Citric acid cycle in metabolism

The Central Role of the Citric Acid Cycle in Metabolism... 

The central role of the citric acid cycle in metabolism The citric acid cycle plays a central role in metabolism. It is the first part of aerobic metabolism it is also amphibolic (both catabolic and anabolic). 

Enzymes work by bringing reactant molecules together, holding them, in the orientation necessary for reaction, and providing any necessary acidic or basic sites to catalyze specific steps. As an example, let s look at citrate synthase, an enzyme that catalyzes the aldol-like addition of acetyl CoA to oxaloacetate to give citrate. The reaction is the first step in the citric acid cycle, in which acetyl groups produced by degradation of food molecules are metabolized to yield C02 and H20. We ll look at the details of the citric acid cycle in Section 29.7. 

Theoretically, a fall in concentration of oxaloacetate, particularly within the mitochondria, could impair the ability of the citric acid cycle to metabolize acetyl-CoA and divert fatty acid oxidation toward ketogenesis. Such a fall may occur because of an increase in the [NADH]/[NAD+] ratio caused by increased P-oxida-tion affecting the equilibrium between oxaloacetate and malate and decreasing the concentration of oxaloacetate. However, pyruvate carboxylase, which catalyzes the conversion of pyruvate to oxaloacetate, is activated by acetyl-CoA. Consequently, when there are significant amounts of acetyl-CoA, there should be sufficient oxaloacetate to initiate the condensing reaction of the citric acid cycle. 

The number of vitamin B 12-dependent reactions is not large. Most of these involve rearrangements of the carbon skeletons of metabolites. Such reactions are important in linking some aspects of fatty acid metabolism to the citric acid cycle. In another form, a vitamin Bi2-derived coenzyme is involved, along with folic acid coenzymes, in the metabolism of one-carbon fragments, including the biosynthesis of methionine. 

In summary, I have provided two examples of catabolic metabolic pathways linked to prodnction of ATP glycolysis, in which glucose is converted to lactate and pyrnvate and the citric acid cycle, in which acetate (derived from pyrnvate) is converted to carbon dioxide and water. In fact, these and other catabolic pathways generate more molecnles of ATP than 1 have so far let on. Now we need to do two things qnantitate the actnal yields of ATP and say something about how they are created. We begin by directing attention to the mitochondria. 

The oxidative cleavage of an a-oxoacid is a major step in the metabolism of carbohydrates and of amino acids and is also a step in the citric acid cycle. In many bacteria and in eukaryotes the process depends upon both thiamin diphosphate and lipoic acid. The oxoacid anion is cleaved to form C02 and the remaining acyl group is combined with coenzyme A (Eq. 15-33). 

Figure 2.7. The complex pathways and processes involved in fat catabolism in vertebrate tissues such as cardiac and skeletal muscles. FFAs arrive at the cell boundary either via VLDL or albumin-associated and enter the cell either by simple diffusion or through transporters. In the cytosol, FFAs are bound by FABPs, which increase the rate and amount of FFA that can be transferred to sites of utilization. Shorter chain FFAs are converted to acetylCoA in peroxisomes longer chain FFAs are directly transferred to mitochondria (via a complex system involving acylcarnitines) as long-chain acylCoA derivatives these enter the /6-oxidation spiral and are released as acetylCoA for entrance into the Krebs or citric acid cycle in the mitochondrial matrix. Fatty acid receptors (FARs) in the nucleus bind to fatty acid response elements (FAREs) and in turn regulate the production of enzymes in their own metabolism. (Modified from Veerkamp and Maatman, 1995.)...

Fats into glucose Fats are usually metabolized into acetyl CoA and then further processed through the citric acid cycle. In Chapter 16. we learned that glucose could be synthesized from oxaloacetate, a citric acid cycle intermediate. Why, then, after a long bout of exercise depletes our carbohydrate stores, do we need to replenish those stores by eating carbohydrates Why do we not simply replace them by converting fats into carbohydrates ... 

As for other genera within this branch, there are few metabolic/enzymological studies of the citric acid cycle. A number of organisms are obligate heterotrophs and are able to use proteins and/or amino acids for growth (e.g. Pyrococcus, Staphylothermus, Thermococcus, Thermophilum [48,49]) it is possible that the citric acid cycle functions in these organisms, but the evidence is not available yet. The oxidation of pyruvate via pathways other than the citric acid cycle in some of these extreme thermophiles will be described in section 4.4. 

As compared to the numerous studies concerning alteration of the acids of the citric acid cycle and metabolically associated acids in blood, there have been only a few investigations on changes in the urinary... 

However, the role of the citric acid cycle in cellular metabolism involves more than just catabolism. It plays a key role in anabolism, or bios)mthesis, as well. Figure 22.13 shows the central role of glycolysis and the citric acid cycle as energyharvesting reactions, as well as their role as a source of bios)mthetic precursors. 

While this book is not the appropriate place for a detailed discussion of the ADP-ATP cycle, perhaps a bit more mechanistic detail is useful. The aerobic metabolism of glucose to produce ATP from ADP can be-considered to consist of three parts the fermentation of glucose to form pyruvate (and a small amount of ATP from ADP), the conversion of the pyruvate to carbon dioxide in the citric acid cycle in which NAD" " and FAD (the oxidized form of flavin adenine dinucleotide) are converted to NADH and FADH2, and their oxidation in the respiratory chain, resulting in the formation of a larger quantity of ATP from ADP. If oxygen is not available, so the reaction is anaerobic, only the first step, formation of pyruvate, occurs with a small amount of ATP production. 

O-Ketoglutaric Acid. 2-Oxopentanedioic acid 2-oxoglutaric acid 2-oxo-l,5-pentanedioic acid. CsH40 mol wt 146.10. C 41.10%, H 4.14%, O 54.76%. HOOC. CH.CHjCOCOOH. Plays an important role in amino add metabolism (transamination) see Severo Ochoa, "Enzymic Mechanisms in the Citric Acid Cycle in Advances fn Enzy-mology 15, 183-270 (1954). Prepn Friedman, Kosower, Org. Syn. cell. vol. Ill, 510 (1955) Bottorff. Moore, ibid. Coll. vol. V, 687 (1973). Microbial synthesis using a strain of Pseudomonas Lockwood et al. U.S. pat. 2,443,919 (1948) Berger, Witt, U.S. pat. 2,841,616 (1958). 

The citric acid cycle is a central metabolic pathway which generates NADH and FADH2 for use in electron transport. It also produces GTP via substrate-level phosphorylation. Many metabolic processes use intermediates of the citric acid cycle in their pathways. The cyclic process is generally considered to "begin" with addition of acetyl-CoA to oxaloacetate to form citrate. Remember, however, that the pathway is cyclic. 

We have seen the metabolism of glucose through glycolysis. Now we see where the GOg comes from—namely, the three decarboxylation reactions associated with the citric acid cycle. In the next chapter, we will see where the water and oxygen come from. 

How is amino acid metabolism related to the citric acid cycle In addition, most of the intermediates have anabolic pathways leading to amino acids and fatty acids, as well as some that lead to porphyrins or pyrimidines. 

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