Transcript
NH
NNH
N
O
Hypoxanthine S
Mo6+S
O
SO
H
B
H
NH
NNH
N
O
S
Mo4+S
O
SO
H
B
N
N
NH
N O
O
R
NH
NNH
N
O
S
Mo5+S
O
SO
NH
N
NH
N O
R
H O
H
B
H
ANH
NNH
N
O
OH
Xanthine
NH
N
NH
N- O
R
H
A
N
N
NH
N- O
R
N+
C
O
NH2
R
N
N
NH
N O
R
N
C
O
NH2
R
O
O
H
HN
N HN
N
O
XanthineS
Mo6+S
O
SO
H
B
HO
S
Mo4+S
O
SO
H
B
N
N
NH
N O
O
R
S
Mo5+S
O
SO
NH
N
NH
N O
R
H O
H
B
H
A
Uric Acid
NH
N
NH
N- O
R
O
HHN
N HN
N
O
HO
HN
N HN
N
O
HO
HN
N HN
N
O
HO
OH
H
A
HN
N NH
N
O
O
Uric Acid
O
H
BH
B
HN
N NH
N
O
-O
O-
O
O
HN
N NH
N
O
O
O-
OOH
A H
H
O-B
A H
H A
HN
N NH
N
O
O
O
H A
HN
N NH
HN
O
O
O
OH
HN
N NH
HN
O
O
O
OH
HO-
B
HA NH2
N NH
HN
O
O
O
OH-O
HA
NH2
NH
NH
HN
O
O
OH
B
HA
NH2
NH
NH
HN
O
O
O
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)
You make n/2 Acetyl-CoA, which enter TCA cycle to yield
n-2/2 NADHn-2/2 FADH2
-oxidation yields
3n/2 NADHn/2 FADH2
n/2 ATP3ATP per NADH2ATP per FADH2
Cn:0 yields(n-2/2 + 3n/2)3ATP + (n-2/2 + n/2)2ATP + n/2 ATP - 2ATP
Lost in activation
What about unsaturated fatty acids?
For every double bond an odd number of carbons away from carbonyl:
O
SCoA
O
SCoA
O
SCoA
3 round -oxidation
Attempt 4th round
Doesn’t work
O
SCoA
N
R
O
H2N
H H
H H
N+
R
O
NH2
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
O
SCoA
Neither dehydrogenase nor isomerase recognize ∆4 unsaturated fatty acids as a substrate.
5 rounds -oxidation
N
R
O
NH2
HH
O
SCoA
H
A
O
SCoA
+ NADP+
Just reduce the double bond
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
One extra ATP is consumed to convert propionyl-CoA to succinyl-CoA
For odd chain fatty acids
You make n-3 Acetyl-CoA and one propionyl-CoA
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
pyruvate
+1 NADPH
4 NADH + 1 FADH2 + ATP
Malic enzyme - decarboxylating
One extra ATP is consumed to convert propionyl-CoA to succinyl-CoA
So.....for odd chain fatty acids
You make n-3 Acetyl-CoA and one propionyl-CoA
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
Fatty Acid Synthase
Ketoacyl-ACP Synthase Malonyl-CoA-ACP transferase
Ketoacyl-ACP reductase
Hydroxyacyl-ACP dehydrataseEnoyl-ACP reductase
Acetyl-CoA-ACP transacetylase
ACP = acyl carrier protein
Fatty acid biosynthesis occurs in cytosol
Acetyl-CoA is made in the mitochondrion
Fatty acid desaturases are oxidases
Fe2+
OFe2+
O O
Fe3+
OFe3+
O- O- + H+
Fe3+
OFe3+
O- OH
H A
Fe4+
OFe4+
O2-
H H
HHTo carboxylate
Fe3+
OFe4+
O-
H
HH
H
Fe3+
OFe3+
O-HH
2 e-
Fe2+
OFe2+
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
Fe2+
OFe2+
O O
Fe3+
OFe3+
O- O- + H+
Fe3+
OFe3+
O- OH
H A
Fe4+
OFe4+
O2-
H H
HHTo carboxylate
Fe3+
OFe4+
O-
H
HH
H
Fe3+
OFe3+
2 e-
Fe2+
OFe2+
HO H
HH
Heme generated tyrosineradical abstracts this proton
COO-COO-
O
HH
O
H
COO-
O O
COO-
O
O
COO-O
O
O O
COO-O
O
OO
O
H
Fe3+
COO-O
O
OO
COO-O
O
OOHHA
COO-O
O
OH
Fe5+
-HOH+ + 2 e-
Fe3+
OH2
O H
Fe4+
-HO
O
Fe3+
OH2
How is the radical generated in the first place?
Fe3+
-HO
H HH
Fe2+
OH2
H
O O
H
O
O
Fe2+
HO H
H
O
OH
Fe3+
-HO
Flavin monooxygenase
OH
A
HO
H
B
HH
HO
Methyl and hydridetransfera
H
HO
HOHO
CH2
HO
CH2
HO
OH
OH
Dihydrocholesterol
125-dihydroxycholecalciferol
CholecalciferolVitamin D3
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