Principles of Biochemistry, Volume 2 - A. Lehninger 1985

Bioenergetics and Metabolism
Fatty Acid Oxidation in Animal Tissues
Formation of Ketone Bodies in the Liver and Their Oxidation in Other Organs

In humans and most other mammals, acetyl-CoA produced via Fatty acid oxidation undergoes further Processing in the Liver through one of two pathways. The first of these pathways—oxidation via The Citric Acid Cycle—has already been described. The second pathway leads to The formation of acetoacetate and D-ß-hydroxybutyrate, which, together with acetone, are collectively known as Ketone Bodies (Fig. 18-14). Acetoacetate and ß-hydroxybutyrate do not undergo further oxidation in the liver; instead, they are transported via the bloodstream to peripheral Tissues, where they are oxidized within The Citric Acid cycle. The initial stage of acetoacetate production in the liver involves the Condensation of two molecules of acetyl-CoA, a reaction catalyzed by thiolase:

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Fig. 18-14. Ketone bodies.

The acetoacetyl-CoA formed in this way undergoes Cleavage of the CoA moiety to yield free acetoacetate through two consecutive reactions (Fig. 18-15) represented by the overall equation:

Acetoacetyl—S—CoA + H₂O →

→ Acetoacetate + CoA—SH.

Next, free acetoacetate is reversibly reduced to D-ß-hydroxybutyrate, a reaction catalyzed by the mitochondrial enzyme D-ß-hydroxybutyrate dehydrogenase:

D-ß-Hydroxybutyrate dehydrogenase exhibits strict Specificity for the D-stereoisomer and does not act on L-isomers of ß-hydroxyacyl-CoA (this enzyme should not be confused with L-3-hydroxyacyl-CoA dehydrogenase; Section 18.4, c). Acetoacetate is also a precursor to acetone, which is produced in small amounts. Being an unstable compound, acetoacetate loses its carboxyl group either spontaneously or through the action of acetoacetate decarboxylase:

Fig. 18-15. Cleavage of CoA from acetoacetyl-CoA. This process is known as deacylation. Hydroxymethylglutaryl-CoA is also an important intermediate in Cholesterol Biosynthesis (Ch. 21).

Acetone is a volatile compound. It accumulates in large quantities in the Blood of patients with Diabetes Mellitus, imparting a characteristic sweetish odor to their breath that is sometimes mistaken for the smell of alcohol. Free acetoacetate and D-ß-hydroxybutyrate, formed in the reactions described above, diffuse from liver Cells into the blood and are delivered to peripheral tissues.

The Biological Significance of ketone body formation is that a portion of the acetyl-CoA derived from fatty acid oxidation in liver cells bypasses further hepatic oxidation and is channeled—in the form of ketone bodies—to other tissues, where it is oxidized to CO₂ and H₂O. Ketone body production serves as a kind of "overflow" pathway, one of several mechanisms the liver uses to supply cellular fuel to other PARTS OF THE body. Under normal conditions, the blood concentration of ketone bodies is very low; however, during starvation or in diabetes mellitus, it can reach exceptionally high levels. This condition, known as Ketosis, occurs when The rate of ketone body production in the liver exceeds the capacity of peripheral tissues to utilize them. In diabetes, the ability of tissues to use blood glucose is impaired. To compensate for this defect, the liver Burns more Fatty acids for fuel. However, this leads to the overproduction of ketone bodies because peripheral tissues cannot oxidize them rapidly enough.

In peripheral tissues, D-ß-hydroxybutyrate is oxidized to acetoacetate by D-ß-hydroxybutyrate dehydrogenase:

This acetoacetate is then activated to form its corresponding CoA ester. The CoA moiety is transferred to acetoacetate from succinyl-CoA (an intermediate in the citric acid cycle; Section 16.5, d) in a reaction catalyzed by 3-ketoacyl-CoA transferase:

Acetoacetyl-CoA is cleaved by thiolase to yield acetyl-CoA:

Acetyl-CoA then enters the citric acid cycle for complete oxidation in peripheral tissues.