R
O
O
N
N
N
B
NH
NH
N
N
H
O
H
O
S
Hypoxanthine
Mo6+
NH
O
N
O
Mo4+
S
S
S
A
H
S
S
B
R
O A
NH
N
NH
OH
N
H
Xanthine
H
N-
O
O
NH
N
H
O
N
H
N
H
N
O
NH
S
R
N
N
H
N
N
H
O
H
O
N
O
N
H
N
H
N
B
O
Mo5+ S
S
R
N
N-
R
O
O
C
NH
N
N
NH2
N
NH
N
H
O
C
R
N
O
R
N+
O
NH2
O
R
N
B
H
N
N
HO
N
N
O
S Mo6+
O
S
R
A
N
N
HN
Uric Acid
N-
H
O
O
O
H
NH
N
H
O
N
H
O
N
O
O
NH
S
R
N
H
H
N
N
HO
O
N
A
B
OH
HN
S
S
H
N
N
Mo4+
H
H
O
S
O
O
S
Xanthine
HO
O
HN
O
N
O
NH
H
H
HN
H
N
N
HO
N
B
Mo5+
S
S
A
H
O
O
O
O
N
HN
O
N
H
N
O
OH
H
N
HN
-O
N
H
N
B
B
H
Uric Acid
OH
O
A
H
A
O
N
HN
ON
O
O
OH
HN
B
H
O-
H
N
O
O
N
N
H
O
H
A
N
HN
O
N
H
O
N
N
H
O
O
OH
A
H
HN
OH
-O
H
N
NH2
H
N
O
O
N
H
N
O
H
B
A
O-
N
H
N
O
H
B
H
O
NH2
O
H
N
H
N
NH2
O
O
O
N
H
N
H
O
N
H
N
H
H
A
Succinyl-CoA
Fatty Acid Metabolism
Phospholipase A1
Phospholipase A2
Phospholipase A1
FADH2
Glycerol = GAP + NADH - ATP
If: GAP = 2 ATP + NADH + Acetyl-CoA
Then: glycerol = Acetyl-CoA + 2 NADH + ATP
If: Acetyl-CoA = 3 NADH + FADH2 + GTP
Then: glycerol = 5 NADH + GTP + ATP + FADH2
If: NADH = 3 ATP, FADH2 = 2 ATP and GTP = ATP
Then: glycerol = 19 ATP
1 NADH is converted to FADH2: 1 less ATP
Fatty acid + CoA + ATP ---> Fatty acyl-CoA + AMP + PPi
AMP + ATP ---> 2 ADP
ADP + Pi ---> ATP
You essentially consume 2 ATP to activate FFAs
Claisen cleavage reaction: reverse of citrate synthase
Thiolase
For a saturated fatty acid with n carbon atoms (even number)
-oxidation yields
n-2/2 NADH
n-2/2 FADH2
You make n/2 Acetyl-CoA, which enter TCA cycle to yield
3n/2 NADH
n/2 FADH2
n/2 ATP
3ATP per NADH
Lost in activation
2ATP per FADH2
Cn:0 yields
(n-2/2 + 3n/2)3ATP + (n-2/2 + n/2)2ATP + n/2 ATP - 2ATP
What about unsaturated fatty acids?
For every double bond an odd number of carbons away from
carbonyl:
O
SCoA
3 round -oxidation
O
SCoA
Attempt 4th round
O
SCoA
Doesn’t work
R
N
H2N
O
H
H
O
SCoA
H
H
O
NH2
N+
R
O
SCoA
Ready for another round of oxidation: however no FADH2 produced. This
ultimately costs 2 ATP in the end.
For every double bond an even number of carbons away from
carbonyl:
O
SCoA
5 rounds -oxidation
O
SCoA
Neither dehydrogenase nor isomerase recognize ∆4
unsaturated fatty acids as a substrate.
Just reduce the double bond
A
H
O
SCoA
H
H
O
NH2
N
R
O
SCoA
+ NADP+
Resume oxidation with the cost of 1 NADPH which ultimately costs one
NADH and 3 ATP in the end.
What about fatty acids with odd number carbons
Last round produces propionyl-CoA instead of Acetyl-CoA
For odd chain fatty acids
You make n-3 Acetyl-CoA and one propionyl-CoA
One extra ATP is consumed to convert propionyl-CoA to succinylCoA
Succinyl-CoA enters TCA cycle
This is can be used as an anapleurotic rxn or the succinyl-CoA
can be converted to malate. In the latter case.....
Conversion of succinyl-CoA to malate makes 1 ATP, 1 FADH2
Malate
Malic enzyme - decarboxylating
+1 NADPH
pyruvate
4 NADH + 1 FADH2 + ATP
So.....for odd chain fatty acids
You make n-3 Acetyl-CoA and one propionyl-CoA
One extra ATP is consumed to convert propionyl-CoA to succinylCoA
One ATP and one FADH2 are made to convert succinyl-CoA
into malate
One NADPH is made converting malate into pyruvate
Pyruvate = 4 NADH, 1 ATP and 1 FADH2
So….propionyl-CoA = 2 FADH2 + 4 NADH + 1ATP + NADPH
Cn(odd):0 yields
(n-3/2 + 3n-3/2 + 4)3ATP + (n-3/2 + n-3/2 + 2)2ATP + (n-3/2 + 1) ATP - 2ATP + NADPH
The glyoxosome is a
special peroxisome in
germinating seeds that
uses Acetyl-CoA from
triacylglycerol to make
glucose
-oxidation: in the ER
-oxidation: peroxisome
Ketone Bodies
Liver
Muscle
Lipid Biosynthesis
Reversing fatty acid
catabolism. What
steps are different?
Starts with malonyl-CoA instead of acetyl-CoA
Cost = (n-2)ATP + 2(n-2)NADPH
Ketoacyl-ACP Synthase
Malonyl-CoA-ACP transferase
Ketoacyl-ACP reductase
Acetyl-CoA-ACP transacetylase
Enoyl-ACP reductase
Hydroxyacyl-ACP dehydratase
ACP = acyl carrier protein
Fatty Acid Synthase
Fatty acid biosynthesis occurs in cytosol
Acetyl-CoA is made in the mitochondrion
Fatty acid desaturases are oxidases
H
O
O
Fe2+
O-
+ H+
O-
Fe3+
Fe2+
O-
OH
Fe3+
Fe3+
Fe3+
O
O
O
H
H
H
H
H
H
To carboxylate
H
H
OFe3+
O2Fe4+
Fe4+
O
H
H
O-
Fe3+
Fe3+
O
A
Fe4+
O
2 eFe2+
Fe2+
O
Much of the fatty acids release by adipocytes is taken up
by tissues and coverted to energy. This is triggered by
low glucose by glucagon or epinephrine
Much is reconverted into triacylglycerol by the liver and released
Glucagon tells the liver to stop glycolysis and make
glucose
How then do you get glycerol?
Glucocorticoids stimulate fatty acid release from
adipose tissue
What cofactor would you use?
What cofactor?
Desaturase
In plants and yeast there is hydroxylation instead of desaturation
H
O
O
Fe2+
O-
+ H+
O-
Fe3+
Fe2+
O-
OH
Fe3+
Fe3+
Fe3+
O
O
O
H
H
H
H
H
H
To carboxylate
H
H
OFe3+
O2Fe4+
Fe4+
O
H
H
2 eFe3+
Fe3+
O
Fe4+
O
H
HO
A
Fe2+
Fe2+
O
Heme generated tyrosine
radical abstracts this proton
COOH
COO-
COO-
H
H
O
O
O
O
COO-
O
O
O
COO-
O
O
COO-
O
O
O
O
O
O
O
COO-
O
COO-
O
O
O
A
O
H
OH
H
Fe3+
O
O
COO-
O
OH
OH2
Fe3+
H+
+2
e-
-HO
Fe5+
How is the radical generated in the first place?
O
H
-HO
Fe4+
O
OH2
Fe3+
O
H
O
H
H
-HO
Fe3+
OH2
H
Fe2+
O
HO H
O
Fe2+
H
OH
-HO
O
Fe3+
H
Flavin monooxygenase
H
H
H
A
H
O
HO
Methyl and hydride
transfera
B
H
HO
HO
HO
Cholecalciferol
Vitamin D3
HO
Dihydrocholesterol
OH
CH2
CH2
HO
OH
125-dihydroxycholecalciferol
HO