Meta-Biol

• Pathways

In the citric acid or tricarboxylic acid (TCA) cycle, the acetyl group of acetyl CoA (derived primarily from oxidative decarboxylation of pyruvate, beta-oxidation of long-chain fatty acids, and catabolism of ketone bodies and several amino acids) can be completely oxidized to CO2 in reactions that also yield one high-energy phosphate bond (as GTP or ATP) and four reducing equivalents (three NADH + H+, and one FADH2). The NADH and FADH2 are then oxidized by the electron transport chain to yield nine more high-energy phosphate bonds (as ATP). All reactions of the citric acid cycle take place in the mitochondrion.

Eight canonical reactions mediate the synthesis of citrate from acetyl-CoA and oxaloacetate and the metabolism of citrate to re-form oxaloacetate. Six additional reactions are included here. Three reversible reactions, the interconversions of citrate and isocitrate, of fumarate and malate, and of malate and oxaloacetate are annotated in both their canonical (forward) and reverse directions. The synthesis of succinate from succinyl-CoA can be coupled to the phosphorylation of either GDP (the canonical reaction) or ADP; both reactions are annotated. Two mitochondrial isocitrate dehydrogenase isozymes catalyze the oxidative decarboxylation of isocitrate to form alpha-ketoglutarate (2-oxoglutarate): IDH3 catalyzes the canonical reaction coupled to the reduction of NAD+, while IDH2 catalyzes the same reaction coupled to reduction of NADP+, a reaction whose normal physiological function is unclear. Both reactions are annotated. Finally, a reaction is annotated in which reducing equivalents are transferred from NADPH to NAD+ coupled to proton import across the inner mitochondrial membrane.

The cyclical nature of the reactions responsible for the oxidation of acetate was first suggested by Hans Krebs, from biochemical studies of pigeon breast muscle (Krebs et al. 1938; Krebs and Eggleston 1940). Many of the molecular details of individual reactions were worked out by Ochoa and colleagues, largely through studies of enzymes purified from pig heart (Ochoa 1980). While the human homologues of these enzymes have all been identified, their biochemical characterization has in general been limited and many molecular details of the human reactions are inferred from those worked out in studies of the model systems.

The metabolism of pyruvate provides one source of acetyl-CoA which enters the citric acid (TCA, tricarboxylic acid) cycle to generate energy and the reducing equivalent NADH. These reducing equivalents are re-oxidized back to NAD+ in the electron transport chain (ETC), coupling this process with the export of protons across the inner mitochondrial membrane. The chemiosmotic gradient created is used to drive ATP synthesis.

Metabolic processes in human cells generate energy through the oxidation of molecules consumed in the diet and mediate the synthesis of diverse essential molecules not taken in the diet as well as the inactivation and elimination of toxic ones generated endogenously or present in the extracellular environment. The processes of energy metabolism can be classified into two groups according to whether they involve carbohydrate-derived or lipid-derived molecules, and within each group it is useful to distinguish processes that mediate the breakdown and oxidation of these molecules to yield energy from ones that mediate their synthesis and storage as internal energy reserves. Synthetic reactions are conveniently grouped by the chemical nature of the end products, such as nucleotides, amino acids and related molecules, and porphyrins. Detoxification reactions (biological oxidations) are likewise conveniently classified by the chemical nature of the toxin.

At the same time, all of these processes are tightly integrated. Intermediates in reactions of energy generation are starting materials for biosyntheses of amino acids and other compounds, broad-specificity oxidoreductase enzymes can be involved in both detoxification reactions and biosyntheses, and hormone-mediated signaling processes function to coordinate the operation of energy-generating and energy-storing reactions and to couple these to other biosynthetic processes.