the reverse of degradation
by a different set of enzymes , in a different part of the cell
� Primarily in the cytoplasm of the following tissues: liver, kidney, adipose, central nervous system and lactating mammary gland
� Rule: Fatty acid biosynthesis is a stepwise assembly of acetyl-CoA units (mostly as malonyl-CoA) ending with palmitate (C16 saturated)
� 3 Phase: Activation, Elongation, Termination
�Liver is the major organ for fatty acid synthesis
FATTY ACID BIOSYNTHESIS
� Cytosol
� Requires NADPH
� Acyl carrier protein
� Mitochondria
� NADH, FADH2
� CoA
Beta OxidationSynthesis
� D-isomer
� CO2 activation
� Keto → saturated
� L-isomer
� No CO2
� Saturated → keto
CH3C~SCoA
O
ACTIVATION
-OOC-CH C~SCoA
HCO3-
NN
O
SCH2CH2CH2CH2CO
HH
LYS
NHCH2CH2CH2CH2 ENZYME
Biotin
CO
Biocytin
Cofactor
ATP
ADP + Pi
-OOC-CH2C~SCoA
O
NN
O
SCH2CH2CH2CH2CO
HC
O
O
Carboxybiocytin
active carbon
Acetyl-CoA carboxylase
CO2
Acyl carrier protein
10 kDa
Cysteamine
Phosphopantetheine
Acyl Carrier ProteinAcyl Carrier Protein
HS-CH2-CH2-N-C-CH2-CH2-N-C-C-C-CH2-O-P-O-CH2-Ser-
O O O
OH H
H
HO CH3
H
ACP
HS-CH2-CH2-N-C-CH2-CH2-N-C-C-C-CH2-O-P-O-P-O-CH2
O O O
OH H
H
HO CH3
H
O
OO Adenine
O-P-O
O
OH
OH
H
Coenzyme A
Overall Reaction
CH3C~SCoA
O
CH3C- CH2C~S- ACP
HS-CoACO2
Acyl Carrier
Protein
Malonyl-CoA + ACP
-OOC-CH2C~S-
O
ACP + HS-CoA
Initiation
CH3C-
O
CH2C~S-
O
ACP
NOTE:
Malonyl-CoA carbons become new COOH end
Nascent chain remains tethered to ACP
CO2, HS-CoA are released at each condensation
CH3C-
O
CH2C~S-
O
ACP
NADPH
CH3C- CH2C~S-
O
ACP
HO
H
-H O
ββββ-Carbon Elongation
D isomer
Reduction
Dehydration
ββββ-Ketoacyl-ACP reductase
CH3CH2CH2C~S-
O
ACP
CH3C- = C- C~S-
O
ACP
H
H
-H2O
NADPH Reduction
ββββ -Hydroxyacyl-ACP dehydrase
Enoyl-ACP reductase
-KS
-S-ACP
TERMINATION Ketoacyl ACP
Synthase
Transfer to KSTransfer to Malonyl-CoA
-CH2CH2CH2C~S- ACP
CO2
Free to bind
Malonyl-CoASplit out CO2
O
When C16 stage is reached, instead of transferring to KS,
the transfer is to H2O and the fatty acid is released
Acetyl-CoA is delivered to cytosol from the
mitochondria as CITRATE
METABOLISM OF CHOLESTEROLS
SOURCES OF CHOLESTEROL
Diet De novo synthesisCholesterol synthesizedin extrahepatic tissues
Liver cholesterolLiver cholesterolpool
Free cholesterolIn bile
Conversion to bile salts/acids
Secretion of HDLand VLDL
CHOLESTEROL SYNTHESIS
�80 % in liver, ~10% intestine, ~5% skin
Occurs in cytosol
�Requires 18Acetyl-CoA、16NADPH、�Requires 18Acetyl-CoA、16NADPH、
36ATP
�Similar to ketogenic pathway
Highly regulated
Cholesterol
Synthesis
(C2)
(C5)
(C30)
(C27)