Pyruvate oxidation of. to acetyl CoA

Pyruvate must first be transported into mitochondria by a specific carrier that cotransports a proton to maintain electrical neutrality. Inside mitochondria pyruvate undergoes oxidative decarboxylation by three enzymes that function sequentially and are present as a complex known as the pyruvate dehydrogenase complex. The overall reaction is physiologically irreversible, has a high negative AG° (—8.0 kcal/mol, or —33.5 kJ/mol), and commits pyruvate to the formation of acetyl-CoA  

Coenzyme A. The terminal sulfhydryl group is the reactive group of the molecule. 

In the first reaction, pyruvate is decarboxylated by reaction with TPP bound to pyruvate dehydrogenase (Ei), with formation of a hydroxyethyl group attached to the thiazole ring of TPP  

In the fourth step, catalyzed by the same enzyme, the hydrogen atoms of the dithiol group of E2 are transferred to the FAD prosthetic group of dihydrolipoyl dehydrogenase (E3). 

In the second step, also catalyzed by pyruvate dehydrogenase, the hydroxyethyl group is transferred to the oxidized form of the lipoyl-lysyl prosthetic group of dihydrolipoyl transacetylase (E2)  

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THE OXIDATION OF PYRUVATE TO ACETYL-CoA IS THE IRREVERSIBLE ROUTE FROM GLYCOLYSIS TO THE CITRIC ACID CYCLE... 

Common Reaction Steps in the Fatty Acid Oxidation Cycle and Citric Acid Cycle Cells often use the same enzyme reaction pattern for analogous metabolic conversions. For example, the steps in the oxidation of pyruvate to acetyl-CoA and of a-ketoglutarate to succinyl-CoA, although catalyzed by different enzymes, are very similar. The first stage of fatty acid oxidation follows a reaction sequence closely resembling a sequence in the citric acid cycle. Use equations to show the analogous reaction sequences in the two pathways. 

Insulin also stimulates the storage of excess fuel as fat (Fig. 23-26). In the liver, insulin activates both the oxidation of glucose 6-phosphate to pyruvate via glycolysis and the oxidation of pyruvate to acetyl-CoA. If not oxidized further for energy production, this acetyl-CoA is used for fatty acid synthesis in the liver, and the fatty acids are exported as the TAGs of plasma lipoproteins (VLDLs) to the adipose tissue. Insulin stimulates TAG synthesis in adipocytes, from fatty acids released... 

Answer The pyruvate dehydrogenase complex can be thought of as performing five enzymatic reactions. The first three (see Fig. 16-6) catalyze the oxidation of pyruvate to acetyl-CoA and reduction of the enzyme. The last two reactions are essential to reoxidize the reduced enzyme, reducing NAD+ to NADH + H+. The moiety on the enzyme that is oxidized/reduced is the lipoamide cofactor. 

The oxidation of pyruvate to acetyl CoA is accomplished by the Pyruvate Dehydrogenase complex, a large, multi-component enzyme with three main enzyme subunits. 

Within the TCA cycle, the oxidative decarboxylation of a-ketoglutarate is catalyzed by the multisubunit a-ketoglutarate dehydrogenase complex, which contains the coenzymes thiamine-pyrophosphate, lipoate, and FAD. A similar complex, the pyruvate dehydrogenase complex (PDC), catalyzes the oxidation of pyruvate to acetyl CoA, thereby providing a link between the pathways of glycolysis and the TCA cycle (see Fig. 20.1)... 

In Al Martini s heart failure, which is caused by a dietary deficiency of the vitamin thiamine, pyruvate dehydrogenase, a-ketoglutarate dehydrogenase, and the branched chain a-keto acid dehydrogenase complexes are less functional than normal. Because heart muscle, skeletal muscle, and nervous tissue have a high rate of ATP production from the NADH produced by the oxidation of pyruvate to acetyl CoA and of acetyl CoA to COj in the TCA cycle, these tissues present with the most obvious signs of thiamine deficiency. 

S5mthesis of ATP in vitro by hssue homogenates was demonstrated in 1937 by Kalckar, who has written a historical account. " In 1941, Ochoa obtained the first reliable measurement of the P/O raho, the number of moles of ATP generated per atom of oxygen utilized in respiration. The P/O raho is also equal to the number of moles of ATP formed for each pair of electrons passing through an electron transport chain. Ochoa established that for the oxidation of pyruvate to acetyl-CoA and CO2, with two electrons passed down the mitochondrial electron transport chain, the P/O raho was 3. This value has since been confirmed many... 

Why are these isotopes important in biochemistry and medicine The isotopes we have mentioned occur at very low natural abundance , e.g. in the world around us only about 1 carbon atom in 10 (a million million) is C. However, with the advent of nuclear physics and specifically the Manhattan Project, the atomic bomb project in World War 11, radioactive isotopes started to be produced artificially, and this meant that chemical compounds could be radioactively labelled , either uniformly (e.g. in every carbon position) or selectively (i.e. with radioactive enrichment in particular positions). In the case of carbohydrate metabolism, it was possible to study the relative importance of glycolysis and PPP by comparing the release of radioactivity from glucose, specifically labelled either in carbon 1 or in carbon 6. If you look at Topic 28, you will see that in the initial reactions of the PPP the CO2 that is produced comes entirely from the Cl position. Over time, as the later molecular rearrangements come into play, C6 atoms could also eventually be released but not initially. On the other hand, if you revisit Topics 13 and 14, you will see that, because the sugar phosphate is split down the middle into two triose phosphate halves that are then handled identically, CO2 released in the oxidation of pyruvate to acetyl CoA will be derived equally from Cl and C6. This allows biochemists to assess the relative activities of PPP and glycolysis in different tissues or in the same tissue over time. This is how it was possible to estimate (Topic 28) that 30% of glucose breakdown in liver is via PPP. 

Pyruvic oxidase —oxidation of pyruvate to acetyl CoA, decarboxylation of pyruvate to acetoin, and dismutation of diacetyl to acetoin and acetate. 

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