Adenosine diphosphate, metabolism

The importance of phosphates in intermediary metabolism became evident with the discovery of the role of ATP, adenosine diphosphate (ADP), and inorganic phosphate (Pj) in glycolysis (Chapter 17). 

Phosphate condensation reactions play an essential role in metabolism. Recall from Section 14.6 that the conversion of adenosine diphosphate (ADP) to adenosine triphosphate (ATP) requires an input of free energy ADP -I-H3 PO4 ATP +H2O AG° — +30.6kJ As also described in that section, ATP serves as a major biochemical energy source, releasing energy in the reverse, hydrolysis, reaction. The ease of interchanging O—H and O—P bonds probably accounts for the fact that nature chose a phosphate condensation/hydrolysis reaction for energy storage and transport. 

Figure 14.1. Outline of the relationship between glucose metabolism, acetylcholine synthesis and energy production. TCA = tricarboxylic acid ADP = adenosine diphosphate P = inorganic phosphate.

In the past decade, a large number of studies emphasized the heterogeneous scale-free degree distribution of metabolic networks Most substrates participate in only a few reactions, whereas a small number of metabolites ( hubs ) participate in a very large number of reactions [19,45,52]. Not surprisingly, the list of highly connected metabolites is headed by the ubiquitous cofactors, such as adenosine triphosphate (ATP), adenosine diphosphate (ADP), and nicotinamide adenine dinucleotide (NAD) in its various forms, as well as by intermediates of glycolysis and the tricarboxylic acid (TCA) cycle. 

For ATP to carry out this function, it has to be produced from adenosine diphosphate (ADP) in an endergonic reaction that must be driven by another exergonic metabolic reaction. One exergonic reaction step that occurs in the overall oxidation of glucose in the cell is the oxidation of 3-phosphoglyceraldehyde to 3-phosphoglycerate by pyruvate, for which AG = —29,300 Jmol ... 

The biological roles of phosphorus include (1) anabolic and catabolic reactions, as exemplified by its essentiality in high-energy bond formation, e.g., ATP (adenosine triphosphate), ADP (adenosine diphosphate), etc., and the formation of phosphorylated intermediates in carbohydrate metabolism ... 

Inhibition of the initial step of a biosynthetic pathway by an end product of the pathway is a recurrent theme in metabolic regulation. In addition, many key enzymes are regulated by ATP, adenosine diphosphate (ADP), AMP, or inorganic phosphate ion (Pi). The concentrations of these materials provide a cell with an index of whether energy is abundant or in short supply. Because ATP, ADP, AMP, or P often are chemically unrelated to the substrate of the enzyme that must be regulated, they usually bind to an allosteric site rather than to the active site. 

Adenosine, in addition to serving as a substrate for the generation of cAMP plays a physiologic role as a platelet inhibitor and a vasodilator and may attenuate neutrophil-mediated damage to endothelial cells, Adenosine diphosphate (ADP)— a potent platelet agonist—is converted to adenosine, which is taken up rapidly by cells, especially erythrocytes and endothelial cells, A small proportion is metabolized to the aforementioned cyclic nucleotides. The remainder is broken down to inosine and subsequently to xanthine. Dipyridamole inhibits the active transport of adenosine into cells, but does not interfere with the passive diffusion. Since the platelet inhibitory effects of adenosine proceed via stimulation of adenylate cyclase, these effects can also be amplified by dipyridamole, In circulating blood, the largest amount of adenosine is found in red blood cells, This may, in part, help explain why dipyridamole is much more effective in whole blood than in plasma. 

An essentially electrochemical model for metabolism and the formation of adenosine tri-phosphate from adenosine diphosphate was suggested by R. J. P. Williams at Oxford University in 1959.18 It is shown in Fig. 14.40. 

ATP plays a central role in cellular maintenance both as a chemical for biosynthesis of macromolecules and as the major soirrce of energy for all cellular metabolism. ATP is utilized in numerous biochemical reactions including the eitric acid cycle, fatty acid oxidation, gluconeogenesis, glycolysis, and pyruvate dehydrogenase. ATP also drives ion transporters sueh as Ca -ATPase in the endoplasmic reticulum and plasma membranes, H+-ATPase in the lysosomal membrane, and Na+/K+-ATPase in the plasma membrane. Chemieal energy (30.5 kJ/mol) is released by the hydrolysis of ATP to adenosine diphosphate (ADP). 

Figure 9.3 Microbial metabolism (primary) of glucose to lactate or ethanol. ADP = adenosine diphosphate ATP = adenosine triphosphate.

Figure 14.19. Adenosine Diphosphate (ADP) Is an Ancient Module in Metabolism. This fundamental building block is present in key molecules such as ATP, NADH, FAD, and coenzyme A. The adenine unit is shown in blue, the ribose unit in red, and the diphosphate unit in yellow.

At the time I was in graduate school, it was recognized that living cells capture energy from oxidation of foodstuffs by making adenosine triphosphate (ATP) from adenosine diphosphate (ADP) and inorganic phosphate. The ATP is then used in a myriad of functions — muscle contraction, nerve, brain, and kidney function, metabolic syntheses, and solute transport. How this oxidative phosphorylation occurrs remained for many years a major unsolved problem in biochemistry. 

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