Succinyl-CoA Fatty Acid Metabolism.

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