Ketogenesis 95

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KETOGENESIS

The enzymes involved and the reactions they catalyzed are shown below:

a-Ketothiolase
This enzyme catalyzes the reversal of the final step of the b-oxidation
pathway resulting in the condensation of 2 acetyl-CoA to produce acetoacetyl-
CoA, with release of one CoASH.

b-HMG-CoA Synthase
This catalyzes condensation of a third acetate moiety (from acetyl-
CoA) with acetoacetyl-CoA to form b-hydroxymethylglutaryl-CoA (HMG-CoA).

b-HMG-CoA Lyase
Lyase cleaves b-HMG-CoA to yield acetoacetate plus acetyl-CoA.

b-Hydroxybutyrate Dehydrogenase
This enzyme catalyzes inter-conversion of the ketone bodies
acetoacetate and b-hydroxybutyrate
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Mechanism

The utilization of ketone bodies occurs in the following steps:

If we start with b-hydroxybutyrate, then it is first oxidized to

acetoacetate with the production of one NADH.
Coenzyme A must now be added to the acetoacetate. The thioester
bond is a high energy bond, so ATP equivalents must be used. In this
case the energy comes from a transesterification of the CoAS from
succinyl CoA to acetoacetate by Coenzyme A transferase. The
succinyl CoA comes from the TCA cycle where a GTP is not made.
The acetoacetyl CoA is now cleaved to two acetyl CoA's with
Thiolase.

The energy provided to the peripheral tissues from acetoacetate and for b-
hydroxybutyrate are shown below:
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Reaction Energy Product Factor Multiplier ATP Equiv.

CoA
succinate (-GTP) 1 1 -1
transferase
Kreb's
NADH 3x3 2 18
NAD+ DH's
Kreb's GTP 1 2 2
Kreb's
FADH2 2 2 4
FADH DH
Acetoacetate Total: 23
Butyrate
NADH 3 1 3
DH
Butyrate Total: 26

1. When are ketone bodies synthesized? Explain briefly.

2. What organs utilize ketone bodies? Explain.
3. How is ketone body synthesis regulated? Why?
4. What is the committed step in ketogenesis?
5. Alcoholism and diabetes can both result in increased ketone body
production. Explain why and show the mechanism for the synthesis of
ketone bodies from ethanol.

References:

1. http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/pentose.
htm
2. Mathews, C.K., Van Holde, K.E., and Ahern, K.G. (2000).
Biochemistry, 3rd Ed. San Francisco: Addison-Wesley Publishing
Company.
3. Horton, R.H., Moran, L.A., Ochs, R.S., Rawn, J.D. and Scrimgeour,
K.G. (1996) Principles of Biochemistry, 2nd ed. New Jersey: Prentice-
Hall International, Inc.