Fatty acyl-CoA reductase

Long-chain alcohols are formed by reduction of long-chain fatty acids. A fatty acyl-CoA reductase has been demonstrated in cabbage, Brassica oleracea (Brassicaceae). Fractionation of the protein fraction isolated in these studies indicated that one protein fraction catalyzed acyl-CoA reduction to the aldehyde stage with NADH as the preferred reductant and another catalyzed reduction of the aldehyde to the alcohol with NADPH as the preferred reductant. The similarity of die naturally occurring fatty aldehydes and fatty alcohols of a given plant is probably due to the fact that aldehydes represent intermediates in the synthesis of fatty alcohols (Kolattukudy, 1980). 

The desert shrub jojoba Simmondsia chinensis, Link) appears to be the only plant system that synthesizes large quantities of liquid wax. Two enzymes are specific to the wax biosynthetic pathway fatty acyl-CoA reductase, which catalyzes the NADPH-specific reduction of the fatty acyl moiety of acyl-CoA to fatty alcohol, and acyl-CoA fatty alcohol acyltransferase, which catalyzes the coupling of fatty acid to fatty alcohol. 

When a double bond appears near the carboxyl carbon of the partially degraded fatty acyl CoA, several isomerases and reductases modify the structure to allow continued (3-oxidation. 

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... 

Fatty acyl-CoA desaturases are terminal oxidases of a membrane-bound enzyme complex that also includes cytochrome b5 and cytochrome b5 reductase (Bloomfield and Bloch, 1960). They remove substrate hydrogen atoms at a position determined by the specificity of the enzyme. They play essential roles in regulating membrane fluidity and are also involved in insect lipid and pheromone metabolism. They share the presence of three highly conserved histidine-rich sequences (H-boxes) that coordinate the diiron-oxo structure at the active sites (Shanklin and Cahoon, 1998) and four hydrophobic a helices that appear to anchor the protein into the lipid bilayer and situate the H-boxes in their correct position in the active site. 

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... 

This reaction is catalyzed by a complex of three membrane-bound proteins NADH-cytochrome bs reductase, cytochrome b, and a desaturase (Figure 22.32). First, electrons are transferred from NADH to the FAD moiety of NADH-cytochrome b reductase. The heme iron atom of cytochrome h-, is then reduced to the Fe state. The nonheme iron atom of the desaturase is subsequently converted into the Fe state, which enables it to interact with and the saturated fatty acyl CoA substrate. A double bond is... 

It has also been proposed that hpids, Upid metabolites and cytosolic lipid-binding proteins interact to regulate sterol biosynthesis [199] (see also Chapter 3). Under this model, the accumulation in cells of certain hpids or free hpid intermediates inhibits sterol biosynthetic enzymes. The level of the binding protein for a particular Upid would determine the threshold concentration of Upid needed to produce inhibition [199]. Such a mechanism would allow coordination between the biosynthesis of sterols and other Upids. Fatty acyl-CoAs and Z-protein, the fatty acyl-CoA-binding protein, may modulate HMG-CoA reductase activity [199-201] since physiological... 

Fig. 8. P-Oxidation of fatty acids in E. coli. Long-chain fatty acids are transported into the cell by FadL and converted to their CoA thioesters by FadD (not shown). The acyl-CoAs are substrates for the (1) acyl-CoA dehydrogenase (YafH) to form a trans-2-enoyl-CoA. The double bond is reduced by (2) rrans-2-enoyl-hydratase (crotonase) activity of FadB. The P-hydroxyacyl-CoA is then a substrate for the NADP -dependent dehydrogenase activity of FadB (3). A thiolase, FadA (4), releases acetyl-CoA from the P-ketoacyl-CoA to form an acyl-CoA for subsequent cycles. (5) Polyunsaturated fatty acyl-CoAs are reduced by the 2,4-dienoyl-CoA reductase (FadH). (6) FadB also catalyzes the isomerization of c/s-unsaturated fatty acids to trans. (7) The epimerase activity of FadB converts O-P-hydroxy thioesters to their L-enantiomers via the /rans-2-enoyl-CoA.

Stearoyl-CoA desaturase (SCD) resides in the ER where it catalyzes the biosynthesis of MUFA from SFA that are either synthesized de novo or derived from the diet (Fig. 2). In conjunction with NADH, the flavoprotein cytochrome reductase, the electron acceptor cytochrome b, and molecular oxygen, SCD introduces a single double bond into a spectrum of methylene-intemipted fatty acyl-CoA substrates (Fig. 3). 

Fatty alcohol precursors of ether lipids and waxes are derived from acyl-CoAs via a fatty aldehyde intermediate in a reaction sequence catalyzed by a membrane-associated acyl-CoA reductase (Fig. 3). The genes encoding two enzymes — FARl and FAR2 — with this activity have been cloned (J.B. Cheng and D.W. Russell, 2004). These proteins are 58%... 

Fig. 3. Enzymatic synthesis and oxidation of long-chain fatty alcohols. These reactions are catalyzed by (I) acyl-CoA reductase and (II) fatty alcohol oxidoreductase, respectively.

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 )... 

When measuring the mitochondrial P-oxidation in liver, 2-methyl EPA did not cause any effect compared to EPA or control, while the other EPA-derivatives increased the fatty acid oxidation in mitochondria. We measured the mitochondrial activity and gene expression of an enzyme involved in the oxidation of unsaturated fatty acids, the 2,4-dienoyl-CoA reductase. Both the activity and gene expression seemed to increase in rats fed 2,2-dimethyl EPA. We also measured the total activity of CPT in liver, and found an increased activity in rats fed 2,2-dimethyl EPA. The increase in total CPT-activity after administration of 2,2-dimethyl EPA seemed to be due to the observed increase in CPT-II transcription, as the mRNA level of CPT-I was unchanged (data to be published). The peroxisomal P-oxidation, the activity and gene e q)ression of fatty acyl-CoA oxidase, the rate-limiting enzyme of peroxisomal P-oxidation, and the gene expression of the peroxisomal multifunctional protein were increased after administration of the EPA-derivatives, as shown in Table 2. 

---