3-Ketoacyl-CoA transferase

CoA, the coenzyme A derivative of acetoacetate, reduces its reactivity as a substrate for /3-ketoacyl-CoA transferase (an enzyme of lipid metabolism) by a factor of 106. Although this requirement for adenosine has not been investigated in detail, it must involve the binding energy between enzyme and substrate (or cofactor) that is used both in catalysis and in stabilizing the initial enzyme-substrate complex (Chapter 6). In the case of /3-ketoacyl-CoA transferase, the nucleotide moiety of coenzyme A appears to be a binding handle that helps to pull the substrate (acetoacetyl-CoA) into the active site. Similar roles may be found for the nucleoside portion of other nucleotide cofactors. 

In extrahepatic tissues, D-/3-hydroxybutyrate is oxidized to acetoacetate by D-/3-hydroxybutyrate dehydrogenase (Fig. 17-19). The acetoacetate is activated to its coenzyme A ester by transfer of CoA from suc-cinyl-CoA, an intermediate of the citric acid cycle (see Fig. 16-7), in a reaction catalyzed by /3-ketoacyl-CoA transferase. The acetoacetyl-CoA is then cleaved by thiolase to yield two acetyl-CoAs, which enter the citric acid cycle. Thus the ketone bodies are used as fuels. 

Acetoacetate + Succinyl-CoA <=> Acetoacetyl-CoA + Succinate (Catalyzed by 3-Ketoacyl-CoA Transferase). 

Ketone bodies, once taken up by the peripheral tissues, are converted into acetoacetyl-CoA by the enzyme 3-ketoacyl-CoA transferase (Fig. 4.10). They... 

The liver is a major metaboUc organ. It is the location of the urea cycle, purine synthesis and is the main site of lipid synthesis. It is also the site of KB synthesis, though it is unable to utilize KBs for energy as it lacks the enzymes 3-ketoacyl CoA transferase or succinyl CoA transferase (also known as thiophorase). Approximately 10 per cent of the liver s mass is glycogen, compared with 1—2 per cent of the mass of muscle. However, as there is far more muscle than liver in the body, about two-thirds of the body s glycogen by weight is stored in muscle. 

KBs are generated from acetyl CoA in liver cell mitochondria. The three KBs are acetoacetate, acetone and 3-hydroxybutyrate. They are carried in the blood to tissues that can use them as an energy source. Liver cells are unable to utilize KBs as fuel, as liver cells lack the enzyme 3-ketoacyl CoA transferase that is necessary to regenerate acetyl CoA from the KBs. 

Fig. 2.3 Biosynthesis pathway of A P(3HB) B P(3HB-co-3HV) C P(3HB-co-3HHx) via fatty acid /S-oxidation and D P(3HB-co-3HHx) via fatty acid de novo synthesis. PhaA, f -ketothiolase PhaB, NADPH dependent acetoacetyl-CoA reductase PhaC, PHA synthase PhaG, 3-hydroxyl-ACP-CoA transferase PhaJ, (J )-enoyl-CoA hydratase FabG, 3-ketoacyl-CoA reductase (Sudesh et al. 2000)...

Thiolytic cleavage of the 3-ketoacyl-CoA is catalysed by acetyl-CoA acyl transferase (EC 2.3.1.16) which liberates acetyl-CoA and an acyl-CoA two carbons shorter than the original substrate (Fig. 11.7). The above enzyme has a broad chain-length specificity but a second, acetyl-CoA acetyl-transferase (EC 2.3.1.9), catalyses the same reaction with acetoacetyl-CoA as substrate. Kinetic and exchange studies indicate that these thiolase reactions occur in two stages (cf. Greville and Tubbs, 1968). 

Figure 7.7 Common metabolic pathways that are involved in the biosynthesis of PHA in microorganisms. FabC malonyl-CoA acyl carrier protein (ACP) transcylase, FabD malonyl-CoA-ACP transacylase, FabG 3-ketoacyl-CoA reductase, PhaA P-ketothiolase, PhaB NAOH-dependent acetoacetyl-CoA reductase, PhaC polyhydroxyalkanoates synthase, PhaG 3-hydroxyacyl-ACP GoA transferase, PhaJ (R)-enoyl-GoA hydratase and TCA tricarboxylic acid...

Mitochondrial P-oxidation is subject to several possible intramitochondrial controls (reviewed ). Here, we will consider control exerted at the levels of the [NAD /[NADH] and [acyl-CoA]/[CoASH] ratios. In cells, the [ATP]/[ADP]-i-[Pi] ratio is fairly constant since the rate of ATP synthesis may not be directly controlled by this ratio. The [NAD /[NADH] and the [acyl-CoA]/[CoASH] sensitivities are consequences of the co-factor requirement of the 3-hydroxyacyl-CoA dehydrogenases or the CoASH requirement of the carnitine palmitoyl transferase II or other carnitine acyl transferases, for the thiolytic cleavage of 3-ketoacyl-CoA and for the transfer of acyl groups from car-... 

Acyl carrier protein (ACP) Acetyl-CoA-ACP transacetylase (AT) j3-Ketoacyl-ACP synthase (KS) Malonyl-CoA-ACP transferase (MT) )3-Ketoacyl-ACP reductase (KR) j8-Hydroxyacyl-ACP dehydratase (HD) Enoyl-ACP reductase (ER)... 

The entire sequence is described in exquisite detail by Smith et al. (2003 see Figure 2.5). The first step is the sequential transfer of the primer, usually acetyl-CoA, to the serine residue of the acyl transferase, then to the ACP, and finally to (3-ketoacyl synthase. The chain extender substrate, usually malonyl-CoA, is transferred via the serine residue of the acyl transferase to ACP. Condensation is accomplished by (3-ketoacylsynthase, aided by the energetically-favourable decarboxylation of the malonyl residue,... 

Abbreviations FASN, fatty acid synthase ACC, acetyl-CoA-carboxylase ACL, ATP-citrate lyase NADPH, nicotinamide adenine dinucleotide phosphate MAT, malonyl acetyl transferases KS, ketoacyl synthase KR, p-ketoacyl reductase DH, p-hydroxyacyl dehydratase ER, enoyl reductase TE, thioesterase ACP, acyl carrier protein VLCFA, very long chain fatty acids ELOVL, elongation of very long chain fatty acids SCDl, stearoyl-CoA desaturase-1 AMPK, AMP-activated kinase ME, malic enzyme FASKOL, liver-specific deletion of FAS PPARa, Peroxisome Proliferator-Activating Receptor alpha HMG-CoA, 3-hydroxy-3-methyl-glutaryl-CoA SREBP, sterol response element binding protein SIP, site-one protease S2P, site-two... 

---