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Chapter 17 Fatty Acid Catabolism

Chapter 17 Fatty Acid Catabolism

Fatty Acyl Carnitine

FIGURE 17-6 Fatty acid entry into mitochondria via the acyl-carnitine/ carnitine transporter. After fatty acyl-carnitine is formed at the outer membrane or in the intermembrane space, it moves into the matrix by facilitated diffusion through the transporter in the inner membrane. In the matrix, the acyl group is transferred to mitochondrial coenzyme

A, freeing carnitine to return to the intermembrane space through the same transporter. Acyltransferase I is inhibited by malonyl-CoA, the first intermediate in fatty acid synthesis (see Fig. 21-1). This inhibition prevents the simultaneous synthesis and degradation of fatty acids.

FIGURE 17-6 Fatty acid entry into mitochondria via the acyl-carnitine/ carnitine transporter. After fatty acyl-carnitine is formed at the outer membrane or in the intermembrane space, it moves into the matrix by facilitated diffusion through the transporter in the inner membrane. In the matrix, the acyl group is transferred to mitochondrial coenzyme

A, freeing carnitine to return to the intermembrane space through the same transporter. Acyltransferase I is inhibited by malonyl-CoA, the first intermediate in fatty acid synthesis (see Fig. 21-1). This inhibition prevents the simultaneous synthesis and degradation of fatty acids.

membrane lipids. Fatty acids destined for mitochondrial oxidation are transiently attached to the hydroxyl group of carnitine to form fatty acyl-carnitine—the second reaction of the shuttle. This transesterification is catalyzed by carnitine acyltransferase I (Mr 88,000), in the outer membrane. Either the acyl-CoA passes through the outer membrane and is converted to the carnitine ester in the intermembrane space (Fig. 17-6), or the carnitine ester is formed on the cytosolic face of the outer membrane, then moved across the outer membrane to the intermembrane space—the current evidence does not reveal which. In either case, passage into the intermembrane space (the space between the outer and inner membranes) occurs through large pores (formed by the protein porin) in the outer membrane. The fatty acyl-carnitine ester then enters the matrix by facilitated diffusion through the acyl-carnitine/carni-tine transporter of the inner mitochondrial membrane (Fig. 17-6).

CH3 OH Carnitine

In the third and final step of the carnitine shuttle, the fatty acyl group is enzymatically transferred from carnitine to intramitochondrial coenzyme A by carni-tine 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-carnitine/car-nitine transporter.

This three-step process for transferring fatty acids into the mitochondrion—esterification to CoA, transes-terification to carnitine followed by transport, and trans-esterification back to CoA—links two separate pools of coenzyme A and of fatty acyl-CoA, one in the cytosol, the other in mitochondria. These pools have different functions. Coenzyme A in the mitochondrial matrix is largely used in oxidative degradation of pyruvate, fatty acids, and some amino acids, whereas cytosolic coen-zyme A is used in the biosynthesis of fatty acids (see Fig. 21-10). Fatty acyl-CoA in the cytosolic pool can be used for membrane lipid synthesis or can be moved into the mitochondrial matrix for oxidation and ATP production. Conversion to the carnitine ester commits the fatty acyl moiety to the oxidative fate.

The carnitine-mediated entry process is the rate-limiting step for oxidation of fatty acids in mitochondria and, as discussed later, is a regulation point. Once inside the mitochondrion, the fatty acyl-CoA is acted upon by a set of enzymes in the matrix.

SUMMARY 17.1 Digestion, Mobilization, and Transport of Fats

■ The fatty acids of triacylglycerols furnish a large fraction of the oxidative energy in animals. Dietary triacylglycerols are emulsified in the small intestine by bile salts, hydrolyzed by intestinal lipases, absorbed by intestinal epithelial cells, reconverted into triacylglycerols, then formed into chylomicrons by combination with specific apolipoproteins.

17.2 Oxidation of Fatty Acids 637

■ Chylomicrons deliver triacylglycerols to tissues, where lipoprotein lipase releases free fatty acids for entry into cells. Triacylglycerols stored in adipose tissue are mobilized by a hormone-sensitive triacylglycerol lipase. The released fatty acids bind to serum albumin and are carried in the blood to the heart, skeletal muscle, and other tissues that use fatty acids for fuel.

■ Once inside cells, fatty acids are activated at the outer mitochondrial membrane by conversion to fatty acyl-CoA thioesters. Fatty acyl-CoA to be oxidized enters mitochondria in three steps, via the carnitine shuttle.

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