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BIOC 460
DR. TISCHLER LECTURE 34
SYNTHESIS & PROCESSING OF FATS
OBJECTIVES
1. Sequence leading from glucose to fatty acids via lipogenesis
including roles of pyruvate carboxylase and pyruvate
dehydrogenase.
2. Malic enzyme and acetyl CoA carboxylase
3. For fatty acid synthase:
a) substrates/key products; b) sources of NADPH;
c) general mechanism
4. Relationship: regulation of carnitine-palmitoyl transferase-I and
preventing oxidation of synthesized palmitoyl CoA
5.
Eicosanoids:
a) fatty acid from which they are derived;
b) specific functions of each eicosanoid;
c) general pathway of production; effects of glucocorticoids
(cortisol) and aspirin
LIPOGENESIS
 principally in adipose tissue and liver
 lipogenesis – cytoplasm; requires acetyl CoA
 adipose: FA stored as triacylglycerols via esterification
 liver: produces TAG packaged into VLDL and exported
 compounds metabolized to acetyl CoA can serve as a fat
precursor
 glucose = primary source of carbons for fat synthesis.
Glucose CYTOPLASM
Fatty
Acids
PPP
MITOCHONDRIAL MATRIX
NADH, CO2
NAD, CoA
Glycolysis
PDH
CO2
NADPH
FAS
Malate
ME
NADP+
NAD+
Malonyl CoA
MDH
ADP, Pi
ACC
NADH
CO2, ATP Oxaloacetate
Acetyl CoA
ADP+Pi
CL
Pyruvate
ATP, CO2
Pyruvate
Acetyl
CoA
PC
ADP, Pi
Oxaloacetate
CS
ATP, CoA
Citrate
Citrate
Figure 1. Export of acetyl CoA as citrate for fatty acid
biosynthesis, generation of NADPH and pathway of lipogenesis.
KEY MITOCHONDRIAL REACTIONS
PYRUVATE CARBOXYLASE
pyruvate + CO2 + ATP  oxaloacetate + ADP + Pi
PYRUVATE DEHYDROGENASE
pyruvate + NAD + coenzyme A (CoA)  acetyl CoA + CO2 + NADH
KEY CYTOPLASMIC REACTIONS
INDIRECTLY NEEDED FOR LIPOGENESIS
Citrate Lyase
citrate + CoA + ATP  acetyl CoA + oxaloacetate + ADP + Pi
Malate dehydrogenase
oxaloacetate + NADH  malate + NAD+
Malic Enzyme
malate + NADP+  pyruvate + NADPH
KEY CYTOPLASMIC REACTIONS DIRECTLY NEEDED
FOR LIPOGENESIS AND FATTY ACID ACTIVATION
Acetyl CoA Carboxylase:
acetyl CoA + HCO3- + ATP  malonyl CoA + ADP + Pi
Fatty Acid Synthase:
acetyl CoA + 7 malonyl CoA + 14 NADPH + 14 H+ 
palmitate + 7 CO2 + 8 CoA + 14 NADP+
Acyl CoA Synthetase:
(also used for fatty acids other than palmitate)
palmitate + ATP + CoA  palmitoyl CoA + AMP + PPi
CE
acp
A
C
P
condensation
CE
acp
CO2
CO2
C=O C=O
CO2
CH2
CHC=O
3
C=O
C=O
CH3C=O - CO2
COO CH
CH2
2
CH
3
acetyl malonyl
C=O
C=O
CoA
CoA
CH3
CH3
A
C
P
reduction
dehydration
reduction
2 NADPH
C=O
C=O
CH2
CH2
C=O
C=O
CH3
CH3
CE
acp
A
C
P
2 NADP+ C=O
CH2
CH2
CH3
4-C
unit
Figure 2. General mechanism for the fatty acid synthase
reaction. CE is condensing enzyme. ACP is acyl carrier
protein. This row represents the initial steps for priming
the reaction with acetyl CoA and the addition of two
carbons from malonyl CoA.
CE
acp
A
C
P
condensation
CE
acp
A
C
P
2 NADPH
CO2
4-C
unit
malonyl
CoA
reduction
dehydration
reduction
6-C
unit
2 NADP+
CE
acp
A
C
P
6-C
unit
Figure 2. General mechanism for the fatty acid synthase
reaction. CE is condensing enzyme. ACP is acyl carrier
protein. This row depicts a typical cycle of adding two
more carbons to the fatty acid chain.
CE
acp
6-C
unit
A
C
P
malonyl
CoA
5 more cycles
adding 10
more carbons
5malonyl CoA
5CO2
10NADPH
10NADP+
CE
acp
A
C
P
thioesterase
cleavage
16-C
unit
palmitate
palmitate
CE
acp
Figure 2. General mechanism for the fatty acid synthase
reaction. CE is condensing enzyme. ACP is acyl carrier
protein. This row shows the release of the finished
product, palmitate, through cleavage by thioesterase.
A
C
P
Sources of NADPH for the Biosynthesis of Fatty Acids.
malic enzyme:
Malate + NADP+  Pyruvate + CO2 + NADPH
pentose phosphate pathway:
Glucose-6-P + 2 NADP+  Ribulose-5-P + 2
NADPH + CO2
Glycerol
ATP
ADP
Dihydroxyacetone phosphate
fatty acyl CoA
glycerol
kinase
CoA
Glycerol-3-P
fatty acyl CoA
Acyldihydroxyacetone phosphate
NADPH
CoA
Lysophosphatidic
acid
fatty acyl CoA
NADP+
Pi
CoA
Phosphatidic
Diacylglycerol
phosphatase
acid
fatty acyl CoA
CoA
Triacylglycerol
Figure 3. Formation of phosphatidic acid from glycerol-3-P or
DHAP, and its conversion to triacylglycerol
EICOSANOIDS
hormones localized to tissues where they are produced.
prostaglandins, thromboxanes and leukotrienes.
derived from arachidonic acid
arachidonic acid from linoleic acid an essential fatty acid
Table 1. Physiological functions of eicosanoids.
Eicosanoid
Functions
prostaglandins
inflammation, fever production, prevent
platelet aggregation (prevent clotting);
induce labor
thromboxanes
produced by platelets to promote their
aggregation (blood clotting)
leukotrienes
allergic reactions
Membrane Phospholipid
Phospholipase A2
inhibited by glucocorticoids
Leuokotrienes
Arachidonic acid
Lipoxygenase
Cyclooxygenase
inhibited by aspirin,
ibuprofen
PGH2
Thromboxanes
in platelets
Prostaglandins in many cells
Figure 4. Conversion of arachidonic acid to eicosanoids.