BIOC 460

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BIOC 460 DR. TISCHLER LECTURE 34
 SYNTHESIS PROCESSING OF FATS
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OBJECTIVES

• Sequence leading from glucose to fatty acids via
  lipogenesis including roles of pyruvate
  carboxylase and pyruvate dehydrogenase.
• Malic enzyme and acetyl CoA carboxylase
• 3. For fatty acid synthase
• a) substrates/key products b) sources of NADPH
  
• c) general mechanism
• 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

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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.

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CYTOPLASM
MITOCHONDRIAL MATRIX
Figure 1. Export of acetyl CoA as citrate for
fatty acid biosynthesis, generation of NADPH and
pathway of lipogenesis.
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KEY MITOCHONDRIAL REACTIONS
PYRUVATE CARBOXYLASE pyruvate CO2 ATP ?
oxaloacetate ADP Pi
PYRUVATE DEHYDROGENASE pyruvate NAD coenzyme
A (CoA) ? acetyl CoA CO2 NADH
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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
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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
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A C P

CE acp
CO2
CO2
CO2
CO2
COO-
malonyl CoA
acetyl CoA
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.
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malonyl CoA
4-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.
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thioesterase cleavage
malonyl CoA
6-C unit
palmitate
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.
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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
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Lysophosphatidic acid
Phosphatidic acid
Diacylglycerol
Triacylglycerol
Figure 3. Formation of phosphatidic acid from
glycerol-3-P or DHAP, and its conversion to
triacylglycerol
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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
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Membrane Phospholipid
Phospholipase A2
inhibited by glucocorticoids
Arachidonic acid
Cyclooxygenase
inhibited by aspirin, ibuprofen
PGH2
Figure 4. Conversion of arachidonic acid to
eicosanoids.