Carnitine acyltransferase

All of the other enzymes of the /3-oxidation pathway are located in the mitochondrial matrix. Short-chain fatty acids, as already mentioned, are transported into the matrix as free acids and form the acyl-CoA derivatives there. However, long-chain fatty acyl-CoA derivatives cannot be transported into the matrix directly. These long-chain derivatives must first be converted to acylearnitine derivatives, as shown in Figure 24.9. Carnitine acyltransferase I, located on the outer side of the inner mitochondrial membrane, catalyzes the formation of... 

Secondary signals Malonyl-CoA inhibits carnitine acyltransferase. 

Carnitine acyltransferase-1 transfers the fatty acjd group to carnitine (outer mitochondrial membrane). 

Carnitine acyltransferase-2 transfers the fetty acyl group back to a CoA (mitochondrial matrix). 

Myopathic carnitine acyltransferase (CAT/CPT) deficiency, primary etiology myopathic... 

Carnitine Acyltransferase (CAT/CPT) Deficiency (Myopathic Form). Although all tissues with mitochondria contain carnitine acyltransferase, the most common form of this genetic deficiency is myopathic and due to a defect in the muscle-specific CAT/CPT gene. Hallmarks of this disease include ... 

The inner mitochondrial membrane has a group-specific transport system for fatty acids. In the cytoplasm, the acyl groups of activated fatty acids are transferred to carnitine by carnitine acyltransferase [1 ]. They are then channeled into the matrix by an acylcar-nitine/carnitine antiport as acyl carnitine, in exchange for free carnitine. In the matrix, the mitochondrial enzyme carnitine acyltransferase catalyzes the return transfer of the acyl residue to CoA. 

The carnitine shuttle is the rate-determining step in mitochondrial fatty acid degradation. Malonyl CoA, a precursor of fatty acid biosynthesis, inhibits carnitine acyltransferase (see p. 162), and therefore also inhibits uptake of fatty acids into the mitochondrial matrix. 

Acyl coenzyme As are introduced into mitochondria following coenzyme A esterification in the cytoplasm. Mitochondrial entry depends upon a double membrane transport involving carnitine acyltransferases II and I. Excess acetyl CoA is used for KB synthesis. KBs are transported in the blood and ultimately metabolized via the Krebs cycle. KBs are necessary to provide energy to the brain during fasting, a true alternative substrate to glucose. 

With the clofibrate type of inducer, other changes are also apparent. Thus, there is a proliferation in the number of peroxisomes (an intracellular organelle) as well as induction of a particular form of cytochrome P-450 involved in fatty acid metabolism. A number of other enzymes associated with the role of this organelle in fatty acid metabolism are also increased, such as carnitine acyltransferase and catalase. This phenomenon is discussed in more detail in chapter 6. 

In the third and final step of the carnitine shuttle, the fatty acyl group is enzymatically transferred from carnitine to intramitochondrial coenzyme A by carnitine acyltransferase II. This isozyme, located on the inner face of the inner mitochondrial membrane, regenerates fatty acyl-CoA and releases it, along with free carnitine, into the matrix (Fig. 17-6). Carnitine reenters the intermembrane space via the acyl-camitine/car-nitine transporter. 

Malonyl-CoA, an early intermediate of fatty acid synthesis, inhibits carnitine acyltransferase I, preventing fatty acid entry into mitochondria This blocks fatty acid breakdown while synthesis is occurring. 

If fatty acid synthesis and J8 oxidation were to proceed simultaneously, the two processes would constitute a futile cycle, wasting energy. We noted earlier (see Fig. 17-12) that /3 oxidation is blocked by malonyl-CoA, which inhibits carnitine acyltransferase I. Thus during fatty acid synthesis, the production of the first intermediate, malonyl-CoA, shuts down J8 oxidation at the level of a transport system in the mitochondrial inner membrane. This control mechanism illustrates another advantage of segregating synthetic and degradative pathways in different cellular compartments. 

Acyl-CoA is not transported across the inner membrane of the mitochondrion. Instead, the acyl-CoA reacts with carnitine to yield the acyl-carnitine derivative. This reaction is catalyzed by carnitine acyltransferase I, which is located on the outer mitochondrial membrane. The acyl-carnitine is transported across the inner membrane by a specific carrier protein. Once inside the matrix of the mitochondrion, the acyl-carnitine is converted back to its acyl-CoA... 

This reaction is catalyzed by carnitine acyltransferase I on the outer membrane (fig. 18.21). A protein carrier in the inner mitochondrial membrane transfers the acyl-carnitine derivatives across the membrane. Once inside the mitochondria, the reaction is reversed by carnitine acyltransferase II to yield a fatty acyl-CoA (see fig. 18.21). Thus, at least two distinct pools of acyl-CoA occur in the cell, one in the cytosol and the other in the mitochondrion. 

Similarly, factors that stimulate acetyl-CoA carboxylase, the first enzyme in the pathway for fatty acid synthesis, also discourage fatty acid catabolism. This dual effect occurs because the first enzyme in the pathway leads to the formation of malonyl-CoA, which is a potent inhibitor of carnitine acyltransferase I. This inhibition prevents the transport of fatty acids into the mitochondrion, thereby, preventing fatty acid breakdown. 

Explain the role of carnitine acyltransferases in fatty acid oxidation. 

Carnitine acyltransferase I, which is located on the outer mitochondrial membrane, transfers the fatty acyl group from fatty acyl-CoA to the hydroxyl (OH) group of carnitine. The acyl-carnitine then moves across the intermembrane space to a translocase enzyme, which, in turn, moves the acyl-carnitine to carnitine acyltransferase II, which exchanges the carnitine for Coenzyme A. 

Mutant Carnitine Acyltransferase What changes in metabolic pattern would result from a mutation in the muscle carnitine acyltransferase I in which the mutant protein has lost its affinity for malonyl-CoA but not its catalytic activity ... 

Elaidoyl-CoA acyltransferase I elaidoyl-Carnitine transport elaidoyl-Carnitine acyltransferase II elaidoyl-CoA of fi oxidation (outside) (outside) (inside) (inside)... 

The reaction is catalyzed by palmitoyl-CoA-carnitine acyltransferase, which is inhibited by malonyl-CoA (see later), and is the limiting reaction of the fatty acid oxidation process. 

Glucagon exerts a ketogenic action on the liver which is more pronounced in insulin-deficient states. This action is thought to be due mainly to the inhibition of acetyl-CoA carboxylase with resulting decrease in malonyl-CoA. Malonyl-CoA is an inhibitor of carnitine acyltransferase I which is the rate-limiting step for mitochondrial fatty acid oxidation. A decrease in malonyl-CoA is thus postulated to lead to overproduction of acetyl-CoA which is then condensed to form ketone bodies. 

A schematic depiction of the intracellular pathway for (5-oxidation of long-chain fatty acids and, ultimately, ketogenesis is shown in Figure 32-5. Long-chain fatty acids are activated prior to entering the mitochondria by converting them to acyl-CoA derivatives. Because the mitochondrial membrane is impermeable to CoA and its derivatives, a specific transport system is required. As shown in Figure 32-5, this system has three components (1) the enzyme carnitine acyltransferase I (CAT I), which transfers the activated acyl unit from fatty acyl-CoA... 

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