POxidation Of Fatty Acids Involves Successive Cleavage With Release Of AcetylcoA

In P-oxidation (Figure 22-2), two carbons at a time are cleaved from acyl-CoA molecules, starting at the car-boxyl end. The chain is broken between the a(2)- and P(3)-carbon atoms—hence the name P-oxidation. The two-carbon units formed are acetyl-CoA; thus, palmi-toyl-CoA forms eight acetyl-CoA molecules.

Palmitoyl-CoA

CH3 —CO^S —CoA Acetyl-CoA Successive removal of acetyl-CoA (C2) units

Figure 22-2. Overview of ß-oxidation of fatty acids.

The Cyclic Reaction Sequence Generates FADH2 & NADH

Several enzymes, known collectively as "fatty acid oxidase," are found in the mitochondrial matrix or inner membrane adjacent to the respiratory chain. These catalyze the oxidation of acyl-CoA to acetyl-CoA, the system being coupled with the phosphorylation of ADP to ATP (Figure 22-3).

The first step is the removal of two hydrogen atoms from the 2(a)- and 3(P)-carbon atoms, catalyzed by acyl-CoA dehydrogenase and requiring FAD. This results in the formation of A2-trans-enoyl-CoA and FADH2. The reoxidation of FADH2 by the respiratory chain requires the mediation of another flavoprotein, termed electron-transferring flavoprotein (Chapter 11). Water is added to saturate the double bond and form 3-hydroxyacyl-CoA, catalyzed by A2-enoyl-CoA hydratase. The 3-hydroxy derivative undergoes further dehydrogenation on the 3-carbon catalyzed by l(+)-3-hydroxyacyl-CoA dehydrogenase to form the corresponding 3-ketoacyl-CoA compound. In this case, NAD+ is the coenzyme involved. Finally, 3-ketoacyl-CoA is split at the 2,3- position by thiolase (3-keto-acyl-CoA-thiolase), forming acetyl-CoA and a new acyl-CoA two carbons shorter than the original acyl-CoA molecule. The acyl-CoA formed in the cleavage reaction reenters the oxidative pathway at reaction 2 (Figure 22-3). In this way, a long-chain fatty acid may be degraded completely to acetyl-CoA (C2 units). Since acetyl-CoA can be oxidized to CO2 and water via the

ACYL-CoA SYNTHETASE

H2-CH2-C

Fatty acid

Mg2"'

Figure 22-3. p-Oxidation of fatty acids. Long-chain acyl-CoA is cycled through reactions 2-5, acetyl-CoA being split off, each cycle, by thiolase (reaction 5). When the acyl radical is only four carbon atoms in length, two acetyl-CoA molecules are formed in reaction 5.

INNER MITOCHONDRIAL MEMBRANE

(outside) C side g CARNITINE TRANSPORTER M side (inside)

ACYL-CoA DEHYDROGENASE

2 Respiratory 2 chain

A 2-frans-Enoyl-CoA

A2-ENOYL-CoA

l(+)-3-HYDROXYACYL-CoA DEHYDROGENASE

NAD+

Respiratory chain

3-Ketoacyl-CoA

11 H

- R — C S — CoA + CH3—C^S— CoA Acyl-CoA Acetyl-CoA

citric acid cycle (which is also found within the mitochondria), the complete oxidation of fatty acids is achieved.

Oxidation of a Fatty Acid With an Odd Number of Carbon Atoms Yields Acetyl-CoA Plus a Molecule of Propionyl-CoA

Fatty acids with an odd number of carbon atoms are oxidized by the pathway of P-oxidation, producing acetyl-CoA, until a three-carbon (propionyl-CoA) residue remains. This compound is converted to succinyl-CoA, a constituent of the citric acid cycle (Figure 19-2). Hence, the propionyl residue from an odd-chain fatty acid is the only part of a fatty acid that is glucogenic.

Oxidation of Fatty Acids Produces a Large Quantity of ATP

Transport in the respiratory chain of electrons from FADH2 and NADH will lead to the synthesis of five high-energy phosphates (Chapter 12) for each of the first seven acetyl-CoA molecules formed by P-oxidation of palmitate (7 X 5 = 35). A total of 8 mol of acetyl-CoA is formed, and each will give rise to 12 mol of ATP on oxidation in the citric acid cycle, making 8 X 12 = 96 mol. Two must be subtracted for the initial activation of the fatty acid, yielding a net gain of 129 mol of ATP per mole of palmitate, or 129 X 51.6* = 6656 kJ. This represents 68% of the free energy of combustion of palmitic acid.

Peroxisomes Oxidize Very Long Chain Fatty Acids

A modified form of P-oxidation is found in peroxi-somes and leads to the formation of acetyl-CoA and H2O2 (from the flavoprotein-linked dehydrogenase step), which is broken down by catalase. Thus, this de-hydrogenation in peroxisomes is not linked directly to phosphorylation and the generation of ATP. The system facilitates the oxidation of very long chain fatty acids (eg, C20, C22). These enzymes are induced by

* AG for the ATP reaction, as explained in Chapter 17.

HYDRATASE

THIOLASE

Figure 22-4. Sequence of reactions in the oxidation of unsaturated fatty acids, eg, linoleic acid. A4-c/'s-fatty acids or fatty acids forming A4-c/'s-enoyl-CoA enter the pathway at the position shown. NADPH for the dienoyl-CoA reductase step is supplied by intramitochondrial sources such as glutamate dehydrogenase, isocitrate dehydrogenase, and NAD(P)H transhydrogenase.

high-fat diets and in some species by hypolipidemic drugs such as clofibrate.

The enzymes in peroxisomes do not attack shorter-chain fatty acids; the P-oxidation sequence ends at oc-tanoyl-CoA. Octanoyl and acetyl groups are both fUrther oxidized in mitochondria. Another role of peroxisomal P-oxidation is to shorten the side chain of cholesterol in bile acid formation (Chapter 26). Peroxisomes also take part in the synthesis of ether glycerolipids (Chapter 24), cholesterol, and dolichol (Figure 26-2).

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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