Chapter 16 (Part 3) Fatty acid Synthesis. Fatty Acid Synthesis In mammals fatty acid synthesis...
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Transcript of Chapter 16 (Part 3) Fatty acid Synthesis. Fatty Acid Synthesis In mammals fatty acid synthesis...
Chapter 16 (Part 3)
Fatty acid Synthesis
Fatty Acid Synthesis• In mammals fatty acid synthesis
occurs primarily in the liver and adipose tissues
• Also occurs in mammary glands during lactation.
• Fatty acid synthesis and degradation go by different routes
• There are four major differences between fatty acid breakdown and biosynthesis
The differences between fatty acid biosynthesis and
breakdown • Intermediates in synthesis are linked
to -SH groups of acyl carrier proteins (as compared to -SH groups of CoA)
• Synthesis in cytosol; breakdown in mitochondria
• Enzymes of synthesis are one polypeptide
• Biosynthesis uses NADPH/NADP+; breakdown uses NADH/NAD+
ACP vs. Coenzyme A
•Intermediates in synthesis are linked to -SH groups of acyl carrier proteins (as compared to -SH groups of CoA)
Fatty Acid Synthesis Occurs in the Cytosol
• Must have source of acetyl-CoA• Most acetyl-CoA in mitochondria• Citrate-malate-pyruvate shuttle provides
cytosolic acetate units and reducing equivalents for fatty acid synthesis
Citrate synthaseCitrate Lyase
Malate dehydrogenase
Malate EnzymePyruvate
carboxylase
Fatty Acid Synthesis• Fatty acids are built from 2-C units
derived from acetyl-CoA• Acetate units are activated for transfer
to growing FA chain by conversion to malonyl-CoA
• Decarboxylation of malonyl-CoA and reducing power of NADPH drive chain growth
• Chain grows to 16-carbons (eight acetyl-CoAs)
• Other enzymes add double bonds and more Cs
Acetyl-CoA Carboxylase
• The "ACC enzyme" commits acetate to fatty acid synthesis
• Carboxylation of acetyl-CoA to form malonyl-CoA is the irreversible, committed step in fatty acid biosynthesis
Acetyl-CoA + HCO3- + ATP malonyl-CoA + ADP
Acetyl-CoA
Carboxylase
Regulation of Acetyl-CoA Carboxylase
(ACCase)• ACCase forms long, active
filamentous polymers from inactive protomers
• Accumulation of palmitoyl-CoA (product) leads to the formation of inactive polymers
• Accumulation of citrate leads to the formation of the active polymeric form
• Phosphorylation modulates citrate activation and palmitoyl-CoA inhibition
• Unphosphorylated ACCase has low Km for citrate and is active at low citrate
• Unphosphorylated ACCase has high Ki for palmitoyl-CoA and needs high palmitoyl-CoA to inhibit
• Phosphorylated E has high Km for citrate and needs high citrate to activate
• Phosphorylated E has low Ki for palmitoyl-CoA and is inhibited at low palmitoyl-CoA
Regulation of Acetyl-CoA Carboxylase (ACCase)
Fatty Acid Synthesis
• Step 1: Loading – transferring acetyl- and malonyl- groups from CoA to ACP
• Step 2: Condensation – transferring 2 carbon unit from malonyl-ACP to acetyl-ACP to form 2 carbon keto-acyl-ACP
• Step 3: Reduction – conversion of keto-acyl-ACP to hydroxyacyl-ACP (uses NADPH)
• Step 4: Dehydration – Elimination of H2O to form Enoyl-ACP
• Step 5: Reduction – Reduce double bond to form 4 carbon fully saturated acyl-ACP
Step 1: Loading Reactions
H3C C
O
S CoA C C
O
S CoACO
O
H
H HS-ACPHS-ACP
HS-CoAHS-CoA
H3C C
O
S ACP C C
O
S ACPCO
O
H
H
acetyl-CoA
acetyl-ACP
malonyl-CoA
malonyl-ACP
acetyl-CoA:ACPtransacylase
malonyl-CoA:ACPtransacylase
Step 2: Condensation Rxn
H3C C
O
S ACP
HS-Ketoacyl-ACP Synthase
HS-ACP
H3C C
O
S ketoacyl-ACP SynthaseC C
O
S ACPCO
O
H
H
CO2
C C
O
S ACPC
H
H
O
H3C
acetyl-ACP
malonyl-ACP
+
keto-ACP synthase
acetoacetyl-ACP
Step 3: Reduction
C C
O
S ACPC
H
H
O
H3C
NADP+
C C
O
S ACPC
H
H
OH
H3C
H
acetoacetyl-ACP
-hydroxybutyryl-ACP
NADPH + H+
Ketoacyl-ACP Reductase
Step 4: Dehydration
C C
O
S ACPC
H
trans-enoyl-ACP
H3C
H
H20
-hydroxyacyl-ACPdehydrase
C C
O
S ACPC
H
H -hydroxyacyl-ACP
OH
H3C
H
Step 5: Reduction
C C
O
S ACPC
H
H3C
H
NADP+
C C
O
S ACPC
H
H3C
H
H
H
trans-enoyl-ACP
enoyl-ACP reductase
NADPH + H+
trans-enoyl-ACP
Step 6: next condensation
C C
O
S ACPC
H
H
H3C
H
HHS-Ketoacyl-ACP Synthase
HS-ACP
C C
O
S KASC
H
H
H3C
H
H
C C
O
S ACPCO
O
H
H
CO2
C C
O
S ACP
H
H
C C
O
C
H
H
H3C
H
H
butyryl-ACP
malonyl-ACP
+
keto-ACP synthase
ketoacyl-ACP
Termination of
Fatty Acid Synthesis
C C
O
S ACPH3C
H
H
HS-ACP
C C
O
OH3C
H
H
AMP + PPi
C C
O
SH3C
H
H
CoA
14
Palmitoyl-ACP
14
Palmitic Acid
14
Thioesterase
ATP + HS-CoA
Palmitoyl-CoA
Acyl-CoA synthetase
Organization of Fatty Acid Synthesis Enzymes• In bacteria and plants, the fatty acid
synthesis reactions are catalyzed individual soluble enzymes.
• In animals, the fatty acid synthesis reactions are all present on multifunctional polypeptide.
• The animal fatty acid synthase is a homodimer of two identical 250 kD polypeptides.
Animal Fatty Acid Synthase
Further Processing of Fatty acids: Desaturation and Elongation
Regulation of FA Synthesis
• Allosteric modifiers, phosphorylation and hormones
• Malonyl-CoA blocks the carnitine acyltransferase and thus inhibits beta-oxidation
• Citrate activates acetyl-CoA carboxylase
• Fatty acyl-CoAs inhibit acetyl-CoA carboxylase
• Hormones regulate ACC• Glucagon activates lipases/inhibits ACC• Insulin inhibits lipases/activates ACC
Allosteric regulation of fatty acid synthesis occurs at ACCase and the carnitine acyltransferase
Glucagon inhibits fatty acid synthesis while increasing lipid breakdown and fatty acid -oxidation
Insulin prevents action of glucagon