Acetyl-CoA transferase

Much of the endogenous lipid that is eventually used by peripheral tissues is transported in the form of water-soluble ketone bodies, the two most important being jS-hydroxybutyrate and acetoacetate. The metabolic pathway of ketone body formation and its relationship to cholesterol biosynthesis is shown in Fig. 4.10. Four enzymes are Involved in the formation of ketone bodies, namely acetyl-CoA transferase (also known as thiolase), hydroxymethylglutaryl-CoA synthase (HMG-CoA synthase), hydroxymethyl-glutaryl-CoA lyase (HMG-CoA lyase) and jS-hy-droxybutyrate dehydrogenase. Tbe last of these catalyses the interconversion of the two principal ketone bodies. All four enzymes are present in liver, the principal site of ketone body formation. Acyl-CoAs are unable to pass through the plasmalemma, and HMG-CoA lyase thus controls the release of ketone... 

With the recognition of acetyl-CoA and its importance in metabolism, Ochoa s laboratory turned to important questions of fatty acid metabolism, among them the identification of the enzymes, crotonase and acetyl-CoA transferase. The latter is closely related to Ochoa s most outstanding contribution in this area the metabolism of propionic acid, a compound produced by oxidation of odd-numbered fatty acids and certain amino acids. 

In extrahepatic tissues, acetoacetate is activated to acetoacetyl-CoA by succinyl-CoA-acetoacetate CoA transferase. CoA is transferred from succinyl-CoA to form acetoacetyl-CoA (Figure 22-8). The acetoacetyl-CoA is split to acetyl-CoA by thiolase and oxidized in the citric acid cycle. If the blood level is raised, oxidation of ketone bodies increases until, at a concentration of approximately 12 mmol/L, they saturate the oxidative machinery. When this occurs, a large proportion of the oxygen consumption may be accounted for by the oxidation of ketone bodies. 

Production of Malonyl-CoA for the Fatty Acid Biosynthesis. Acetyl-CoA serves as a substrate in the production of malonyl-CoA. There are several routes by which acetyl-CoA is supplied to die cytoplasm. One route is the transfer of acetyl residues from the mitochondrial matrix across the mitochondrial membrane into the cyto-plasm. This process resembles a fatty acid transport and is likewise effected with the participation of carnitine and the enzyme acetyl-CoA-camitine transferase. Another route is the production of acetyl-CoA from citrate. Citrate is delivered from the mitochondria and undergoes cleavage in the cytoplasm by the action of the enzyme ATP-citrate lyase ... 

Sanfilippo C MPS IIIC Acetyl CoA glucosamine N-acetyl transferase Heparan sulfate... 

Figure 7.17 The pathway of ketone body oxidation hydroxybutyrate to acetyl-CoA. Hydroxybutyrate is converted to acetoacetate catalysed by hydroxybutyrate dehydrogenase acetoacetate is converted to acetoacetyl-CoA catalysed by 3-oxoacid transferase and finally acetoacetyl-CoA is converted to acetyl-CoA catalysed by acetyl-CoA acetyltransferase, which is the same enzyme involved in synthesis of acetoacetyl-CoA.

Figure 7.18 Oxoacid transferase is the key reaction in acetoacetate oxidation. The reaction produces acetoacetyl-CoA and succinate the former produces the substrate acetyl-CoA, and the latter produces the co-substrate, oxaloacetate, for the first reaction in the Krebs cycle.

Spatially, the enzyme activities are arranged into three different domains. Domain 1 catalyzes the entry of the substrates acetyl CoA and malonyl CoA by [ACPj-S-acetyltransferase [1] and [ACPJ-Smalonyl transferase [2] and subsequent condensation of the two partners by 3-oxoacyl-[ACP] synthase [3]. Domain 2 catalyzes the conversion of the 3-0X0 group to a CH2 group by 3-oxoacyl-[ACP]-reductase [4], 3-hydroxyacyl-[ACP -dehydratase [5], and enoyl-[ACP]-re-... 

Degradation of acetoacetate to acetyl CoA takes place in two steps (not shown). First, acetoacetate and succinyl CoA are converted into acetoacetyl CoA and succinate (enzyme 3-oxoacid-CoA transferase 2.8.3.5). Acetoacetyl CoA is then broken down by p-oxidation into two molecules of acetyl CoA (see p. 164), while succinate can be further metabolized via the tricarboxylic acid cycle. 

Histone acetyltransferases (H ATs) catalyze the transfer of an acetyl moiety from acetyl-CoA to the E-amino group of certain lysine residues within core histone proteins. This transferase reaction produces acetylated histones and the deacetylated cofactor CoA-SH. As HATs are important enzymes in the regulation of gene expression, there are also a number of assays available to detect acetyltransferases activity. 

The processes involved in neurochemical transmission in a cholinergic neuron are shown in Figure 9.2. The initial substrates for the synthesis of acetylcholine are glucose and choline. Glucose enters the neuron by means of facilitated transport. There is some disagreement as to whether choline enters cells by active or facilitated transport. Pyruvate derived from glucose is transported into mitochondria and converted to acetylcoenzyme A (acetyl-CoA). The acetyl-CoA is transported back into the cytosol. With the aid of the enzyme choline acetyl-transferase, acetylcholine is synthesized from acetyl-CoA and choline. The acetylcholine is then transported into and stored within the storage vesicles by as yet unknown mechanisms. 

In cases of missing //-hexosaminidase activity (Sandhoff disease), the detected acetyl CoA a-glucosaminide N-acetyltransferase activity will be low because liberation of the fluorophore is the rate-limiting step. Therefore, low measured activity of acetyl-transferase with normal / -galaclosidase activity should always trigger an assessment of the //-hexosaminidase activity from the same material. In contrast, missing jS-hex-osamindase A activity (Tay-Sachs disease) does not impede the assay. 

Figure 3.8 One complete cycle and the first step in the next cycle of the events during the synthesis of fatty acids. ACP = acyl carrier protein, a complex of six enzymes i.e. acetyl CoA-ACP transacetylase (AT) malonyl CoA-ACP transferase (MT) /3-keto-ACP synthase (KS) /J-ketoacyl-ACP reductase (KR) / - hydroxyacyl-ACP-dehydrase (HD) enoyl-ACP reductase (ER).

In extraliepatic tissues, d-/3-hydroxybutyrate is oxidized to acetoacetate by o-/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 P-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. 

One enzyme regulated by AMPK is acetyl-CoA carboxylase, which produces malonyl-CoA, the first intermediate committed to fatty acid synthesis. Malonyl-CoA is a powerful inhibitor of the enzyme carnitine acyl-transferase I, which starts the process of ]3 oxidation by transporting fatty acids into the mitochondrion (see Fig. 17-6). By phosphorylating and inactivating acetyl-CoA carboxylase, AMPK inhibits fatty acid synthesis while relieving the inhibition (by malonyl-CoA) of )3 oxidation (Fig. 23-37). 

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