Long-chain fatty-acid-CoA

Long-chain-fatty-acid-coA ligase R223-RXN 0.008890324... 

It also appears that tiaprofenic acid, an NSAID that also undergoes inversion in rats, is not a substrate for purified microsomal rat liver long-chain acyl-CoA synthetase for which R-ibuprofen is a substrate [25]. This data may suggest that metabolic pathways involved in the inversion of tiaprofenic acid and possibly other 2-APA NSAIDs are different from those known for R-ibuprofen. It has been recently reported that in both an in vitro cell-free system and in rat liver homogenates the chiral inversion of ibuprofen was apparent when both CoA and ATP were present however, the NSAID KE-748 was not inverted [26]. To induce hepatic microsomal and outer mitochondrial long-chain fatty acid CoA ligase, rats were treated with clofibric acid [27]. Whereas chiral inversion of ibuprofen was enhanced significantly compared to controls, this was not the case for R(—)-KE-748. 

Knights, K.M. Jones, M.E. Inhibition kinetics of hepatic microsomal long chain fatty acid-CoA ligase by 2-arylpropionic acid non-steroidal antiinflammatory drugs. Biochem. Pharmacol. 1992, 44, 2415-2417. 

Engel, C.K., Kiema, T.R., Hiltunen, J.K. Wierenga, R.K. (1998) J. Mol Biol 275, 847-859. The crystal stmcture of enoyl-CoA hydratase complexed with octanoyl-CoA reveals the structural adaptations required for binding of a long chain fatty acid-CoA molecule. 

Lessire, R. and Cassagne, C. (1979) Long chain fatty acid CoA-activation by microsomes from Allium porrum epidermal cell. 

The fatty acid in its ionized form is activated in the long-chain-fatty-acid-CoA ligase outer surface of the eukaryotic outer mitochon- q substrates butyrate-CoA... 

A more direct pathway for unsaturated fatty acid biosynthesis was first demonstrated in Saccharomyces cerevisiae by Bloomfield and Bloch (1960). Their studies revealed that the formation of unsaturated fatty acid CoA esters could proceed by a desaturation of the corresponding long-chain fatty acid CoA ester, as shown in Fig. 7. The particulate enzyme involved was found to have characteristics typical of mixed function oxidases, requiring molecular oxygen and ITNH. In contrast, the p,y dehydration mechanism outlined above is essentially... 

All of the other enzymes of the /3-oxidation pathway are located in the mitochondrial matrix. Short-chain fatty acids, as already mentioned, are transported into the matrix as free acids and form the acyl-CoA derivatives there. However, long-chain fatty acyl-CoA derivatives cannot be transported into the matrix directly. These long-chain derivatives must first be converted to acylearnitine derivatives, as shown in Figure 24.9. Carnitine acyltransferase I, located on the outer side of the inner mitochondrial membrane, catalyzes the formation of... 

Kim, K-H., et al., 1989. Role of rever.sible pho.sphorylation of acetyl-CoA carboxyla.se in long-chain fatty acid. syndie.sis. The EASEB Journal 3 22 0-2256. 

Long-chain fatty acids (e.g., palmitate Cig) diffuse through pores in the outer mitochondrial membrane, and then form long-chain acyl-CoA esters catalyzed reversibly by palmitoyl-CoA synthase (assumed to be on the inner face of the outer membrane). 

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 ...

The rate of mitochondrial oxidations and ATP synthesis is continually adjusted to the needs of the cell (see reviews by Brand and Murphy 1987 Brown, 1992). Physical activity and the nutritional and endocrine states determine which substrates are oxidized by skeletal muscle. Insulin increases the utilization of glucose by promoting its uptake by muscle and by decreasing the availability of free long-chain fatty acids, and of acetoacetate and 3-hydroxybutyrate formed by fatty acid oxidation in the liver, secondary to decreased lipolysis in adipose tissue. Product inhibition of pyruvate dehydrogenase by NADH and acetyl-CoA formed by fatty acid oxidation decreases glucose oxidation in muscle. 

The source of long-chain fatty acids is either dietary lipid or de novo synthesis from acetyi-CoA derived from carbohydrate. Fatty acids may be oxidized to acetyl-CoA (P-oxidation) or esterifred with glycerol, forming triacylglycerol (fat) as the body s main fuel reserve. 

Acetyl-CoA is also used as the precursor for biosynthesis of long-chain fatty acids steroids, including cholesterol and ketone bodies. 

Acetyl-CoA, formed from pyruvate by the action of pyruvate dehydrogenase, is the major building block for long-chain fatty acid synthesis in nonruminants. (In ruminants, acetyl-CoA is derived directly from acetate.)... 

The synthesis of long-chain fatty acids (lipogenesis) is carried out by two enzyme systems acetyl-CoA carboxylase and fatty acid synthase. 

Figure 22-1. Role of carnitine in the transport of long-chain fatty acids through the inner mitochondrial membrane. Long-chain acyl-CoA cannot pass through the inner mitochondrial membrane, but its metabolic product, acylcarnitine, can. 

A modified form of P-oxidation is found in peroxisomes and leads to the formation of acetyl-CoA and H2O2 (from the flavoprotein-linked dehydrogenase step), which is broken down by catalase. Thus, this dehydrogenation 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, Cjq, C22). These enzymes are induced by... 

However, if we can design some sophisticated routes to generate carbanion equivalents in the active site of the enzyme, carboxylation reaction might be possible. In fact, acetyl-CoA is carboxylated with the aid of biotin in the biosynthetic pathway of long-chain fatty acids. 

Long-chain fatty acids can slowly cross the mitochondrial membrane by themselves, but this is too slow to keep up with their metabolism. The carnitine shuttle provides a transport mechanism and allows control of (3 oxidation. Malonyl-CoA, a precursor for fatty acid synthesis, inhibits the carnitine shuttle and slows down (3 oxidation (Fig. 13-5). 

Alkyl PAT, alkyl-dihydroxy phosphate synthase Bif, bifunctional enzyme DHAPAT, dihydroxyphosphate acyltransferase deficiency DHCA, dihydroxycholestanoic acid N, normal nd, not determined Ox, acyl-CoA oxidase Rac, 2-methylacyl-CoA racemase RCDP, rhizomelic chondrodysplasia punctata Ref, Refsum s disease THCA, trihydroxycholestanoic acid VLCFA, very-long-chain fatty acid. 

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