Fatty acyl CoA dehydrogenases

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. 

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. 

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

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... 

Fatty acyl-CoA dehydrogenase FAD Fatty acid oxidation... 

Two other enzymes that we will encounter later, glycerol phosphate drogenase (p. 528) and fatty acyl CoA dehydrogenase (p. 624), likewise transfer their high-potential electrons from FAD Hi to Q to form ubiquinol (QH f), the reduced state of ubiquinone. These enzymes oxidize glycerol and fats, respectively, providing electrons for oxidative phosphorylation, These enzymes also do not pump protons. 

Genetic Defects in Fatty Acyl-CoA Dehydrogenases Cause Serious Disease... 

Fatty acyl-CoA + E-FAD <=> Trans- A2-Enoyl-CoA + E-FADH2 (catalyzed by Fatty Acyl-CoA Dehydrogenase)(Figure 18.16). The FAD and FADH2 in the reaction are enzyme-bound. Electrons from FADH2 are donated to coenzyme Q in the electron transport system (Figure 18.17). 

FADH2 is an important carrier of electrons. FAD is the oxidized form of the molecule (lacks electrons). FADH2 is the reduced form (carries electrons). FAD and FADH2 function in many oxidation reactions, such as those catalyzed by succinate dehydrogenase and fatty acyl-CoA dehydrogenase. Electrons carried by FADH2 do not pass through complex I of the mitochondrial electron transport system and thus do not result in synthesis of as many ATPs in oxidative... 

Fatty acyl-CoA dehydrogenase catalyzes the initial step in the process of oxidation of fatty acids. 

Enzymes that act on acyl-CoAs include thiolase, fatty acyl-CoA ligase, fatty acyl-CoA dehydrogenase, enoyl-CoA hydratase, 3-hydroxyacylCoA dehydrogenase, enoyl-CoA isomerase, and 2,4 dienoyl-CoA reductase. 

Describe the entry of electrons into the respiratory chain at the succinate-Q reductase complex (Complex 11) from flavoproteins such as succinate dehydrogenase (a component of Complex II), glycerol phosphate dehydrogenase, and fatty acyl CoA dehydrogenase by way of FADH.2. Appreciate that Complex II is not a proton pump. 

Flavoproteins Yeast fatty acyl-CoA oxidase Porcine liver fatty acyl-CoA dehydrogenase Yeast glutathione reductase Egg-white flavoprotein Old yellow enzyme D-amino acid oxidase NADPH-cytochrome P-450 reductase Flavin Type of bonding between flavin and protein. Chemistry of charge-transfer complexes involving flavin and second ligand (e.g. phenolor amino-acid derivative )... 

Fig. 13.1.1. Schematic overview of mitochondrial oxidative phosphorylation. A part of the mitochondrion is represented, showing the outer mitochondrial membrane (OMM), inner mitochondrial membrane (IMM) and crista (an invagination of the inner membrane). Substrates for oxidation enter the mitochondrion through specific carrier proteins, e.g., the pyruvate transporter, (PyrT). Reducing equivalents from fatty acyl CoA dehydrogenases, pyruvate dehydrogenase and the TCA cycle are delivered to the electron transport chain through NADH, succinate ubiquinol oxidoreductase (SQO), electron transfer flavoprotein (ETF) and its ubiquinol-...

Liver and heart mitochondria from ten normal and ten VPA-treated rats were separately pooled and used for enzyme assay and immunoblot analysis. Enzyme assays by a dye reduction method revealed that fatty acyl-CoA dehydrogenase (SCAD, MCAD and LCAD) activities in VPA-treated rat heart mitochondria were moderately decreased (57-79% of control), however, those in VPA-treated liver mitochondria were slightly reduced (78-95% of control). IVD activities in liver and heart were almost unchanged by VPA. We then estimated each enzyme protein by immunoblot analysis. The intensity of signals of fatty acyl-CoA dehydrogenases in VPA-treated heart decreased significantly compared to controls (Fig. 1). There were no reductions of any of the ACD proteins in liver (data not shown). 

Fig. 3. (a) Biosynthesis of SCL PHA 1,3-ketothiolase 2, NADPH-dependent acetoacetyl-CoA reductase 3, SCL PHA polymerase 4, SCL PHA depolymerase 5, d(-)-3-hydroxybutyrate-dimer hydrolase, (b) Biosynthesis of P(HB-co-HV), 1, 3-ketothiolase 2a, NADPH-dependent acetoacetyl-CoA reductase 2b, NADH-dependent acetoacetyl-CoA reductase 3, SCL PHA polymerase 4, fatty acyl-CoA dehydrogenase 5, enoyl-CoA hydratase. 

Metallo-Flavoproteins. As was mentioned in the case of cytochrome reductase, enzymes are known that contain metal cofactors in addition to flavin. These are called metallo-flavoproteins. The presence of metals introduces complexity into the reaction, since the metals involved, iron, molybdenum, copper, and manganese, all exist in at least two valence states and can participate in oxidation-reduction reactions. The enzymes known to be metallo-flavoproteins include xanthine oxidase, aldehyde oxidase, nitrate reductase, succinic dehydrogenase, fatty acyl CoA dehydrogenases, hydrogenase, and cytochrome reductases. Before these are discussed in detail some physical properties of flavin will be presented. 

Riboflavin and flavoprotein pass through semiquinonoid states during two-equivalent reduction (303,456,457,547,548,699,704 compare 393). Furthermore, radicals and semiquinones appear to be stabilized by adsorption (69). Beinert has observed the spectrum of an intermediate reduction stage of FAD and of a flavoprotein enzyme, fatty acyl CoA dehydrogenase (36,37). This intermediate form (at pH 7.4 and 4.3) shows a band at 580 m which can be produced (1) by reduction of enzyme by dithionite in absence of substrate or by substrate in the absence of dithionite, ( ) by reduction of free flavin by dithionite or by sodium amalgam, and (S) by leoxidation of either reduced enzyme or reduced free flavin with oxygen. The intermediate is stable when formed in the presence of substrate, although it is unstable when produced by dithionite in the absence of substrate. The.se relationships can be interpreted in terms of an enzyme-sub-... 

Fig. 37. Mechanism for oxidation of substrate (SHi) by flavoprotein (36). Y represents the yellow enzyme, fatty acyl CoA dehydrogenase FAD and FADH2 represent the oxidized and reduced forms, respectively, of enzyme-bound flavin and S and SHt represent the oxidized and reduced forms of substrate.

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