Acetyl coenzyme acetate

The form in which acetate is used in most of its important biochemical reactions is acetyl coenzyme A (Figure 26 la) Acetyl coenzyme A is a thwester (Section 20 13) Its for matron from pyruvate involves several steps and is summarized m the overall equation... 

The introduction to Section 26 8 pointed out that mevalonic acid is the biosynthetic pre cursor of isopentenyl pyrophosphate The early steps m the biosynthesis of mevalonate from three molecules of acetic acid are analogous to those m fatty acid biosynthesis (Sec tion 26 3) except that they do not involve acyl earner protein Thus the reaction of acetyl coenzyme A with malonyl coenzyme A yields a molecule of acetoacetyl coenzyme A... 

Chemists and biochemists And it convenient to divide the principal organic substances present m cells into four mam groups carbohydrates proteins nucleic acids and lipids Structural differences separate carbo hydrates from proteins and both of these are structurally distinct from nucleic acids Lipids on the other hand are characterized by a physical property their solubility m nonpolar solvents rather than by their structure In this chapter we have examined lipid molecules that share a common biosynthetic origin m that all their carbons are derived from acetic acid (acetate) The form m which acetate occurs m many of these processes is a thioester called acetyl coenzyme A... 

The acetyl-coenzyme A decarbonylase synthase complex contains five polypeptide sub-nnits and in acetate-degrading methanotrophs, such as Methanosarcina barkeri and M. thermophila, catalyzes the formation of methane and COj from acetyl-CoA ... 

The degradation of vinyl chloride and ethene has been examined in Mycobacterium sp. strain JS 60 (Coleman and Spain 2003) and in Nocardioides sp. strain JS614 (Mattes et al. 2005). For both substrates, the initially formed epoxides underwent reaction with reduced coenzyme M and, after dehydrogenation and formation of the coenzyme A esters, reductive loss of coenzyme M acetate resulted in the production of 5-acetyl-coenzyme A. The reductive fission is formally analogous to that in the glutathione-mediated reaction. 

All polyketides use the same general mechanism for chain elongation. Acetyl coenzyme A provides acetate (C2) units, which are condensed by a ketosynthase (KS). This in turn catalyzes condensation of the growing chain onto an acyl carrier protein (ACP), as generalized in Fig. 1.4. Enzymes such as ketoreductase (KR), enoyl reductase (ER), and dehydratase (DH) establish the oxidation state of caibon during translation, imparting structural diversity. Successive translation of each module leads to a chain of the required length that is eventually passed to thioeste-rase (TE), which releases the chain as a free acid or lactone. 

Chenoweth believes that an explanation of the above results may lie in the reactions occurring before the entrance of fatty acid metabolites into the citric acid cycle. Activated acetate, i.e. acetyl coenzyme A (AcCoA) is the end-product of fatty acid metabolism prior to its condensation with oxalacetate to form citrate. Possibly fluoro-fatty acids behave like non-fluorinated fatty acids. The end-product before the oxalacetate condensation could be the same for all three fluorinated inhibitors, viz. fluoroacetyl coenzyme A (FAcCoA). Fluorocitrate could then be formed by the condensation of oxalacetate with FAcCoA, thereby blocking the citric acid cycle. The specificity of antagonisms must therefore occur before entrance of the metabolites into the citric acid cycle. 

ATP and magnesium were required for the activation of acetate. Acetylations were inhibited by mercuric chloride suggesting an SH group was involved in the reaction either on the enzyme or, like lipoic acid, as a cofactor. Experiments from Lipmann s laboratory then demonstrated that a relatively heat-stable coenzyme was needed—a coenzyme for acetylation—coenzyme A (1945). The thiol-dependence appeared to be associated with the coenzyme. There was also a strong correlation between active coenzyme preparations and the presence in them of pantothenic acid—a widely distributed molecule which was a growth factor for some microorganisms and which, by 1942-1943, had been shown to be required for the oxidation of pyruvate. 

This is a complex molecule, made up of an adenine nucleotide (ADP-3 -phosphate), pantothenic acid (vitamin B5), and cysteamine (2-mercaptoethylamine), but for mechanism purposes can be thought of as a simple thiol, HSCoA. Pre-eminent amongst the biochemical thioesters is the thioester of acetic acid, acetyl-coenzyme A (acetyl-CoA). This compound plays a key role in the biosynthesis and metabolism of fatty acids (see Sections 15.4 and 15.5), as well as being a building block for the biosynthesis of a wide range of natural products, such as phenols and macrolide antibiotics (see Box 10.4). 

In nature, the biologically active form of acetic acid is acetyl-coenzyme A (acetyl-CoA) (see Box 7.18). Two molecules of acetyl-CoA may combine in a Claisen-type reaction to produce acetoacetyl-CoA, the biochemical equivalent of ethyl acetoacetate. This reaction features as the start of the sequence to mevalonic acid (MVA), the precursor in animals of the sterol cholesterol. Later, we shall see another variant of this reaction that employs malonyl-CoA as the nucleophile (see Box 10.17). 

Soluble cytoplasmic sulfotrans-ferases conjugate activated sulfate (3 -phosphoadenine-5 -phosphosulfate) with alcohols and phenols. The conjugates are acids, as in the case of glucuronides. In this respect, they differ from conjugates formed by acetyltransfe-rases from activated acetate (acetyl-coenzyme A) and an alcohol or a phenol... 

Alkaloid biosynthesis needs the substrate. Substrates are derivatives of the secondary metabolism building blocks the acetyl coenzyme A (acetyl-CoA), shikimic acid, mevalonic acid and 1-deoxyxylulose 5-phosphate (Figure 21). The synthesis of alkaloids starts from the acetate, shikimate, mevalonate and deoxyxylulose pathways. The acetyl coenzyme A pathway (acetate pathway) is the source of some alkaloids and their precursors (e.g., piperidine alkaloids or anthraniUc acid as aromatized CoA ester (antraniloyl-CoA)). Shikimic acid is a product of the glycolytic and pentose phosphate pathways, a construction facilitated by parts of phosphoenolpyruvate and erythrose 4-phosphate (Figure 21). The shikimic acid pathway is the source of such alkaloids as quinazoline, quinoline and acridine. 

The biosynthesis of steroids is complex, as one wonld expect since all the compounds in this group must be derived from a single precnrsor (cholesterol (5.4)). The primary sonrce of all the compounds involved in steroid synthesis is acetate, in the form of acetyl-coenzyme A. Cholesterol, besides being ingested in food, is synthesized in large amounts, and an adnlt human contains about 250 g of cholesterol. In contrast, the steroid hormones are produced at the milligram level or lower. 

Problem 16.47 In living cells, alcohols are converted to acetate esters (acetylated) by the thiol ester CH,COS—(CoA), acetyl coenzyme A. CoA is an abbreviation for a very complex piece. Illustrate this reaction using glycerol-1-phosphate. 4... 

Acetylcholine is an ester composed of acetate (from acetyl coenzyme A) and choline (either synthesized de novo or taken in the diet as lecithin). The enzyme choline acetyl transferase catalyzes the reaction to form Ach. The breakdown of Ach back to acetate and choline, which will terminate its activity, is catalyzed by the enzyme acetylcholineesterase (Achase). 

S ATP -P acetate <1-18> (<8> acetate kinase/phosphotransacetylase, major role of this two-enzyme sequence is to provide acetyl coenzyme A which may participate in fatty acid synthesis, citrate formation and subsequent oxidation [1] <3> function in the metabolism of pyruvate or synthesis of acetyl-CoA coupling with phosphoacetyltransacetylase [15] <11> function in the initial activation of acetate for conversion to methane and CO2 [19] <10> key enzyme and responsible for dephosphorylation of acetyl phosphate with the concomitant production of acetate and ATP [30]) (Reversibility r <1-18> [1, 2, 5-21, 24-27, 29-33]) [1, 2, 5-21, 24-27, 29-33]... 

FIGURE 16-3 Coenzyme A (CoA). A hydroxyl group of pantothenic acid is joined to a modified ADP moiety by a phosphate ester bond, and its carboxyl group is attached to /3-mercaptoethylamine in amide linkage. The hydroxyl group at the 3 position of the ADP moiety has a phosphoryl group not present in free ADP. The —SH group of the mercaptoethylamine moiety forms a thioester with acetate in acetyl-coenzyme A (acetyl-CoA) (lower left). 

R and S isomers of HDT]acetic acid were synthesized by chemical and enzymatic methods that yield products of known stereochemistry.1819 The two isomers were then distinguished by using the following ingenious enzymatic assays. The acetic acid was first converted to acetyl-coenzyme A (by a reaction of the carboxyl group—and not the methyl—of acetic acid). The acetyl-coenzyme A was then condensed with glyoxylate to form malate in an essentially irreversible reaction catalyzed by malate synthase (equation 8.27). The crucial feature of this reaction is that it is subject to a normal kinetic isotope effect, so that more H than D... 

Steroids are members of a large class of lipid compounds called terpenes. Using acetate as a starting material, a variety of organisms produce terpenes by essentially Lire same biosynlheLic scheme (Fig. 3). The sell-condensation of two molecules of acetyl coenzyme A (CoA) forms acetoacetyl CoA. Condensation of acetoacetyl CoA with a third molecule of acetyl CoA, then followed by an NADPH-mediated reduction of the thioester moiety produces mevalonic acid (22). Phosphorylation of (22) followed by concomitant decarboxylation and dehydration processes... 

Acetyl-CoA. Acetyl-coenzyme A, a high-energy ester of acetic acid that is important both in the tricarboxylic acid cycle and in fatty acid biosynthesis. 

Three molecules of acetyl-coenzyme A are used to form mevalonic acid. Two molecules combine initially in a Claisen condensation to give acetoacetyl-CoA, and a third is incorporated via a stereospecific aldol addition giving the branched-chain ester P-hydroxy-P-methylglutaryl-CoA (HMG-CoA) (Figure 5.4). This third acetyl-CoA molecule appears to be bound to the enzyme via a thiol group, and this linkage is subsequently hydrolysed to form the free acid group of HMG-CoA. In the acetate... 

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