Pyruvate carbon atoms from glucose

As stated earlier, glucose can be formed from pyruvate (Section 16.3). However, the formation of acetyl CoAfrom pyruvate is an irreversible step in animals and thus they are unable to convert acetyl Co A back into glucose. The oxidative decarboxylation of pyruvate to acetyl CoA commits the carbon atoms of glucose to two principal fates oxidation to CO2 by the citric acid... 

Each mole of glucose that goes through the Cori cycle costs the liver 6 ATP equivalents. If the Cori cycle were perfect and there were an endless supply of ATP, liver could supply glucose equivalents forever just using the same carbon atoms (6 in as lactate, 6 out as glucose). However, some of the lactate (pyruvate) in the nonliver tissues is burned to C02 by the TCA cycle in die muscle and other tissues. It s this pool that must be replaced by fresh glucose from liver. 

Key PEP-CK = PEP carboxykinase this enzyme begins the re-cycling of carbon atoms derived from amino acids (via pyruvate, 2-OG or OAA) or lactate (via pyruvate) to glucose (gluconeogenesis). 

In discussing the studies of Brechot et al. (24) and Peynaud et al. (25), Kunkee (I) found it odd that bacteria which ordinarily produce d or DL-lactic acid from glucose produce L-lactic acid in wine as a result of malo-lactic fermentation. Peynaud et al. (26) reported that organisms which produced only D-lactic acid from glucose produced only L-lactic acid from L-malic acid. He postulated further that the malo-lactic fermentation pathway has no free pyruvic acid as an intermediate because the optical nature of L-malic acid would be lost when it was converted to pyruvic acid since pyruvic acid has no asymmetric carbon atom. Therefore, if pyruvic acid were the intermediate, one would expect d, l, or DL-lactic acid as the end product whereas L-lactic acid is always obtained. These results lend considerable support to the hypothesis that free pyruvic... 

The anomeric carbon of glucose ends up in position 3 (methyl) of pyruvate and then in the methyl group of acetyl-CoA. From this point on, follow the starred carbon atom marked by an asterisk in Figure 18.7. 

It is important to note that animals are unable to effect the net synthesis of glucose from fatty acids. Specifically, acetyl CoA cannot be converted into pyruvate or oxaloacetate in animals. The two carbon atoms of the acetyl group of acetyl CoA enter the citric acid cycle, but two carbon atoms leave the cycle in the decarboxylations catalyzed by isocitrate dehydrogenase and a-ketoglutarate dehydrogenase. Consequently, oxaloacetate is regenerated, but it is not formed de novo when the acetyl unit of acetyl CoA is oxidized by the citric acid cycle. In contrast, plants have two additional enzymes enabling them to convert the carbon atoms of acetyl CoA into oxaloacetate (Section 17.4.). 

Thus, citrate not only modulates the rate of fatty acid synthesis but also provides carbon atoms for the synthesis. The oxaloacetate formed from pyruvate may eventually be converted (via malate) to glucose by the gluconeogenic pathway. The glucose oxidized via the pentose phosphate pathway augments fatty acid synthesis by providing NADPH. Pyruvate generated from oxaloacetate can enter mitochondria and be converted to oxaloacetate, which is required for the formation of citrate. 

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. 

Figure 2. Time course of the change in the fractional enrichment of glutamate, aspartate, and alanine carbon atoms in hearts perfused with 5 mM glucose and 1 mM [S- C] pyruvate. The experimentally determined values for the fractional enrichment of alanine C-3 (YAL3) is represented by the open circles, that of glutamate C-4 (YG4) is represented by the open squares, while mean values for those of glutamate C-2 and C-3 (YG2, YG3) are represented by open triangles, and mean values for those of aspartate C-2 and C-3 (YA2, YA3) are represented by closed circles. The lines shown are derived from the optimized fit of the mathematical model to the data points.

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