1

Figure 1 Fatty-acid structure and nomenclature. (A) Chemical formula and carbon atom numbering system for a 16-carbon saturated fatty acid (16:0). (B) Schematic representation of 16:0. (C) A monounsaturated fatty acid, 18:1 n-9, showing the double bond nine carbon atoms from the methyl end (carbon 18). (D) The essential n-6 fatty acid 18:2n-6, where the first double bond is found six carbon atoms from the methyl end. The two double bonds are separated by a methylene (-CH2-) group. (E) The essential n-3 fatty acid 18:3n-3, where the first double bond is found three carbon atoms from the methyl end. (F) Phytanic acid, a dietary ,3-methyl-branched-chain fatty acid (3,7,11,15-tetramethyl 16:0). The methyl group on carbon 3 prevents this fatty acid from degradation by ^-oxidation. (G) Pristanic acid (2,6,10,14-tetramethyl 15:0) is the product of phytanic acid a-oxidation, in which a single carbon (carbon 1) is lost. The methyl group on carbon 2 does not preclude subsequent degradation by ^-oxidation.

hydrophobic fatty acids can traverse the plasma membrane by simple diffusion, a role for membrane transport proteins in this process remains controversial. Once inside the cell, fatty acids are thought to be moved to the mitochondria (or other intracellular sites) by intracellular fatty-acid binding proteins.

Acyl-CoA synthetase activity towards long-chain fatty-acid substrates is present in the outer mito-chondrial membrane. However, fatty acyl-CoAs do not readily traverse biological membranes such as the inner mitochondrial membrane. A highly sophisticated transport system has evolved to allow tight regulation of fatty-acid entry into the mitochondrion

(Figure 2). Carnitine palmitoyl transferase 1 (CPT1), located on the inner aspect of the outer mitochon-drial membrane, catalyzes a transesterification reaction:

fatty acyl-CoA + carnitine

! fatty acyl-carnitine + CoA-SH

Carnitine-acylcarnitine translocase (CACT), located in the inner mitochondrial membrane, carries the fatty acyl-carnitine inside the mitochondrion in exchange for a free carnitine molecule. CPT2, located inside the mitochondrion, then catalyzes the reversal of the CPT1 reaction. Thus, the concerted actions of CPT1, CACT, and CPT2

Cytoplasm FA

Cytoplasm FA

Mitochondrial matrix

ACS - Acyl-CoA synthetase

CPT1,2 - Carnitine palmitoyl transferase 1 & 2

CACT - Carnitine-acylcarnitine translocase

OMM, IMM - Outer and inner mitochondrial membranes

1 - Acyl-CoA dehydrogenase

2 - Enoyl-CoA hydratase

3 - 3-Hydroxyacyl-CoA dehydrogenase

4 - 3-Oxoacyl-CoA thiolase

Figure 2 Mitochondrial fatty-acid (FA) ^-oxidation pathway. Long-chain fatty acids are activated, converted to carnitine esters, transported across the inner mitochondrial membrane, and re-converted to their CoA thioester once in the mitochondrial matrix. Four sequential mitochondrial enzyme reactions shorten the fatty acyl-CoA (FA-CoA) by two carbon atoms, which are released as acetyl-CoA. The shortened fatty acyl-CoA can undergo additional cycles of degradation until the entire carbon chain has been converted to acetyl-CoA units. FADH2 and NADH, produced in reactions 1 and 3, respectively, can enter the electron transport chain for ATP production. Acetyl-CoA enters the tricarboxylic acid (TCA) cycle, yielding additional NADH and FADH2 for ATP production. Mitochondrial ^-oxidation is the primary pathway for recovering the energy stored as triacylglycerol or 'fat'.

Figure 2 Mitochondrial fatty-acid (FA) ^-oxidation pathway. Long-chain fatty acids are activated, converted to carnitine esters, transported across the inner mitochondrial membrane, and re-converted to their CoA thioester once in the mitochondrial matrix. Four sequential mitochondrial enzyme reactions shorten the fatty acyl-CoA (FA-CoA) by two carbon atoms, which are released as acetyl-CoA. The shortened fatty acyl-CoA can undergo additional cycles of degradation until the entire carbon chain has been converted to acetyl-CoA units. FADH2 and NADH, produced in reactions 1 and 3, respectively, can enter the electron transport chain for ATP production. Acetyl-CoA enters the tricarboxylic acid (TCA) cycle, yielding additional NADH and FADH2 for ATP production. Mitochondrial ^-oxidation is the primary pathway for recovering the energy stored as triacylglycerol or 'fat'.

effectively translocate fatty acyl-CoA across the inner mitochondrial membrane.

Entry of fatty acids into the mitochondrion is regulated by several mechanisms. Although long-chain fatty acids can readily diffuse across the lipophilic inner mitochondrial membrane, the mitochondrial matrix lacks long-chain acyl-CoA synthetase activity. Thus, long-chain fatty acids cannot be activated intramitochondrially to enter the ^-oxidation pathway. Control is also exerted extramitochondrially via malonyl-CoA, a cytoplas-mic intermediate in fatty-acid biosynthesis and an indicator of high cellular energy status. Malonyl-CoA is a potent inhibitor of CPT1, prohibiting fatty acids from entering the mitochondria to be degraded.

As depicted in Figure 2, the four primary enzymes of mitochondrial ^-oxidation act on intramitochondrial fatty acyl-CoA by sequential dehydrogenation, hydration, dehydrogenation, and thiolytic cleavage reactions. The products are (1) fatty acyl-CoA that has been shortened by two carbon atoms, (2) acetyl-CoA, (3) reduced flavin adenine dinucleotide (FADH2), and (4) reduced nicotinamide adenine dinucleotide (NADH). FADH2 and NADH can directly enter the electron transport chain at complex 2 and complex 1, respectively, yielding about five ATP molecules. Acetyl-CoA can be further degraded to carbon dioxide and water by the tricarboxylic acid cycle, yielding additional reducing equivalents that can enter the electron transport chain and produce ATP. Importantly, the entire ^-oxidation process can be repeated using the shortened fatty acyl-CoA as a substrate. This process can be repeated until the entire carbon skeleton of the fatty acid has been degraded to two-carbon acetyl-CoA units. Theoretically, complete oxidation of one molecule of 16:0 (^-oxidation and tricarboxylic acid cycle) will yield more than 160 ATP molecules.

Essentially all cells and tissues can use carbohydrate (glucose) for fuel, and a few (e.g., nerves and erythrocytes) are dependent on this fuel source. An important nutritional consideration is that carbon derived from fatty acids via ^-oxidation cannot be converted to glucose in net quantities. In the postprandial state, however, most cell types other than nerves and erythrocytes derive the majority of their energy from fatty-acid oxidation under normal physiologic conditions. Some tissues, e.g., skeletal muscle, completely oxidize fatty acids to carbon dioxide and water. Others, e.g., liver, only partially oxidize fatty acids, using the acetyl-CoA product for biosynthethic needs. In particular, liver uses intramitochondrial acetyl-CoA for the synthesis of ketone bodies, acetoacetate and /3-hydroxybutyrate (Figure 3). Ketone bodies can be oxidized by all tissues except the liver and provide an alternative fuel source during starvation. In particular, nervous tissue can oxidize ketone bodies. During prolonged starvation, increased ketone-body use spares the brain's requirement for glucose.

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