Branched-chain phytanic acid, a product of chlorophyll metabolism, is not a substrate for acyl CoA dehydrogenase because of the methyl group on its βcarbon (Fig. 16.21). Instead, it is hydroxylated at the α-carbon by phytanoyl CoA α-hydroxylase (PhyH); carbon 1 is released as CO2; and the product, 15-carbon-long pristanal, is oxidized to pristanic acid, which is activated to its CoA derivative and undergoes β-oxidation. Refsum disease is a rare, autosomal-recessive disorder caused by a deficiency of peroxisomal PhyH. This results in the accumulation of phytanic acid in the plasma and tissues. The symptoms are primarily neurologic, and the treatment involves dietary restriction to halt disease progression. [Note: ω-Oxidation (at the methyl terminus) also is known and generates dicarboxylic acids. Normally a minor pathway of the SER, its upregulation is seen with conditions such as MCAD deficiency that limit fatty acid β-oxidation.]
V. KETONE BODIES: ALTERNATIVE FUEL FOR CELLS
Liver mitochondria have the capacity to convert acetyl CoA derived from fatty acid oxidation into ketone bodies. The compounds categorized as ketone bodies are acetoacetate, 3-hydroxybutyrate (also called β-hydroxybutyrate), and acetone (a nonmetabolized side product, Fig. 16.22). [Note: The two functional ketone bodies are organic acids.] Acetoacetate and 3-hydroxybutyrate are transported in the blood to the peripheral tissues. There they can be reconverted to acetyl CoA, which can be oxidized by the TCA cycle. Ketone bodies are important sources of energy for the peripheral tissues because they 1) are soluble in aqueous solution and, therefore, do not need to be incorporated into lipoproteins or carried by albumin as do the other lipids; 2) are produced in the liver during periods when the amount of acetyl CoA present exceeds the oxidative capacity of the liver; and 3) are used in proportion to their concentration in the blood by extrahepatic tissues, such as skeletal and cardiac muscle, the intestinal mucosa, and the renal cortex. Even the brain can use ketone bodies to help meet its energy needs if the blood levels rise sufficiently. Thus, ketone bodies spare glucose, which is particularly important during prolonged periods of fasting (see p. 332). [Note: Disorders of fatty acid oxidation present with the general picture of hypoketosis (because of decreased availability of acetyl CoA) and hypoglycemia (because of increased reliance on glucose for energy).] carbon dioxide.
A. Ketone body synthesis by the liver: Ketogenesis
During a fast, the liver is flooded with fatty acids mobilized from adipose tissue. The resulting elevated hepatic acetyl CoA produced by fatty acid oxidation inhibits pyruvate dehydrogenase (see p. 111) and activates pyruvate carboxylase ([PC] see p. 119). The OAA produced by PC is used by the liver for gluconeogenesis rather than for the TCA cycle. Additionally, fatty acid oxidation decreases the NAD+/NADH ratio, and the rise in NADH shifts OAA to malate (see p. 113). The decreased availability of OAA for condensation with acetyl CoA results in the increased use of acetyl CoA for ketone body synthesis. [Note: Acetyl CoA for ketogenesis is also generated by the catabolism of ketogenic amino acids (see p. 262).] 1.