Analogous toSuccinatedehydrogenase

Analogous tofumarase

Analogous tomalatedehydrogenase

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 ATP

2ATP lost in activation

What about unsaturated fatty acids?

For every double bond that is on a carbon that is an odd number of carbons away from carbonyl:

O

SCoA

O

SCoA

O

SCoA

3 rounds -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

For every double bond that is on a carbon that is an even number of carbons away from carbonyl:

O

SCoA

O

SCoA

Reductase can’t 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

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-3/2 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 1ATP, 1 FADH2

Malate

pyruvate

Acetyl-CoA

+1NADPH is converted to NADH

3NADH + 1FADH2 + ATP

Malic enzyme - decarboxylating

+1NADH

COO-

CO H

CH2

H

C

O O-

B

N+

C

O

NH2

R

COO-

CO

CH2

C

O O-

N

C

O

NH2

R

COO-

C-O

CH2

CO2

H

A

COO-

CO

CH3

One extra ATP is consumed to convert propionyl-CoA to succinyl-CoA

So.....for odd chain fatty acids

You make n-3/2 Acetyl-CoA and one propionyl-CoA

One ATP and one FADH2 are made to convert succinyl-CoA into malate

One NADH is made converting malate into Acetyl-CoA

3NADH, 1ATP and 1FADH2 are made oxidizing the Acetyl-CoA

Net 1 propionyl-CoA = 2FADH2 + 4NADH + 1ATP

In plants the peroxisome is the major site of -oxidation. In animals the peroxisome is mainly responsible for oxidation of very long chain fatty acids.

The first step is different because there is no enzyme that can directly inject electrons into the e- transport chain. Instead electrons are put directly onto O2 by an FAD-dependent oxidase. This generates H2O2 which must be degraded by catalase.

Ketone Bodies

Liver Muscle

Other sources of central metabolites?

Goin’ Backwards

Can you run these pathways in reverse to make glucose?

Can the TCA cycle be run in reverse?

The Reductive TCA cycle

How do you reverse -KGDH?

Ketoglutarate synthase

2-oxoglutarate:ferredoxin oxidoreductase

Hydrogenase takes electrons from H2 and gives them to ferredoxin which ultimately puts them on -KG.

What about isocitrate dehydrogenase?

This step can be made reversible if you use a different source of electrons. Use NADPH instead of NADH.

Citrate lyase

C

CH2

C

CH2

COO-

COO-HO

EN

-O P

O

O-

O ADP

N P

O

O-

O-E

O-O

C

CH2

C

CH2

COO-

COO-O

OCoAS

H

B

C

CH2

C

CH2

COO-

COO-O

O2-O3PO

H

CoA S

H

B

C

CH2

COO-

COO-

O H3C C

O

SCoA

Pyruvate synthase

Acetyl-CoA + CO2 ---> pyruvate

Pyruvate:ferredoxin oxidoreductase

Uses TPP and is essentially the same mechanismExcept that the electrons come from H2

The TCA cycle cannot convert Acetyl-CoA into malate. Malate is only part of a pathway to regenerate the catalyst.

Malic enzyme decarboxylating

What if you could skip the

decarboxylation steps?

Pyruvate

Claisencondensation

C

CH2

C

C

H

CH

O-O

OH

O

O-

B

C

CH2

C

CH

COO-

C

O-O

O

O-

O-

H Mg2+

COO-H

A

C

CH2

C C

O-O

O

O-

H

H

Isocitrate lyase

Related to enolase

2Acetyl-CoA + NAD+ + 2H2O --->succinate + 2CoA + NADH + H+

Succinate enters TCA cycle and is converted to oxaloacetate with the generation of FADH2

and NADH

Oxaloacetate is converted to PEP

Notice that acetyl-CoA can only be converted to glycolytic intermediates if there is a glyoxalate cycle or a

pyruvate synthase

Reversing homolactic fermentation

This reaction is reversible in liver and muscle∆G ~ 0

What about ethanolic fermentation?

Irreversible

What about going from acetaldehyde to acetyl-CoA?

Aldehyde dehydrogenase: similar to glyceraldehyde DH

CH3 C

O

H

ES

H

B

CH3 C

O-

H

ES

N+

CNH2

O

R

CH3 C

O

ES

N

CNH2

O

R

NADP+

NADPH

CH3 C

O

ES

HS

B

H

A

CH3 C

O

SCoACoA