Fatty acyl-CoA synthase

The outer mitochondrial membrane contains monoamine oxidase, cytochrome b5, fatty acyl-CoA synthase, and enzymes of cardiolipin synthesis223 as well as other proteins. Cardiolipin (diphosphatidyl-glycerol Fig. 21-4) is found only in the inner mitochondrial membrane and in bacteria. It is functionally important for several mitochondrial enzymes including cytochrome oxidase and cytochome bc1.22a c It is also... 

Activation of the fatty acids to their respective CoA esters, is a necessary step prior to oxidation. DHA was converted to its CoA ester in all subcellular fractions, but was a poor substrate for oxidation in both the mitochondrial- and the peroxisomal fractions. Compared to EPA-CoA, DHA-CoA was more effectively synfliesized in the peroxisomal than the mitochondrial fraction, espedally in animals treated with 3-thia fatty acids. It has been reported that very long chain fatty acyl-CoA synthases as lignoceryl-CoA are absent in mitochondria and DHA-CoA syndiase activity measured in the mitochondrial fraction, might also be due to contamination of peroxisomes. ... 

Figure 3. Mitochondrial fatty acid oxidation. Long-chain fatty acids are converted to their CoA-esters as described in the text, and their fatty-acyl-groups transferred to CoA in the matrix by the concerted action of CPT 1, the acylcarnitine/carnitine exchange carrier and CPT (A) as described in the text. Medium-chain and short-chain fatty acids (Cg or less) diffuse directly into the matrix where they are converted to their acyl-CoA esters by a acyl-CoA synthase. The mechanism of p-oxidation is shown below (B). Each cycle of P-oxidation removes -CH2-CH2- as an acetyl unit until the fatty acids are completely converted to acetyl-CoA. The enzymes catalyzing each stage of P-oxidation have different but overlapping specificities. In muscle mitochondria, most acetyl-CoA is oxidized to CO2 and H2O by the citrate cycle (Figure 4) some is converted to acylcamitine by carnitine acetyltransferase (associated with the inner face of the inner membrane) and exported from the matrix. Some acetyl-CoA (if in excess) is hydrolyzed to acetate and CoASH by acetyl-CoA hydrolase in the matrix. Enzymes ...

Once fatty acids have been made 16 carbons long, they can be lengthened by adding 2 carbon atoms at a time with malonyl-CoA in a reaction that looks a lot like the first step of fatty acid synthesis. However, the elongation reaction is carried out on the fatty acyl-CoA and by an enzyme that is different from fatty acid synthase.4 ... 

YPClp exhibits reverse activity in cells and in vitro. This activity is not inhibited by FBI and is fatty acyl-CoA independent, suggesting that the reverse activity of YPClp is distinct from the FBI inhibitable ceramide synthase activity which uses fatty acyl-CoA as substrate, but not a free fatty... 

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

Scheme 23.4 Production of methylketones from fatty acids by Penicillium roqueforti. 1 ATP-de-pendent acylcoenzyme A (acyl-CoA) synthase 2 flavin adenine dinucleotidedependent acyl-CoA dehydrogenase 3 enoyl-CoA hydratase 4 NAD-dependent 3-hydroxyacyl-CoA dehydrogenase 5 3-oxoacyl-CoA thiolase 6 3-oxoacyl-CoA thiolester hydrolase and 3-oxoacid decarboxylase. (Adapted from [46])...

The condensation of acetyl CoA and oxaloacetate to form citrate is catalyzed by citrate synthase (Figure 9.5). This aldol condensation has an equilibrium far in the direction of citrate synthesis. Citrate synthase is allosterically activated by Ca2+ and ADP, and inhibited by ATP, NADH, succinyl CoA, and fatty acyl CoA derivatives (see Figure 9.9). However, the primary mode of regulation is also deter mined by the availability of its substrates, acetyl CoA and oxaloac etate. [Note Citrate, in addition to being an intermediate in the TCA cycle, provides a source of acetyl CoA for the cytosolic synthesis of... 

Pantothenic acid is a component of coenzyme A, which functions in the transfer of acyl groups (Figure 28.17). Coenzyme A contains a thiol group that carries acyl compounds as activated thiol esters. Examples of such structures are succinyl CoA, fatty acyl CoA, and acetyl CoA. Pantothenic acid is also a component of fatty acid synthase (see p. 182). Eggs, liver, and yeast are the most important sources of pan tothenic acid, although the vitamin is widely distributed. Pantothenic acid deficiency is not well characterized in humans, and no RDA has been established. 

Citrate is synthesized from oxaloacetate (OAA) and acetyl CoA by citrate synthase. This enzyme is allosterically activated by ADP, and inhibited by ATP, NADH, succinyl CoA, and fatty acyl CoA derivatives. Citrate is isomerized to isocitrate by aconitase, an enzyme that is targeted by the rat poison, fluoroacetate. 

Figure 18-5 A current concept of the electron transport chain of mitochondria. Complexes I, III, and IV pass electrons from NADH or NADPH to 02, one NADH or two electrons reducing one O to HzO. This electron transport is coupled to the transfer of about 12 H+ from the mitochondrial matrix to the intermembrane space. These protons flow back into the matrix through ATP synthase (V), four H+ driving the synthesis of one ATP. Succinate, fatty acyl-CoA molecules, and other substrates are oxidized via complex II and similar complexes that reduce ubiquinone Q, the reduced form QH2 carrying electrons to complex III. In some tissues of some organisms, glycerol phosphate is dehydrogenated by a complex that is accessible from the intermembrane space.

In contrast to the anaerobic pathway found in E. coli, the aerobic pathway in eukaryotic cells introduces double bonds after the saturated fatty acid has been synthesized. Stearoyl-CoA (18 0) is the major substrate for desaturation. Stearic acid is made by the fatty acid synthase as a minor product, the major product being palmitic acid, and is activated to its CoA derivative by acyl-CoA synthase. In eukaryotic cells an enzyme complex associated with the endoplasmic reticulum desaturates stearoyl-CoA to oleoyl-CoA (18 1A9). This remarkable reaction requires NADH and 02 and results in the formation of a double bond in the middle of an acyl chain with no activating groups nearby. The chemical mechanism for desaturation of long-chain acyl-CoAs remains unclear. 

Martin, G., Poirier, H., Hennuyer, N., Crombie, D., Fruchart, J. C., Heyman, R. A., Besnard, P., and Auwerx, J. (2000). Induction Of The Fatty Acid Transport Protein 1 and Acyl-Coa Synthase Genes by Dimer-Selective Rexinoids Suggests That the Peroxisome Proliferator-Activated Receptor-Retinoid X Receptor Heterodimer is Their Molecular Target./ Bid. Chem. 275, 12612-12618. 

Figure 10-5. Intrahepatic metabolism of free fatty acids (FFA). CPT I, CPT II, carnitine palmitoyltransferase I, II, respectively LCFA, long-chain fatty acid VLDL, very low-density lipoprotein. 1, Long-chain acyl-CoA synthase 2, acetoacetyl-CoA thiolase 3, hydrox-ymethylglutaryl-CoA synthase 4, hydroxymethylglutaryl-CoA lyase 5, 3-hydroxybutyrate dehydrogenase 6, acetyl-CoA carboxylase 7, fatty acid synthase 8, glycerolphosphate acyltransferase Reprinted with permission from Girard et al. (1992).

For many years, it was assumed that the inability of patients with X-ALD to degrade VLCFA was due to a primary deficiency of the first enzyme in this pathway, very long chain fatty acyl-CoA (VLCF-CoA) synthase. Indeed, studies in cultured skin fibroblasts from patients with X-ALD have revealed that this enzyme activity is decreased when compared to cells from normal controls. However, when the X-ALD gene was isolated in 1993, it was discovered that the underlying defect is the deficiency of a peroxisomal membrane protein, called ALD... 

The major product of the fatty acid synthase is palmitate. In eukaryotes, longer fatty acids are formed by elongation reactions catalyzed by enzymes on the cytosolic face of the endoplasmic reticulum membrane. These reactions add two-carbon units sequentially to the carboxyl ends of both saturated and unsaturated fatty acyl CoA substrates. Malonyl CoA is the two-carbon donor in the elongation of fatty acyl CoAs. Again, condensation is driven by the decarboxylation of malonyl CoA. 

The final step in fatt acid synthesis is the dischar ge of the fatty acid from the sulfhydryl group of fatty acid synthase. This discharge involves the attack of a molecule of coenzyme A, resulting in the release of the fatly acid as fatty acyl-CoA, as shown in Figure 5.14. 

Palmitate, the product released by the fatty acid synthase complex, is converted to a series of other fatty acyl CoAs by elongation and desaturation reactions. 

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