TCA cycle (三羧酸循环)
Tricarboxylic acid cycle (TCA cycle) is also called citric acid cycle or Krebs cycle (after its discoverer, Sir Hans Krebs). TCA cycle or citric acid cycle is the central metabolic hub of the cell and is the gateway to the aerobic metabolism of any molecule that can be transformed into an acetyl group or dicarboxylic acid.
In glycolysis the glucose molecule is broken down in pyruvate. Although the pyruvate is converted to various fermentation products as a result of fermentation, it is oxidized fully to CO2 in respiration.
Krebs cycle is found in nearly all mammalian cells, with the notable exception of mature red blood cells, which lack mitochondria. The cycle oxidizes acetyl CoA derived from carbohydrates, ketone bodies, fatty acids and amino acids, to produce NADH and FADH2 for ATP synthesis in the respiratory chain. Furthermore, components of the cycle form essential links with the pathways for gluconeogenesis, lipogenesis and amino acid metabolism.
The TCA cycle is an amphibolic pathway, meaning that it not only functions in the oxidative catabolism of carbohydrates, fatty acids, and amino acids but also provides precursors for many biosynthetic pathways, particularly gluconeogenesis.
The reactions of the tricarboxylic acid (TCA) cycle allow the controlled combustion of fat and carbohydrate. In principle, TCA cycle intermediates are regenerated on every turn and can facilitate the oxidation of an infinite number of nutrient molecules. However, TCA cycle intermediates can be lost to cataplerotic pathways that provide precursors for biosynthesis, and they must be replaced by anaplerotic pathways that regenerate these intermediates. Together, anaplerosis and cataplerosis help regulate rates of biosynthesis by dictating precursor supply, and they play underappreciated roles in catabolism and cellular energy status.
Kornberg’s definition leaves room for interpretation: Anaplerosis serves “solely to maintain the function of the tricarboxylic acid cycle and other amphibolic routes.” In other words, any pathway that contributes intermediates to the TCA cycle, other than the synthesis of citrate from OAA and acetyl-CoA, is usually considered anaplerotic. Likewise, any pathway that removes carbon from the TCA cycle, other than CO2, is usually considered cataplerotic. Such a broad definition includes futile cycles, redox shuttles, and catabolic pathways of amino acid metabolism and nitrogen trafficking.
Anaplerosis （回补途径）
As described by Sir Hans Kornberg, anaplerosis is the reloading of metabolic intermediates in the TCA cycle, which is a crucial part of energy production and biosynthetic pathways.
Anaplerosis is the re-filling of the catalytic intermediates of the cycle that carry acetyl-CoA as it is oxidized. The main anaplerotic substrates are pyruvate, glutamine/glutamate and precursors of propionyl-CoA (odd-chain fatty acids, specific amino acids, C5-ketone bodies). Cataplerosis balances anaplerosis by removing excess intermediates from the citric acid cycle.
Cancer cells use precursors derived from the TCA cycle intermediates to synthesize proteins, lipids, and nucleic acids. In order to maintain
mitochondrial activity, these cells must compensate for lost TCA cycle intermediates caused by their metabolic diversions. This process of
replenishing metabolic intermediates is known as anaplerosis. For continuous proliferation, cancer cells must maintain the necessary precursors of biosynthetic pathways, and glutamine serves as a major substrate for anaplerosis in many cancer cells.
Normally, most cells import lipids. In contrast, under nutrient-replete conditions, numerous cancer cell types synthesize a significant amount of free fatty acids, monoacyl-, diacyl-, and triacyl glycerides, and phospholipids to meet the demands of new membrane synthesis (Corbet and Feron 2015). This process is called De Novo Lipogenesis (DNL) and utilizes carbons that exit the TCA cycle (this is called cataplerosis) as citrate, which exits the mitochondria. The carbons that exit the TCA cycle as citrate must be replaced (this is called anaplerosis). A major anaplerotic source of carbon in several cancers is glutamine (Gln), which is the most abundant amino acid in the circulation (0.5 mM).
Cataplerosis （流失反应）
Cataplerosis describes reactions involved in the disposal of citric acid cycle intermediates generated by the entry of compounds into the cycle during the breakdown of amino acids and other metabolites (i.e. propionyl CoA), or by the carboxylation of pyruvate to oxalacetate . The biological necessity for cataplerosis resides in citric acid cycle dynamics.
This removal of carbons from the TCA cycle (called cataplerosis) must be matched by entry of carbons at another step (called anaplerosis).
If intermediates can be added to the TCA cycle, it is equally important to remove them to avoid the accumulation of anions in the mitochondrial matrix. Cataplerosis describes reactions involved in the disposal of TCA cycle intermediates. There are several cataplerotic enzymes; these include PEPCK, aspartate aminotransferase, and glutamate dehydrogenase. Each of these reactions has as substrate a TCA cycle anion that is converted to a product that effectively removes intermediates from the cycle. In the liver and kidney, the role of PEPCK in cataplerosis is of special importance because it is a common route for the generation of PEP from oxalacetate to be used for gluconeogenesis.
Although gluconeogenic enzymes and gluconeogenesis reactions are localized in the cytosol, the substrate of PCK1 and PCK2, OAA, is produced mainly in mitochondria by either pyruvate carboxylase or tricarboxylic acid cycle (TCA) enzyme malate dehydrogenase. The conversion of OAA to PEP catalyzed by PCK1 is closely linked to the TCA flux, which is reciprocally modulated by the processes of replenishing (anaplerosis) and removal (cataplerosis) of TCA intermediates
PEPCK-C is required not only for gluconeogenesis and glyceroneogenesis but also for cataplerosis (i.e. the removal of citric acid cycle anions) and that the failure of this process in the livers of PEPCK-C-/- mice results in a marked reduction in citric acid cycle flux and the shunting of hepatic lipid into triglyceride, resulting in a fatty liver.
The regulation of anaplerosis and cataplerosis depends upon the metabolic and physiologic state and the specific tissue/organ involved. For example, during starvation, cataplerosis via phosphoenolpyruvate to support gluconeogenesis may be regulatory in the liver, whereas in the kidney anaplerosis via uptake of glutamine may be regulatory.
Outputs and inputs into the tricarboxylic acid (TCA) cycle. A functioning TCA cycle requires a continuous pool of acetyl-CoA and supply of TCA cycle intermediates that can be used to synthesize oxaloacetate. A, removal of TCA cycle intermediates (“cataplerosis”) occurs at multiple steps of the cycle to supply precursors for biosynthetic processes or feed into other metabolic pathways. B, replacement of TCA cycle intermediates (“anaplerosis”) is required to support continuous production of oxaloacetate. Sources of anaplerosis are shown in this panel. Several pathways either produce acetyl-CoA directly or produce pyruvate, an indirect source of acetyl-CoA through the activity of the pyruvate dehydrogenase complex.
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