Hydroxyacyl CoA

FIGURE 24.15 The conversion of trans- and m-enoyl CoA derivatives to l- and d-/3-hydroxyacyl CoA, respectively. These reactions are catalyzed by enoyl-CoA hydratases (also called crotonases), enzymes that vary in their acyl-chain length specificity. A recently discovered enzyme converts ram-enoyl-CoA directly to D-/3-hydroxyacyl-CoA. 

Hiltnnen, J. K., Palosaari, R, and Knnan, W.-H., 1989. Epimerization of 3-hydroxyacyl-CoA esters in rat liver. Journal of Biological Chemistry 264 13535-13540. 

One of the steps in the metabolism of fats is the reaction of an unsaturated acyl CoA with water to give a /3-hydroxyacyl CoA. Propose a mechanism. 

Conjugate nucleophilic addition of water to the double bond gives a /3-hydroxyacyl CoA. 

Step 3 of Figure 29.3 Alcohol Oxidation The /3-hydroxyacyl CoA from step 2 is oxidized to a /3-ketoacyl CoA in a reaction catalyzed by one of a family of L-3-hydroxyacyl-CoA dehydrogenases, which differ in substrate specificity according to the chain length of the acyl group. As in the oxidation of sn-glycerol 3-phosphate to dihydroxyacetone phosphate mentioned at the end of Section 29.2, this alcohol oxidation requires NAD+ as a coenzyme and yields reduced NADH/H+ as by-product. Deprotonation of the hydroxyl group is carried out by a histidine residue at the active site. 

Inherited defects in the enzymes of (3-oxidation and ketogenesis also lead to nonketotic hypoglycemia, coma, and fatty hver. Defects are known in long- and short-chain 3-hydroxyacyl-CoA dehydrogenase (deficiency of the long-chain enzyme may be a cause of acute fetty liver of pr nancy). 3-Ketoacyl-CoA thiolase and HMG-CoA lyase deficiency also affect the degradation of leucine, a ketogenic amino acid (Chapter 30). 

The oxidation of fatty acids within the Knoop-Lynen cycle occurs in the matrix. The Knoop-Lynen cycle includes four enzymes that act successively on acetyl-CoA. These are acyl-CoA dehydrogenase (FAD-dependent enzyme), enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase (NAD-dependent enzyme), and acetyl-CoA acyltrans-ferase. Each turn, or revolution, of the fatty acid spiral produces... 

Synthesis of PHAMCL from fatty acids such as octanoic acid or from the corresponding alkanes such as octane was first detected in P. oleovorans [119]. The alkanes are oxidized to the fatty acids the latter are activated by thiokinases and then degraded via the fatty acid /1-oxidation pathway. Obviously intermediates of this pathway accumulate under conditions favorable for the synthesis of PHA and are subsequently converted into substrates for the PHA synthase. Many reactions for the conversion of an intermediate of the -oxidation cycle into R-(-)-3-hydroxyacyl-CoA were considered. These were ... 

An epimerase directly converting the l-(+) of 3-hydroxyacyl-CoA into the r-(-) stereoisomer... 

The NADPH-dependent reductase is active with C4 to C6 D-(-)-3-hy-droxyacyl-CoAs, it has no activity with L-(+)-substrates, and the reduction of acetoacetyl-CoA yields only D-(-)-3-hydroxybutyryl-CoA. The NADH-de-pendent reductase can use the L-(+)-enantiomers of these compounds and, in addition, C7, C8, and C10 L-(+)-3-hydroxyacyl-CoAs as substrates. From aceto-acetyl-CoA the NADH-dependent reductase produces only L-(+)-3-hydro-xybutyryl-CoA, but in the reverse direction it is active with both substrates [15]. 

Hydrate cis-2 C=C to D-3-hydroxyacyl-CoA, epimerize D-3-hydroxy to L and continue normal (3 oxidation. 

Fatty acids are degraded by two-carbon units in a reverse manner analogous to their biosynthesis. The acyl-CoAs are first dehydrogenated to a,(3-unsaturated acyl-CoA, and then hydrated to (3-hydroxyacyl-CoA, followed by oxidation to (3-ketoacyl-CoA. The C-C bond between C-2 and C-3 of the latter compound is broken by a free CoA molecule via thiolysis to form an acyl-CoA that is two carbons shorter and acetyl-CoA. Unlike fatty acid biosynthesis, each step of the (3 oxidation of fatty acids is... 

Bifunctional protein deficiency. The enzyme defect involves the D-bifunctional protein. This enzyme contains two catalytic sites, one with enoyl-CoA hydratase activity, the other with 3-hydroxyacyl-CoA activity [13]. Defects may involve both catalytic sites or each separately. The severity of clinical manifestations varies from that of a very severe disorder that resembles Zellweger s syndrome clinically and pathologically, to somewhat milder forms. Table 41-6 shows that biochemical abnormalities involve straight chain, branched chain fatty acids and bile acids. Bifunctional deficiency is often misdiagnosed as Zellweger s syndrome. Approximately 15% of patients initially thought to have a PBD have D-bifunctional enzyme deficiency. Differential diagnosis is achieved by the biochemical studies listed in Table 41-7 and by mutation analysis. 

Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency has been described in three patients. It is associated with additional defects of (3-oxidation, which have been associated with limb weakness and attacks of myoglobinuria, and it is potentially fatal. 

LCHAD long chain 3-hydroxyacyl-CoA dehydrogenase mtDNA mitochondrial DNA... 

PLP proteolipid protein SCHAD short chain 3-hydroxyacyl-CoA dehydrogenase... 

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