Gluconeogenesis Fatty acids

The citric acid cycle is amphibolic, since in addition to oxidation it is important in the provision of carbon skeletons for gluconeogenesis, fatty acid synthesis, and interconversion of amino acids. 

Triose phosphate isomerase (TPI) catalyzes the interconversion of glyceralde-hyde-3-phosphate and dihydoxyacetone phosphate and has an important role in glycolysis, gluconeogenesis, fatty acid synthesis, and the hexose monophosphate pathway. Red blood cell TPI activity measured in vitro is approximately 1000 times that of Hx, the least active glycolytic enzyme. TPI is a dimer of identical subunits, each of molecular weight 27,000, and does not utilize cofactors or metal ions. Posttranslational modification of one or both subunits may occur by deamidination, resulting in multiple forms of the enzymes and creating a complex multibanded pattern on electrophoresis. 

GLUCONEOGENESIS FATTY ACID OXIDATION PROTEIN DEGRADATION KETONE BODY FORMATION... 

Although, as discussed below (section 5.7), oxaloacetate is the precursor for gluconeogenesis, fatty acids and other compounds that give rise to acetyl CoA or acetoacetate cannot be used for net synthesis of glucose. As can be seen from Figure 5.18, although two carbons are added to the cycle by acetyl CoA, two carbons are lost as carbon dioxide in each turn of the cycle. Therefore, when acetyl CoA is the substrate, there is no increase in the pool of citric acid cycle intermediates, and therefore oxaloacetate cannot be withdrawn for gluconeogenesis. 

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.

In the following sections we will deal with three specific metabolic processes—gluconeogenesis, fatty acid oxidation, and lipogenesis— which are regulated in part by the compartmentation of key enzyme systems. 

Step 1 of Figure 29.13 Carboxylation Gluconeogenesis begins with the carboxyl-afion of pyruvate to yield oxaloacetate. The reaction is catalyzed by pyruvate carboxylase and requires ATP, bicarbonate ion, and the coenzyme biotin, which acts as a carrier to transport CO2 to the enzyme active site. The mechanism is analogous to that of step 3 in fatty-acid biosynthesis (Figure 29.6), in which acetyl CoA is carboxylated to yield malonyl CoA. 

Biomolecules are synthesized as well as degraded, but the pathways for anabolism and catabolism are not the exact reverse of one another. Fatty acids are biosynthesized from acetate by an 8-step pathway, and carbohydrates are made from pyruvate by the 11-step gluconeogenesis pathway. 

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 citric acid cycle is not only a pathway for oxidation of two-carbon units—it is also a major pathway for interconversion of metabolites arising from transamination and deamination of amino acids. It also provides the substtates for amino acid synthesis by transamination, as well as for gluconeogenesis and fatty acid synthesis. Because it fimctions in both oxidative and synthetic processes, it is amphibolic (Figure 16—4). 

Cj5 and Cj7 fatty acids are found particularly in the lipids of ruminants. Dietary odd-carbon fatty acids upon oxidation yield propionate (Chapter 22), which is a substrate for gluconeogenesis in human liver. 

Increased fatty acid oxidation is a characteristic of starvation and of diabetes meUims, leading to ketone body production by the Ever (ketosis). Ketone bodies are acidic and when produced in excess over long periods, as in diabetes, cause ketoacidosis, which is ultimately fatal. Because gluconeogenesis is dependent upon fatty acid oxidation, any impairment in fatty acid oxidation leads to hypoglycemia. This occurs in various states of carnitine deficiency or deficiency of essential enzymes in fatty acid oxidation, eg, carnitine palmitoyltransferase, or inhibition of fatty acid oxidation by poisons, eg, hypoglycin. 

In adipose tissue, the effect of the decrease in insulin and increase in glucagon results in inhibition of lipo-genesis, inactivation of lipoprotein lipase, and activation of hormone-sensitive lipase (Chapter 25). This leads to release of increased amounts of glycerol (a substrate for gluconeogenesis in the liver) and free fatty acids, which are used by skeletal muscle and liver as their preferred metabolic fuels, so sparing glucose. 

Kidney Excretion and glu-coneogenesis Gluconeogenesis Free fatty acids, lactate, glycerol Glucose Glycerol kinase, phosphoenolpyruvate carboxy kinase... 

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