bR

1
Fat mobilization in adipocytes
bR
Note insulin inhibits TAG mobilization
PKA
PKA
P
Hormone-sensitive lipase
Hormone-sensitive lipase
glycerol
MAG
DAG
TAG
FFA
FFA
FFA
See Fig 16.7 Horton
2
Fatty acid oxidation

• Activation
• Transport into mitochondria
• b oxidation cycle

• Acyl CoA synthetase (thiokinase)

• acylcarnitine transferase/acylcarnitine
  translocase

• acyl CoA dehydrogenase
• enoyl CoA hydratase
• L-3-hydroxy CoA dehydrogenase
• Thiolase

3
Acyl CoA synthetase
Note 4 different enzymes specific for FA of
differing chain length. location outer
membrane of mitochondria, ER membranes
4
Transport of fatty acyl CoA into mitochondria
Carnitine
Malonyl CoA
Carnitine acyltransferase I
Fatty AcylCoA carnitine
acylcarnitine CoA
translocase
Mito matrix
Fatty AcylCoA carnitine
acylcarnitine CoA
Carnitine acyltransferase II
5
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6
Net yield of ATP
C16 FA CoA ATP C16 acyl CoA AMP
PP1
C16 acyl CoA 7 NAD 7 FAD 8 AcCoA
7 NADH 7 FADH2
8 AcCoA 24 NADH 8 FADH2 8 GTP
16 CO2
31 NADH
77.5 ATP 15 FADH2
22.5 ATP 8 GTP

8 ATP
108 ATP - 2 ATP
Net 106 ATP
7
b-oxidation of unsaturated fatty acids

• 2,4 dieonyl-CoA reductase converts cis to
  trans double bond

• Enoyl-CoA isomerase converts diene to single
  double bond

8
b-oxidation of unsaturated fatty acids
e.g. Linoleic acid C18 cis,cis-D9,12
C
CO-S-CoA
C
H
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
3
16
2
8
14
18
6
10
12
4
C12 cis,cis-D3,6
g
b
a
C12 trans,cis-D2,6
g
a
b
CO-S-CoA
H
C
C
C
C
C
C
C
C
C
C
C
3
10
2
8
12
6
4
9
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10
b-oxidation of odd numbered fatty acids

• Requires
• Propionyl CoA carboxylase (biotin)
• - adds CO2
• methyl malony CoA racemase
• - converts D isomer of methyl malonyl CoA to L
  isomer
• methyl malonyl CoA mutase (adenosylcobalamin)
• - rearranges MMCoA to yield succinyl CoA

11
Oxidation of odd-numbered fatty acids
Proprionyl CoA
CO2
Biotin, ATP
D-methylmalonyl CoA
racemase
L-methylmalonyl CoA
adenosylcobalamin
mutase
succinyl CoA
12
Cobalamin B12
methylcobalamin R CH3 - transfer of methyl
groups
adenosylcobalamin R 5-deoxyadenosinyl -
intramolecular rearrangements
See fig 7.24 Horton
13

• Fatty acid biosynthesis
• Where cytoplasm
• liver, fat cells
• When good energy charge, insulin
• Process
• Transfer of AcCoA from mito to cyto
• Acetyl CoA carboxylase
• Fatty acid synthase

14

1. Transfer of AcCoA from mito to cyto

15
Question Incubation of tissue using the
above pathway with only one of succinate-2,3-14C
or succinate-1,4-14C will result in the
production of radiolabeled fatty acid. Identify
which substrate will yield 14C-fatty acids.
16
Acetyl-CoA carboxylase 1 (ACC 1)
biotin
AcCoA CO2 ATP malonyl
CoA ADP Pi

• Regulation
• Hormonal control
• - AMP kinase
• - inhibited by PKA mediated
  phosphorylation
• - enhanced by insulin
• Allosteric regulation
• - citrate activates phospho form
• - inhibited by palmitoyl CoA

• glucagon (liver)
• adrenalin (adipocytes)

• Nutritional status

17
Regulation of FA metabolism by phosphorylation
Adrenalin Glucagon
activates
inhibits
cAMP
ACT
PKA
FA synthesis
Malonyl CoA
TAG lipase (inactive)
ACC(active)
AMP- activated kinase
PP2A
phosphatase
TAG lipase-PO4 (active)
ACC-PO4(inactive)
Note insulin activates ACC by stimulating the
dephosphorylation reaction
18
Steps in FA biosynthesis
1. Loading transfer to ACP and
ketoacyl-ACPsynthase
19
2. Condensation

C S-Synthase
CH3
CH2
C S-ACP
CH2
C S-ACP
-OOC-
20
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21
Subsequent rounds of synthesis - transfer of
growing FA to S-Synthase - addition of 2 carbon
units from malonyl-S-ACP
Synthase-SH
ACP-SH
-OOC-
CH2
CO2 Synthase-SH
CH
CH2
CH3
CH2
22

• Chain elongation
• introduction of double bonds
• linoleic and linolenic acids
• synthesis of arachidonic acid an important
  precursor of
• several biologically active molecules