Tricarboxylic acid cycle functions

The tricarboxylic acid cycle (see p. 136) is often described as the hub of intermediary metabolism. It has both catabolic and anabolic functions—it is amphibolic. 

As a catabolic pathway, it initiates the terminal oxidation of energy substrates. Many catabolic pathways lead to intermediates of the tricarboxylic acid cycle, or supply metabolites such as pyruvate and acetyl-CoA that can enter the cycle, where their C atoms are oxidized to CO2. The reducing equivalents (see p. 14) obtained in this way are then used for oxidative phosphorylation—I e., to aerobically synthesize ATP (see p. 122). 

The tricarboxylic acid cycle also supplies important precursors for anabolic pathways. 

The intermediates of the tricarboxylic acid cycle are present in the mitochondria only in very small quantities. After the oxidation of acetyl-CoA to CO2, they are constantly regenerated, and their concentrations therefore remain constant, averaged over time. Anabolic pathways, which remove intermediates of the cycle (e.g., gluconeogenesis) would quickly use up the small quantities present in the mitochondria if metabolites did not reenter the cycle at other sites to replace the compounds consumed. Processes that replenish the cycle in this way are called anaplerotic reactions. 

The degradation of most amino acids is anaplerotic, because it produces either intermediates of the cycle or pyruvate glucogenic amino acids see p. 180). Gluconeogenesis is in fact largely sustained by the degradation of amino acids. A particularly important anaplerotic step in animal metabolism leads from pyruvate to oxaloacetic acid. This ATP-dependent reaction is catalyzed by pyruvate 

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SOME STEPS IN THE TRICARBOXYLIC ACID CYCLE Oxidative Decarboxylation of Pyruvate The Intracellular Function of Vitamin Bj... 

Marine organisms concentrate metals in their tissues and skeletal materials. Many of these trace metals are classified as micronutrients because they are required, albeit in small amounts, for essential metabolic functions. Some are listed in Table 11.4, illustrating the role of metals in the enzyme systems involved in glycolysis, the tricarboxylic acid cycle, the electron-transport chain, photosynthesis, and protein metabolism. These micronutrients are also referred to as essential metals and, as discussed later, have the potential to be biolimiting. 

Proteins containing iron-sulfur clusters are ubiquitous in nature, due primarily to their involvement in biological electron transfer reactions. In addition to functioning as simple reagents for electron transfer, protein-bound iron-sulfur clusters also function in catalysis of numerous redox reactions (e.g., H2 oxidation, N2 reduction) and, in some cases, of reactions that involve the addition or elimination of water to or from specific substrates (e.g., aconitase in the tricarboxylic acid cycle) (1). 

The tricarboxylic acid cycle (TCA cycle, also known as the citric acid cycle or Krebs cycle) is a cyclic metabolic pathway in the mitochondrial matrix (see p. 210). in eight steps, it oxidizes acetyl residues (CH3-CO-) to carbon dioxide (CO2). The reducing equivalents obtained in this process are transferred to NAD"" or ubiquinone, and from there to the respiratory chain (see p. 140). Additional metabolic functions of the cycle are discussed on p. 138. 

Using the so-called glyoxylic acid cycle, plants and bacteria are able to convert acetyl-CoA into succinate, which then enters the tricarboxylic acid cycle. For these organisms, fat degradation therefore functions as an anaplerotic process. In plants, this pathway is located in special organelles, the glyoxysomes. 

The degradation of the fatty acids occurs in the mitochondrial matrix through an oxidative cycle in which C2 units are successively cleaved off as acetyl CoA activated acetic acid). Before the release of the acetyl groups, each CH2 group at C-3 of the acyl residue (the P-C atom) is oxidized to the keto group— hence the term p-oxidation for this metabolic pathway. Both spatially and functionally, it is closely linked to the tricarboxylic acid cycle (see p. 136) and to the respiratory chain (see p. 140). 

In this section we have seen that fatty acids are oxidized in units of two carbon atoms. The immediate end products of this oxidation are FADH2 and NADH, which supply energy through the respiratory chain, and acetyl-CoA, which has multiple possible uses in addition to the generation of energy via the tricarboxylic acid cycle and respiratory chain. Unsaturated fatty acids can also be oxidized in the mitochondria with the help of auxiliary enzymes. Ketone body synthesis from acetyl-CoA is an important liver function for transfer of energy to other tissues, especially brain, when glucose levels are decreased as in diabetes or starvation. 

All plants contain a PEPCase enzyme which, among other likely roles (Vidal et al., 1986), serves to replenish tricarboxylic acid cycle intermediates that are consumed during ammonium assimilation (Latzko Kelly, 1983). The role of this enzyme, other than its presumed housekeeping function, has not been studied in any detail and its activity is probably not controlled by environmental factors. Isoforms of PEPCase have been observed in many plants (C3, C4 and CAM) for example, in rice five isoforms have been detected immunologically and in most plants two to four bands that react with anti-PEPCase antibodies are found (Matsuoka Hata, 1987). It is not clear how these isoforms arise, e.g. by post-translational modification of one form, or whether all of these forms are products of different genes. The housekeeping-type PEPCase enzyme, concerned with anaplerotic functions, is distinct from other PEPCase enzymes that function in plants with C4 and CAM metabolism (see below). 

The reductive tricarboxylic acid cycle is basically the reverse of the oxidative tricarboxylic acid cycle that heterotrophs use to generate reducing equivalents (NADH, FADH2) that function as electron donors for energy generation. The 3-hydroxyproprionate cycle was found in the green nonsulfur bacterium Chloroflexus (Strauss and Fuchs, 1993) and more recently also in some autotrophic Archea (Mendez et al., 1999). In this pathway, 3-hydroxyproprionate is a key intermediate. 

A recent investigation of the current model for the tricarboxylic acid cycle in Dictyostelium discoideum may be viewed as a case study that illustrates the uses of local representation within the Power-Law Formalism (Shiraishi and Savageau, 1992a,b,c,d 1993). First, it demonstrates that systemic analysis is a powerful tool to evaluate the quality of biochemical models especially those representing the function of a complex system in vivo. Second, it demonstrates that systemic analysis allows one to diagnose deficiencies and to predict modifications that are likely to improve the model. 

The soluble isozyme is generally considered to take part in the cytoplasmic side of the malate shuttle, providing a means of transporting NADH equivalents, in the form of malate, across the mitochondrial membrane. The mitochondrial enzyme, in addition to its role in the other half of the malate shuttle, is also a necessary component of the tricarboxylic acid cycle. The microbody malate dehydrogenase found in some plants appears to function in the glyoxylate cycle (5) or possibly in photorespiration ( ). 

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