Acetyl-coenzyme A CoA

Iron Sulfur Compounds. Many molecular compounds (18—20) are known in which iron is tetrahedraHy coordinated by a combination of thiolate and sulfide donors. Of the 10 or more stmcturaHy characterized classes of Fe—S compounds, the four shown in Figure 1 are known to occur in proteins. The mononuclear iron site REPLACE occurs in the one-iron bacterial electron-transfer protein mbredoxin. The [2Fe—2S] (10) and [4Fe—4S] (12) cubane stmctures are found in the 2-, 4-, and 8-iron ferredoxins, which are also electron-transfer proteins. The [3Fe—4S] voided cubane stmcture (11) has been found in some ferredoxins and in the inactive form of aconitase, the enzyme which catalyzes the stereospecific hydration—rehydration of citrate to isocitrate in the Krebs cycle. In addition, enzymes are known that contain either other types of iron sulfur clusters or iron sulfur clusters that include other metals. Examples include nitrogenase, which reduces N2 to NH at a MoFe Sg homocitrate cluster carbon monoxide dehydrogenase, which assembles acetyl-coenzyme A (acetyl-CoA) at a FeNiS site and hydrogenases, which catalyze the reversible reduction of protons to hydrogen gas. 

The neurotransmitter must be present in presynaptic nerve terminals and the precursors and enzymes necessary for its synthesis must be present in the neuron. For example, ACh is stored in vesicles specifically in cholinergic nerve terminals. It is synthesized from choline and acetyl-coenzyme A (acetyl-CoA) by the enzyme, choline acetyltransferase. Choline is taken up by a high affinity transporter specific to cholinergic nerve terminals. Choline uptake appears to be the rate-limiting step in ACh synthesis, and is regulated to keep pace with demands for the neurotransmitter. Dopamine [51 -61-6] (2) is synthesized from tyrosine by tyrosine hydroxylase, which converts tyrosine to L-dopa (3,4-dihydroxy-L-phenylalanine) (3), and dopa decarboxylase, which converts L-dopa to dopamine. 

Acetyl coenzyme A (acetyl CoA) is the key intermediate in food metabolism. What sugar is present in acetyl CoA ... 

The initial stages of catabolism result in the conversion of both fats and carbohydrates into acetyl groups that are bonded through a thioester link to coenzyme A. Acetyl CoA then enters the next stage of catabolism—the citric acid cycle, also called the tricarboxylic acid (TCA) cycle, or Krebs tycle, after Hans Krebs, who unraveled its complexities in 1937. The overall result of the cycle is the conversion of an acetyl group into two molecules of C02 plus reduced coenzymes by the eight-step sequence of reactions shown in Figure 29.12. 

Where two enzymes compete for the same substrate, we expect to see some form of metabolic control and in this case the concentrations of NADH and acetyl-CoA are the key controlling factors (Figure 6.44). When glucose is not available as a fuel, metabolism switches to 3- oxidation of fatty acids, which generates more than sufficient quantities of both NADH and acetyl-CoA to drive the TCA cycle and to maintain oxidative phosphorylation. Pyruvate dehydrogenase activity is suppressed and pyruvate carboxylase is stimulated by ATP, NADH and acetyl-CoA (strictly speaking by low mitochondrial ratios of ADP/ATP, NAD+/NADH and coenzyme A/acetyl-CoA), so... 

Thioesters are more reactive towards nucleophilic substitution than oxygen esters, and are widely employed in natural biochemical processes because of this property. Coenzyme A is a structurally complex thiol, and functions in the transfer of acetyl groups via its thioester acetyl coenzyme A (acetyl-CoA CH3CO-SC0A). 

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). 

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. 

Pyruvate (CH3-CO-COOH) is an intermediate metabolite, the product of carbohydrate, fat or protein metabolism. Pyruvate is the end point of glycolysis. In mitochondria, pyruvate may be oxidized to C02 and H20, reduced to acetyl coenzyme A (acetyl CoA) by PDH, or carboxylated by PC into oxaloacetate (Fig. 1.4.2). 

RGURE 13-6 Hydrolysis of acetyl-coenzyme A Acetyl-CoA is a thioester with a large, negative, standard free energy of hydrolysis Thioesters contain a sulfur atom in the position occupied by an oxygen atom in oxygen esters. The complete structure of coenzyme A (CoA, or CoASH) is shown in Rgure 8-41. 

Cellular respiration occurs in three major stages (Fig. 16-1). In the first, organic fuel molecules—glucose, fatty acids, and some amino acids—are oxidized to yield two-carbon fragments in the form of the acetyl group of acetyl-coenzyme A (acetyl-CoA). In the sec-... 

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). 

The first step has a AG0 of —0.05 kcal/mole, which is close to zero it does not occur to any great extent unless the concentrations of acetyl-coenzyme A (acetyl-CoA) and oxaloacetate are greater than the concentration of citryl-CoA. The second step, however, has a highly favorable AG0 of — 8.4 kcal/mole. When the two steps are combined, AG0 for the overall reaction is about —8.3 kcal/mole, and the equilibrium constant lies far in the forward direction. These two reactions are catalyzed by the enzyme citrate synthase, by a mechanism that ensures that they always occur together. 

The activation event Acetylcholine is synthesized from choline and acetyl coenzyme A (Acetyl-CoA) by the enzyme choline acetyltransferase (ChAT) and is immediately stored in small vesicular compartments closely attached to the cytoplasmic side of the presynaptic membranes. 

Acetylcholine is synthesized from acetyl coenzyme A (acetyl-CoA) and choline within the presynaptic terminal by the enzyme choline acetylase. The acetylcholine formed is stored in small, lightly staining synaptic vesicles that are concentrated around the synaptic contact area. The release of acetylcholine is calcium dependent. The entire content of a synaptic vesicle is released into the cleft in an all-or-none manner, where it interacts with its receptors and then is rapidly destroyed by acetylcholinesterase. Under normal circumstances, the half-life for acetylcholine in the synaptic cleft is about 1 ms. The acetylcholine is hydrolyzed to choline and acetate, and the choline is actively pumped back into the presynaptic terminal to be used to synthesize more acetylcholine. 

Practically all tissues can degrade glucose by the process of glycolysis. In this pathway, glucose is converted to two molecules of pyruvate, with the production of two ATP molecules. Two molecules of NAD+ are also reduced to NADH. Pyruvate may proceed in at least two directions toward the formation of lactate, in which case the glycolysis is anaerobic, or toward the formation of acetyl coenzyme A (acetyl-CoA) and oxidation via the Krebs cycle (also called the tricarboxylic acid cycle). In the former case, pyruvate is reduced by NADH and... 

The Krebs-citric acid cycle is the final common pathway for the oxidation of fuel molecules amino acids, fatty acids and carbohydrates. Most fuel molecules enter the cycle as a breakdown product, acetyl coenzyme A (acetyl CoA), which reacts with oxaloacetate (a four-carbon compound) to produce citrate (a six-carbon compound), which is then converted in a series of enzyme-catalysed steps back to oxaloacetate. In the process, two molecules of carbon dioxide and four energy-rich molecules are given off, and these latter are the precursors of the energy-rich molecule ATP, which is subsequently formed and which acts as the fuel source for all aerobic organisms. 

The glycolysis of glucose proceeds through several steps involving enol intermediates to afford pyruvate, which can be converted into acetyl coenzyme A (acetyl-CoA) to participate in the Krebs cycle. Kinetic and crystal structure studies point to the key role played in enzyme catalysis by the stabilization of such intermediates on binding of enolate to the metal ion(s) of the enzymes. 

The two-carbon precursor, acetyl coenzyme A (acetyl-CoA), is the initial substrate for synthesis of the carbon backbone of plant polyketides. As the name implies, polyketides are naturally occurring polymers of ketene (CH2CO) and contain alternating carbonyl and methylene groups derived from the acetate pathway. Polyketides and their derivatives are ubiquitous and are found in all organisms known to produce secondary metabolites. Because of their immense stmctural diversity, a... 

Only a fraction of the energy of glucose is released in its anaerobic conversion into ethanol or lactate. Much more energy can be extracted aerobically by means of the citric acid cycle and the electron-transport chain. The entry point to this oxidative pathway is acetyl coenzyme A (acetyl CoA), which is formed inside mitochondria by the oxidative decarboxylation of pyruvate. 

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