Fatty Acyl dehydrogenase

FIGURE 21.V The fatty acyl-CoA dehydrogenase reaction, emphasizing that the reaction involves reduction of enzyme-bonnd FAD (indicated by brackets). 

This is a crucial point because (as we will see) proton transport is coupled with ATP synthesis. Oxidation of one FADHg in the electron transport chain results in synthesis of approximately two molecules of ATP, compared with the approximately three ATPs produced by the oxidation of one NADH. Other enzymes can also supply electrons to UQ, including mitochondrial 5w-glyc-erophosphate dehydrogenase, an inner membrane-bound shuttle enzyme, and the fatty acyl-CoA dehydrogenases, three soluble matrix enzymes involved in fatty acid oxidation (Figure 21.7 also see Chapter 24). The path of electrons from succinate to UQ is shown in Figure 21.8. 

Step 1 of Figure 29.3 Introduction of a Double Bond The /3-oxidation pathway begins when a fait)7 acid forms a thioester with coenzyme A to give a fatty acyl Co A. Two hydrogen atoms are then removed from C2 and C3 of the fatty acyl CoA by one of a family of acyl-CoA dehydrogenases to yield an a,/3-unsaturated acyl CoA. This kind of oxidation—the introduction of a conjugated double bond into a carbonyl compound—occurs frequently jn biochemical pathways and usually involves the coenzyme flavin adenine dinucleotide (FAD). Reduced FADH2 is the by-product. 

The situation is simpler for odd numbered fatty acyl derivatives as [3-oxidation proceeds normally until a 5-carbon unit remains, rather than the usual 4-carbon unit. The C5 moiety is cleaved to yield acetyl-CoA (C2) and propionyl-CoA (C3). Propionyl CoA can be converted to succinyl CoA and enter the TCA cycle so the entire molecule is utilized but with a slight reduction in ATP yield as the opportunity to generate two molecules of NADH by isocitrate dehydrogenase and 2-oxoglutarate dehydrogenase is lost because succinyl-CoA occurs after these steps in the Krebs cycle (Figure 7.18). 

Pantothenic acid CoA i Fatty acid synthase Fatty acyl CoA synthetase Pyruvate dehydrogenase ci-Ketoglutarate dehydrogenase Fatty acid metabolism PDH TCA cycle Rare... 

A peroxisomal dehydrogenase initiates the 3-oxidation reactions that shorten the chain to -18 carbons or less, at which point the fatty acyl CoA is transferred to mitochondria for complete degradation by (3-oxidation. 

This first step is catalyzed by three isozymes of acyl-CoA dehydrogenase, each specific for a range of fatty-acyl chain lengths veiy-long-chain acyl-CoA dehydrogenase (VLCAD), acting on fatty acids of 12 to 18... 

The last three steps of this four-step sequence are catalyzed by either of two sets of enzymes, with the enzymes employed depending on the length of the fatty acyl chain. For fatty acyl chains of 12 or more carbons, the reactions are catalyzed by a multienzyme complex associated with the inner mitochondrial membrane, the trifunctional protein (TFP). TFP is a heterooctamer of 4/34 subunits. Each a subunit contains two activities, the enoyl-CoA hydratase and the /3-hydroxyacyl-CoA dehydrogenase the /3 subunits contain the thiolase activity. This tight association of three enzymes may allow efficient substrate channeling from one active site to the... 

Bole of FAD as Electron Acceptor Acyl-CoA dehydrogenase uses enzyme-bound FAD as a prosthetic group to dehydrogenate the a and j3 carbons of fatty acyl-CoA. What is the advantage of using FAD as an electron acceptor rather than NAD+ Explain in terms of the standard reduction potentials for the Enz-FAD/EADH2 (E ° = —0.219 V) and NAD+/NADH (E ° = —0.320 V) half-reactions. 

Other substrates for mitochondrial dehydrogenases pass electrons into the respiratory chain at the level of ubiquinone, but not through Complex II. The first step in the J8 oxidation of fatty acyl-CoA, catalyzed by the... 

Updates coverage of the medical consequences of genetic defects in fatty acyl-CoA dehydrogenases... 

Medium-chain fatty acyl CoA dehydrogenase (MCAD) deficiency ... 

In mitochondria, there are four fatty acyl CoA dehydrogenase species, each of which has a specificity for either short-, mediurr-long-, or very-long-chain fatty acids. MCAD deficiency, an autos mal, recessive disorder, is one of the most common inborn errors of metabolism, and the most common inborn error of fatty add oxidation, being found in 1 in 12,000 births in the west, and 1 in 40,000 worldwide. It causes a decrease in fatty acid oxidation and severe hypoglycemia (because the tissues cannot obtain full ener getic benefit from fatty acids and, therefore, must now rely on glu cose). Treatment includes a carbohydrate-rich diet. [Note Infants are particularly affected by MCAD deficiency, because they rely for their nourishment on milk, which contains primarily MCADs. 

Polyunsaturated fatty acids are also degraded by [3 oxidation, but the process requires enoyl-CoA isomerase and an additional enzyme, 2,4-dienoyl-CoA reductase (fig. 18.6). For example, the degradation of linoleoyl-CoA (18 2A9-12) begins, like that of oleoyl-CoA, with three rounds of /3 oxidation and results in a A3-cis unsaturated fatty acyl-CoA that is not a substrate for acyl-CoA dehydrogenase. Isomerization of the double bond to the A2-trans position by enoyl-CoA isomerase allows the resumption of... 

Oxidation of the fatty acyl CoA to enoyl CoA forming a trans A2-double bond on the fatty acyl chain and producing FADH2 (catalyzed by acyl CoA dehydrogenase). 

The association of proton movement with electron transport is not reflected in the fatty acyl desaturase system universal to endomembranes. In these enzymes the dehydrogenase, NADH cyt b5 reductase and the cytochrome b5 (a single heme cytochrome) are associated exclusively with the cytosolic side of the membrane by acyl groups and have no transmembrane segment. The cytochrome b5 oxidase associated with the desaturation of fatty acyl CoA may be transmembranous but has not been associated with proton movement. It is an iron-containing protein. The other type of endomembrane cytochromes are the P-450 group of cytochrome bs... 

In the mitochondrion, even-numbered fatty acyl-CoA is broken into acetyl-CoA units starting from the carboxyl end. The first reaction is dehydrogenation by an FAD-dependent dehydrogenase to form an enoyl-CoA. 

The fatty acyl-CoA dehydrogenase reaction is analogous to the succinate dehydrogenase reaction both are FAD-requiring oxidations ... 

Answer The /3-oxidation pathway includes two dehydrogenase enzymes that remove hydrogen (H-H) from the fatty acyl-CoA chain, first at a —CH2—CH2— and then at a —CH2—CH(OH)—. The net result of the two reactions is removal of one of the two hydrogens at the point of formation of the enoyl-CoA intermediate. The two other hydrogens in the methyl group of acetyl-CoA come from water. 

FAD Sucdnate —> furmarate3 Fatty acyl CoA —> enoyl CoAb Glycerol-3-phosphate —> dihydroxyacetone phosphate (mitochondrial)c Succinate dehydrogenase Fatty acyl CoA dehydrogenase Glycerol-3-phosphate dehydrogenase... 

---