Transcript SYNTHESIS OF FATTY ACID Acetyl

Hendra Wijaya
Esa unggul University
TRANSPORT OF ACETYL-COA INTO THE CYTOSOL
TRANSPORT OF ACETYL-COA INTO THE CYTOSOL
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Acetyl-CoA generated in the mitochondrion
Mitochondrial membrane is impermeable to acetyl-CoA
Acetyl-CoA enters the cytosol in the form of citrate
Processing of malate to pyruvate generates NADPH for fatty
acid biosynthesis
OVERVIEW OF FATTY ACID SYNTHESIS
SYNTHESIS OF FATTY ACID
SYNTHESIS OF FATTY ACID
MOVIE
Acetyl-CoA Carboxylase reaction
Acetyl-CoA Carboxylase reaction
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Irreversible reaction that is the committed step in fatty acid
synthesis
Biotin-dependent
Mechanism similar to that of pyruvate carboxylase
Subject to allosteric and hormonal control
– Stimulated by citrate, inhibited by long-chain fatty acids
– Phosphorylation, which inhibits enzyme activity, is
promoted by glucagon and reversed by insulin
Intermediates in Fatty Acid Synthesis are Linked to
Acyl Carrier Protein (ACP)
REACTION SEQUENCE FOR FATTY ACID
BIOSYNTHESIS
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Intermediates attached to the sulfhydryl terminus of a
phosphopantetheine group
Phosphopantetheine linked to Ser hydroxyl of ACP, while
attached to AMP in CoA
ACP can be considered a big CoA molecule
Individual enzymes in bacteria, enzyme complex in eukaryotes
Condensation of malonyl-CoA and acetyl-CoA driven by
decarboxylation
Stereochemistry and reducing agent are different between
synthesis and degradation
In subsequent round of elongation, butyryl thioester
condenses with malonyl-ACP after transfer to condensing
enzyme
Elongation cycles continue until palmitoyl(C16)-ACP is formed,
which is hydrolyzed to give palmitate and ACP
STOICHIOMETRY OF FATTY ACID BIOSYNTHESIS
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Stoichiometry of palmitate synthesis:
Acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14H+
palmitate + 7CO2 + 14NADP+ + 8CoA + 6H2O
Malonyl-CoA synthesis:
7 Acetyl-CoA + 7CO2 + 7ATP
7 malonyl-CoA + 7ADP + 7Pi + 7H+
Overall stoichiometry of palmitate synthesis:
8 Acetyl-CoA + 14 NADPH + 7ATP + 7H+
palmitate + 14NADP+ + 8CoA + 6H2O + 7ADP + 7Pi
FATTY ACID ELONGATION
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In eukaryotes, elongation occurs in both mitochondria and the
endoplasmic reticulum (ER), but the ER system has much
higher activity
Reactions occur on separate enzymes rather than in a complex
Fatty acid is elongated as its CoA derivative
Two carbon units are added sequentially the carboxyl end of
both saturated and unsaturated fatty acids
Malonyl-CoA is again the two-carbon donor
FATTY ACID DESATURATION
NADH + H+
NAD
+
E-FAD
Fe2+
Fe3+
Oleoyl-CoA + 2H2O
E-FADH2
Fe3+
Fe2+
Stearoyl-CoA + O2
NADH-cytochrome cytochrome b5
b5 reductase
desaturase
-O
O
stearate
O
oleate
-O
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Double bonds are introduced into long-chain acyl-CoAs through
an electron-transfer process coupled to the reduction of
molecular oxygen
Reaction catalyzed by a complex of membrane-bound enzymes
Double bonds inserted such that the new double bond is three
carbons closer to the CoA group, and never beyond the C9
position
ESSENTIAL FATTY ACID
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The formation of D12 and D15 double bonds is not possible in
animals
Animals cannot synthesize linoleic acid (18:2D9,12), linolenic
acid (18:3D9,12,15), or arachidonic acid (20:4 D5,8,11,14), which are
used in the synthesis of eicosanoid hormones
– Prostaglandins
– Leukotrienes
These are called essential fatty acids because they are
essential lipid components that must be provided in the diet
TRIACYLGLYCEROL (TG) SYNTHESIS
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Generally synthesized from glycerol 3-phosphate, which is
produced by the reduction of dihydroxyacetone phosphate
(DHAP)
Acylations performed with acyl-CoA and acyltransferases
Fatty acyl chain at C1 is usually saturated, fatty acyl chain at C2
is usually unsaturated
TG and phospholipid pathways generally diverge at
phosphatidic acid and diacylglycerol
– Diacylglycerol formed by phosphatase
– Acyltransferase forms TG
CONFORMATIONAL MODEL OF (A) PHOSPHOLIPID
PHOSPHATIDYLCHOLINE AND (B) TRIACYLGLYCEROL
GLYCEROPHOSPHOLIPIDS: Membrane
O
O
O
O
R2
O
O
R2
H O
O
O
R1
O
O
R2
O
R1
+
H O
O
N(CH3)3
O-
phosphatidylethanolamine (PE)
O
+
P O
NH3
O-
O
R1
H O
+
P O
O
NH3
P O
O-
O-
O
phosphatidylserine (PS)
phosphatidylcholine (PC)
Lesitin
O
O
R2
O
O
phosphatidylinositol (PI)
OH OH
P O
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O
HO
OH
phosphatidylglycerol (PG)
O
R1
H O
O
OH
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R2
O
R2
P O
O-
CHOH
CH2OH
O
O
O
O
R1
O-
O
O
H O
O
O
O
R1
R2
O
H O
O
O
P OCH2CHCH2O
P O
O-
O-
OH
cardiolipin (CL)
C1 substituents mostly saturated fatty acids, C2 substituents
mostly unsaturated fatty acids
PE, PG, and CL found in bacteria, eukaryotes contain all six
Phospholipases serve as digestive enzymes and as generators
of signal molecules
R1
CTP: Citidene Tryphosphate
Biosynthesis Of PhospatidylserineI:
CDP-Diacylglycerol Pathway
NH2
O
O
O
R2
O
O
N
O
R1
H
2-
R2
CTP PPi
O
O
H
O
O
P
OPO3
phosphatidic acid
R1
N
O
O
O-
P
O
Sytosin
O
O
O-
CDP-diacylglycerol H
H
H
OH
H
H
serine
CMP
O
O
R2
O
O
R1
H
O
O
P
O
O-
CTP: Citidene Tryphosphate
+
NH3
phosphatidylserine (PS)
OO
Biosynthesis Of Phospatidylcholine:
CDP-Choline & CDP-ethanolamine
NH2
N
ATP ADP
HO
+
N(CH3)3
choline
CTP PPi
O
-O P O
O-
+
N(CH3)3
O
+
N
O
O P O P O
(H3C)3N
O-
O-
CDP-choline
phosphocholine
O
H
H
H
OH
H
H
1,2 diacylglycerol
CMP
O
O
R2
O
O
R1
H O
O P O
O-
+
N(CH3)3
phosphatidlycholine (PC, lecithin)
O
PHOSPHOLIPID SYNTHESIS
4/12/2016
36
KETONE BODIES
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Acetyl-CoA from fatty acid oxidation enters
the citric acid cycle when fat and carbohydrate
breakdown are balanced
– Entry depends on oxaloacetate
– Oxaloacetate consumed to form glucose
by gluconeogenesis in fasting, diabetes,
and starvation
In the absence of oxaloacetate, acetyl-CoA is
converted to acetoacetate or D-bhydroxybutyrate through ketogenesis
Acetone is formed by the non-enzymatic
decarboxylation of acetoacetate
Ketone bodies are important fuel molecules
O
O
O-
acetoacetate
O
acetone
OH
O
O-
D-b-hydroxybutyrate
OVERVIEW
Formation of keton
bodies from acytil-CoA
1. Initial condensation
2. Ester condensation to
form HMG-CoA (also
precursor in cholesterol
biosynthesis)
3. Acetoacetate and acetylCoA formed in a
mechanism similar to the
reverse of the citrate
synthase reaction
Metabolic Conversion of Ketone Bodies to Acetyl-CoA S
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Acetoacetate reduced to
hydroxybutyrate in an
NADH-dependent reaction
Acetoacetyl-CoA can be
cleaved by thiolase to give
2 acyl-CoA
The liver can supply
acetoacetate to other
tissues
SPHINGOLIPIDS
OH
O
R2
N
H
(CH2)12CH3
H
O X
sphingolipid
X=H
ceramide
X = carbohydrate
glycosphingolipid
X = phosphate ester sphingophospholipid
OH
O
R2
N
H
(CH2)12CH3
H O
O
P
O
O-
sphingomyelin
+
N(CH3)3
SPHINGOLIPIDS
SPHINGOLIPIDS
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Backbone is ceramide rather than glycerol
Most sphingolipids contain carbohydrates as their head
group
Sphingolipids play important roles in nervous tissue
– Sphingomyelin is an important component of the
myelin sheath
– Gangliosides constitute 6% of the lipids in gray matter
SYNTHESIS OF CERAMIDA
Toy-Sachs Disease: A Disorder of Ganglioside
Breakdown
ceramide
GalNAc Gal Glc
NAN
ganglioside GM2
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Gangliosides are degraded inside
lysosomes by the sequential removal of
terminal sugars
In Tay-Sachs disease, ganglioside GM2
accumulates because hexosaminidase
activity is absent
This ganglioside interferes with neuronal
function
Genetic recessive disease
ceramide
Gal Glc
NAN
ganglioside GM3
+
N-acetyl
galactosamine
MEMBRANE LIPIDS
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Have a hydrophilic and hydrophobic component
– 1,2-diacylglycerol or N-acetylsphingosine (ceramide) linked
to a polar head group
– Hydrophobic acyl chains
Form bilayered membranes in aqueous media
Membranes are noncovalent, fluid assemblies
Membrane lipids synthesized predominantly on the
cytoplasmic face of the ER, then transported in vesicles to
their destinations
β
FATTY ACID BIOSYNTHESIS VS
β-OXIDATION