Acetyl-SCoA

Detoxifica.tlon. Detoxification systems in the human body often involve reactions that utilize sulfur-containing compounds. For example, reactions in which sulfate esters of potentially toxic compounds are formed, rendering these less toxic or nontoxic, are common as are acetylation reactions involving acetyl—SCoA (45). Another important compound is. Vadenosylmethionine [29908-03-0] (SAM), the active form of methionine. SAM acts as a methylating agent, eg, in detoxification reactions such as the methylation of pyridine derivatives, and in the formation of choline (qv), creatine [60-27-5] carnitine [461-06-3] and epinephrine [329-65-7] (50). 

To render this system more effective, it must be coupled with the regeneration of acetyl-SCoA from HSCoA and acetyl phosphate under catalysis by phosphotransacetylase (PTA) (Fig. 19). 

Fig. 19. Reaction scheme for the electrochemically driven enzymatic carboxylation of acetyl-SCoA to form pyruvic acid...

Note that this overall reaction requires three coenzymes that we encountered as metabolites of vitamins in chapter 15 NAD+, derived from lucotiiuc acid or nicotinamide FAD, derived from riboflavin and coenzyme A(CoASH), derived from pantothenic acid. In the overall process, acetyl-SCoA is oxidized to two molecules of carbon dioxide with the release of CoASH. Both NAD+ and FAD are reduced to, respectively, NADH and FADH2. Note that one molecule of guanosine triphosphate, GTP, functionally equivalent to ATP, is generated in the process. 

As noted earlier, coenzymes are frequently altered structurally in the course of an enzymatic reaction. However, they are usually reconverted to their original structure in a subsequent reaction, as opposed to being further metabolized. One turn of the citric acid cycle converts NAD+ into NADH, FAD into FADH2, and acetyl-SCoA into CoASH. Coenzyme A is consumed in the metabolism of pyruvate (see below) but regenerated in the citric acid cycle. Both NADH and FADH2 are reconverted into NAD+ and FAD by the electron transport chain. 

In this reaction, pyruvic acid is oxidized to carbon dioxide with formation of acetyl-SCoA and NAD+ is reduced to NADH. As noted in chapter 15, this reaction requires the participation of thiamine pyrophosphate as coenzyme. Here too the NADH formed is converted back to NAD+ by the electron transport chain. As noted above, the acetyl-SCoA is consumed by the citric acid cycle and CoASH is regenerated. 

We should recognize that the citric acid cycle is catalytic. Specifically, the molecule that is required to condense with acetyl-SCoA in the first step of the cycle is regenerated in the last step. In principle therefore, the cycle is capable of consuming acetyl-SCoA and producing carbon dioxide endlessly as it turns. Here is a schematic... 

First, the conversion of pyruvate to acetyl-SCoA produces one molecule of NADH. Coupling the oxidation of the NADH to the electron transport chain will generate... 

We still need to consider the outcome of converting the two molecules of acetyl-SCoA to carbon dioxide and water via the citric acid cycle. Each of these will yield a total 12 ATPmolecules one from a specific reaction in the cycle, nine from the oxidation of the three molecules of NADH, and two from the oxidation of one molecule of FADH2. So the two molecules of acetyl-SCoA will yield a total of 24 ATP molecules from two turns of the citric acid cycle. That brings the grand total to 14 - - 24 = 38 ATP molecules per molecule of glucose converted to carbon dioxide and water ... 

Acetylcholine is synthesized from choline and acetyl-SCoA in a reaction catalyzed by choline acetyltransferase ... 

Considerable confusion is possible because of the way in which biochemists use abbreviated names and formulas for the acyl derivatives of coenzyme A. To emphasize the vital —SH group, coenzyme A is usually written as CoASH. However, the acyl derivatives most often are called acetyl CoA and the like, not acetyl SCoA, and you could well get the erroneous impression that the sulfur has somehow disappeared in forming the acyl derivative. We will include the sulfur in formulas such as CH3COSCoA, but use the customary names such as acetyl CoA without including the sulfur. To make clear that CoA does not contain cobalt, CoA is printed in this text in boldface type. 

Similarly, the pyruvate (oxidase) dehydrogenase complex (PYOX) can be activated directly by electrogenerated methyl viologen radical cations (MV" ) as mediator. Thus, the naturally PYOX-catalyzed oxidative decarboxylation of pyruvic acid in the presence of coenzyme A (HSCoA) to give acetylcoenzyme A (acetyl-SCoA) (see section on oxidases) can be reversed. In this way, electroenzymatic reductive carboxylation of acetyl-SCoA is made possible (Fig. 15). 

To render this system more effective, it must be coupled with the regeneration of acetyl-SCoA from HSCoA and acetyl phosphate under catalysis by phosphotransacetylase (PTA). A turnover number of 500 for PYOX was obtained after 50 h, at which point a saturation occurred and the reaction stopped. Under the reaction conditions, between 0.55 and 0.98 pmol of pyruvic acid was obtained [72]. 

Figure 15. Electroenzymatic reductive carboxylation of acetyl-SCoA to give pyruvate.

Pyruvate dehydrogenase complex Pyruvate + CoASH + NAD" acetyl-SCoA + CO2 + NADH -E dephosphorylated... 

E. Acetylation N-acetyltransferases Aromatic amines sulphonamides RNH2 + acetyl SCoA RNHCOCH3 + CoASH where RNH2 is a xenobiotic containing an amino group... 

Aklanonic acid is synthesized via the condensation of nine Cj units derived from mal-onyl-SCoA on a propionyl starter moiety (124,126,236,247,299,304,310). Malonyl-SCoA, the primary precursor of anthracyclinone biosynthesis, is synthesized in Sfrepto-myces sp. strain C5 by acetyl-SCoA carboxylase (318), as expected from the results of K3-labeling experiments (232-234). 

This type of stoichiometry is obvious and is tacitly assumed in any discussion of metabolism. It is mentioned explicitly here only for the sake of completeness. For example, 1 /imole of acetyl-SCoA will condense with 1 /zmole of oxaloacetate to form 1 //mole of citrate. Summation of such reaction stoichiometries leads to carbon balances and similar stoichiometries of sequences thus, 1 /imole of glucose can be converted to 2 //moles of lactate or 6 jumoles of CO2. 

Oxidation-reduction coupling between sequences, usually mediated by TPN, is as fixed by the chemistry of the sequences involved as are simple reaction stoichiometries of the type just discussed. Thus if the 14 //moles of TPNH required for the conversion of 8 //moles of acetyl-SCoA to 1 //mole of palmitate are supplied by the oxidation of glucose-6-P to ribulose-5-P and CO2, 7 //moles of CO2 will be produced. If the ribu-lose-5-P is quantitatively reconverted to glucose-6-P by the reactions of the pentose phosphate cycle, the net utilization of glucose-6-P wiU be 1.17 //moles per micromole of palmitate synthesized. 

It was evident from early studies that in the presence of CoASH, ATP could in some way be used to activate acetate so that it will acetylate sulfanilamide (7) and choline (8). Chou and Lipmann (9) succeeded in partially purifying the enzyme(s) responsible for this activation from pigeon-liver extracts and they concluded that the phosphate bond energy of ATP is utilized to bring about the synthesis of acetyl coenzyme A (acetyl-SCoA) however, the mechanism of this activation remained obscure. The nature of the over-all process was further elucidated through the experiments of Lipmann et al. (10) who demonstrated that ATP, CoASH, and acetate react to form acetyl-SCoA, AMP, and inorganic pyrophosphate (P-P) in stoichiometric amounts [reaction (4)]. They also demonstrated that the reaction is freely reversible. More recently, the studies of Jones et al. (11) have indicated that the mechanism of this conversion is as follows ... 

In view of the above experiments on acetyl-SCoA formation, it might be... 

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