Gluconeogenesis connections

Gluconeogenesis in the liver can be fueled by molecules other than pyruvate or lactate. Alanine, a product of protein degradation, yields pyruvate by simple transamination, and this pyruvate can be converted 

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The citric acid cycle is the final common pathway for the aerobic oxidation of carbohydrate, lipid, and protein because glucose, fatty acids, and most amino acids are metabolized to acetyl-CoA or intermediates of the cycle. It also has a central role in gluconeogenesis, lipogenesis, and interconversion of amino acids. Many of these processes occur in most tissues, but the hver is the only tissue in which all occur to a significant extent. The repercussions are therefore profound when, for example, large numbers of hepatic cells are damaged as in acute hepatitis or replaced by connective tissue (as in cirrhosis). Very few, if any, genetic abnormalities of citric acid cycle enzymes have been reported such ab-normahties would be incompatible with life or normal development. 

The organization of glycolysis and gluconeogenesis as a series of connected metabolic pools makes it possible for most of the same enzymes to function in both directions. Only the reactions connecting the metabolic pools require different enzymes and a coupling to the ATP-ADP system to make them thermodynamically feasible in the direction of gluconeogenesis. 

Within each pool, the direction of reaction is determined by simple mass-action considerations. The direction of overall conversion (glycolysis or gluconeogenesis) depends on the rates at which the connecting reactions supply and remove materials from the pool. 

The problem of how to oxidize oxaloacetate is solved by the action of phosphoenolpyruvate carboxykinase, which we discussed in connection with gluconeogenesis (see equa-... 

Carbohydrateiand. The Main Powerhouse connects with Carbohydrateiand, which provides it with molecules that can be broken down to either be used as fuel (glycolysis) or converted to other molecules. Conversely, the Main Powerhouse, when acting in reverse (gluconeogenesis) can produce carbohydrates. 

Many aroma compounds in fruits and plant materials are derived from lipid metabolism. Fatty acid biosynthesis and degradation and their connections with glycolysis, gluconeogenesis, TCA cycle, glyoxylate cycle and terpene metabolism have been described by Lynen (2) and Stumpf ( ). During fatty acid biosynthesis in the cytoplasm acetyl-CoA is transformed into malonyl-CoA. The de novo synthesis of palmitic acid by palmitoyl-ACP synthetase involves the sequential addition of C2-units by a series of reactions which have been well characterized. Palmitoyl-ACP is transformed into stearoyl-ACP and oleoyl-CoA in chloroplasts and plastides. During B-oxi-dation in mitochondria and microsomes the fatty acids are bound to CoASH. The B-oxidation pathway shows a similar reaction sequence compared to that of de novo synthesis. B-Oxidation and de novo synthesis possess differences in activation, coenzymes, enzymes and the intermediates (SM+)-3-hydroxyacyl-S-CoA (B-oxidation) and (R)-(-)-3-hydroxyacyl-ACP (de novo synthesis). The key enzyme for de novo synthesis (acetyl-CoA carboxylase) is inhibited by palmitoyl-S-CoA and plays an important role in fatty acid metabolism. 

Generally anabolic in liver (gluconeogenesis) and catabolic in muscle, skin, lymph, adipose, and connective tissue) ... 

This reaction, which produces oxaloacetate from pyruvate, provides a connection between the amphibolic citric acid cycle and the anabolism of sugars by gluconeogenesis. On this same topic of carbohydrate anabolism, we should note again that pyruvate cannot be produced from acetyl-GoA in mammals. Because acetyl-GoA is the end product of catabolism of latty acids, we can see that mammals could not exist with fats or acetate as the sole carbon source. The intermediates of carbohydrate metabolism would soon be depleted. Garbohydrates are the principal energy and carbon source in animals (Figure 19.11), and glucose is especially critical in humans because it is the preferred fuel for our brain cells. Plants can carry out the conversion of acetyl-GoA to pyruvate and oxaloacetate, so they can exist without carbohydrates as a carbon source. The conversion of pyruvate to acetyl-GoA does take place in both plants and animals (see Section 19.3). 

Tissues which are more active in the synthesis of lipids than nucleotides require NADPH rather than ribose moieties. In such tissues, e.g. adipose tissue, the ribose 5-phosphate enters a series of sugar interconversion reactions which connect the pentose phosphate pathway with glycolysis and gluconeogenesis. These interconversion reactions constitute the non-oxidative phase of the pathway (Figure 11.14) and since oxidation is not involved, NADPH is not produced. Two enzymes catalyse the important reactions transketolase which contains thiamin diphosphate (Figure 12.3a) as its prosthetic group and transaldolase. Both enzymes function in the transfer of carbon units transketolase transfers two-carbon units and transaldolase transfers three-carbon units. The transfer always occurs from a ketose donor to an aldose acceptor. The interconversion sequence requires the oxidative phase to operate three times, i.e. three molecules of glucose 6-phosphate yield three molecules of ribulose 5-phosphate. 

Figure 2. Diagram representing anaplerotic (solid lines and shapes) and cataplerotic (dashed lines and shapes) sequences connecting the Krebs cycle to gluconeogenesis, fatty acid metabolism, and dispensible AA synthesis. Some sequences can serve both anaplerotic and cataplerotic roles, thus linked metabolites (bold) can be catabolized or synthesized. a-KG, a-ketoglutarate OAA, oxaloacetate PEP, phosphoenolpyruvate.

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