The adenine nucleotides

Nucleotides consist of a purine or pyrimidine base linked to the five-carbon sugar ribose. The base plus sugar is a nucleoside in a nucleotide the sugar is phosphorylated. Nucleotides may be mono-, di- or triphosphates. 

In the nucleic acids (DNA and RNA sections 9.2.1 and 9.2.2 respectively) it is the purine or pyrimidine that is important, carrying the genetic information. However, in the link between energy-yielding metabolism and the performance of physical and chemical work, what is important is the phosphorylation of the ribose. Although most reactions are linked to adenosine triphosphate, a small number are linked to guanosine triphosphate (GTP see, for example, sections 5.7 and 9-2.3-2) or uridine triphosphate (UTP section 5.5.3). 

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Several classes of vitamins are related to, or are precursors of, coenzymes that contain adenine nucleotides as part of their structure. These coenzymes include the flavin dinucleotides, the pyridine dinucleotides, and coenzyme A. The adenine nucleotide portion of these coenzymes does not participate actively in the reactions of these coenzymes rather, it enables the proper enzymes to recognize the coenzyme. Specifically, the adenine nucleotide greatly increases both the affinity and the speeifieity of the coenzyme for its site on the enzyme, owing to its numerous sites for hydrogen bonding, and also the hydrophobic and ionic bonding possibilities it brings to the coenzyme structure. 

Pantothenic acid, sometimes called vitamin B3, is a vitamin that makes up one part of a complex coenzyme called coenzyme A (CoA) (Figure 18.23). Pantothenic acid is also a constituent of acyl carrier proteins. Coenzyme A consists of 3, 5 -adenosine bisphosphate joined to 4-phosphopantetheine in a phosphoric anhydride linkage. Phosphopantetheine in turn consists of three parts /3-mercaptoethylamine linked to /3-alanine, which makes an amide bond with a branched-chain dihydroxy acid. As was the case for the nicotinamide and flavin coenzymes, the adenine nucleotide moiety of CoA acts as a recognition site, increasing the affinity and specificity of CoA binding to its enzymes. 

In both intermediate and maximum rates of respiration, control is distributed between several different steps, including the activity of the adenine nucleotide translocator (Groen et al., 1983). It is now recognized that the idea of a simple rate-limiting step for a metabolic pathway is simplistic and that control is shared by all steps although to different extents (Kacserand Bums, 1978 Fell, 1992). Each step in a pathway has a flux control coefficient (FCC) defined as ... 

A combination of the above reactions makes it possible for phosphate to be recycled and the adenine nucleotides to interchange (Figure 10-8). 

Figure 12-11. Combination of phosphate transporter ( ) with the adenine nucleotide transporter ((2)) in ATP synthesis. The H+ZP, symport shown is equivalent to the P /OH antiport shown in Figure 12-10. Four protons are taken into the mitochondrion for each ATP exported. However, one less proton would be taken in when ATP is used inside the mitochondrion.

Adenylate kinase (AK) is a ubiquitous monomeric enzyme that catalyzes the interconversion of AMP, ADP, and ATP. This interconversion of the adenine nucleotides seems to be of particular importance in regulating the equilibrium of adenine nucleotides in tissues, especially in red blood cells. AK has three isozymes (AK 1,2, and 3). AK 1 is present in the cytosol of skeletal muscle, brain, and red blood cells, and AK 2 is found in the intermembrane space of mitochondria of liver, kidney, spleen, and heart. AK 3, also called GTP AMP phosphotransferase, exists in the mitochondrial matrix of liver and heart. 

Joseph-Iiauzun, E., Farges, R., Delmas, P., Ferrara, P. Loison, G. (1997). The Mr 18,000 subunit of the peripheral-type benzodiazepine receptor exhibits both benzodiazepine and isoquinoline carboxamide binding sites in the absence of the voltage-dependent anion channel or of the adenine nucleotide carrier. J. Biol. Chem. 272, 28102-6. 

Several different changes in mitochondria occur during apoptosis. These include a change in membrane potential (usually depolarization), increased production of reactive oxygen species, potassium channel activation, calcium ion uptake, increased membrane permeability and release of cytochrome c and apoptosis inducing factor (AIF) [25]. Increased permeability of the mitochondrial membranes is a pivotal event in apoptosis and appears to result from the formation of pores in the membrane the proteins that form such permeability transition pores (PTP) may include a voltage-dependent anion channel (VDAC), the adenine nucleotide translocator, cyclophilin D, the peripheral benzodiazepine receptor, hexokinase and... 

Somlyo You might want to consider what the adenine nucleotide concentrations are when these measurements are made. As you know, the InsP3 channel is also highly adenine nucleotide sensitive, and is also sensitive to a few other things in the cells that we may not even know about. 

Cardiolipin forms also tight complexes, with the adenine nucleotide translocator (ATM) affecting its translocator activity (Beyer and Nuscher, 1996). Six cardiohpin residues are tightly bound to lysines (Beyer and Klingenberg, 1985). Removal of these lipids renders the translocator inactive, but activity can be reconstituted by adding cardiolipin. It has also a pivotal role as a boundary hpid of various proteins such as NADH ubiquinone oxireductase (Hoch, 1992) or cytochrome c oxidase (Ushmorov et al, 1999 Vik et al, 1981). 

McEnery, M.W., Snowman, A.M., Trifiletti, R.R., and Snyder, S.H., 1992, Isolation ofthe mitochondrial benzodiazepine receptor association with the voltage-dependent anion channel and the adenine nucleotide carrier, Proc.Natl.Acad.Sci. U.S.A. 89 3170-3174. 

Crompton, M., Virji, S., and Ward, J. M., 1998, CyclophUin-D binds strongly to complexes of the voltage-dependent anion channel and the adenine nucleotide translocase to form the permeabihty transition poie. EurJ Biochem 258 729-735. 

The adenine nucleotide transporter is known as a translocase - it transports ADP into and ATP out of the mitochondrion in such a way that, when one molecule of ADP is transported in, one molecule of ATP is transported out... 

Figure 9.19 Adenine nucleotide translocase and phosphate transfer into the matrix. Phosphate is transported into the mitochondria with protons in a symport transport system. The adenine nucleotide translocase transports ADP into and ATP out of the mitochondria, i.e. it is electrogenic. The charge is neutralised by H movement into the matrix from the proton motive force which utilises about 25% of the energy in the proton motive force.

An increase in the rate of cross-bridge cychng increases force of contraction of muscle, which decreases the cytosolic concentration of ATP and increases that of ADP. This results, via the adenine nucleotide translocase, in a similar change in direction of ATP and ADP concentrations within the mitochondrial matrix (i.e. a decrease in the ATP/ADP concentration ratio). 

The changes in the cytosolic ADP and ATP concentrations increase the mitochondrial matrix concentration of ADP and decrease that of ATP, via the adenine nucleotide translocase, which stimulates the flux of electrons along the transfer chain. 

An index of the phospho anhydride (i.e.,P—O—P) bond content of the adenine nucleotides of a cell, based on a hypothetical modeP that attempts to explain the metabolic basis for control of ATP utilization and regeneration. Later studies demonstrated that the energy charge model is overly simplistic and that its principles are unlikely to constitute a useful model for the control of energy metabolism within biological systems. 

The energy charge quotient has a value of unity (or, 1.00) when only ATP is present and a value of zero when only AMP is present. Thus, the adenine nucleotide system is said to be fully charged at EC = 1 and fully discharged at EC = 0. At intermediate values, the adenine nucleotides are interconverted by adenylate kinase, and their concentrations are constrained by the adenylate kinase mass action ratio ... 

In a series of papers, we have proposed the torsional mechanism of energy transduction and ATP synthesis, the only unified and detailed molecular mechanism of ATP synthesis to date [16-20,56] which addresses the issues of ion translocation in Fq [16, 20, 56], ionmotive torque generation in Fq [16, 20, 56], torque transmission from Fq to Fj [17,18], energy storage in the enzyme [17], conformational changes in Fj [18], and the catalytic cycle of ATP synthesis [18, 19]. We have also studied the thermodynamic and kinetic aspects of ATP synthesis [19,20,41,42,56]. A kinetic scheme has been developed and mathematically analyzed to obtain a kinetic model relating the rate of ATP synthesis to pHjn and pH m in the Fq portion and the adenine nucleotide concentrations in the Fj portion of ATP synthase. Analysis of these kinetic models reveals a wealth of mechanistic details such as the absence of cooperativity in the Fj portion of ATP synthase, order of substrate binding and product release events, and kinetic inequivalence of ApH and Aip. 

The affinities of the transport protein for the nucleoside triphosphates ITP and GTP and the corresponding diphosphates deduced from the concentration dependence of either calcium-dependent phosphate liberation or phosphate incorporation during calcium efflux are at least 10 to 400 times lower than the affinity of the adenine nucleotides (Fig. 12). The affinities for acetyl phosphate, carbamyl phosphate, para-nitro-... 

A variety of enzyme cofactors serving a wide range of chemical functions include adenosine as part of their structure (Fig. 8-41). They are unrelated structurally except for the presence of adenosine. In none of these cofactors does the adenosine portion participate directly in the primary function, but removal of adenosine generally results in a drastic reduction of cofactor activities. For example, removal of the adenine nucleotide (3 -phosphoadenosine diphosphate) from acetoacetyl-... 

The adenine nucleotide translocase, integral to the inner membrane, binds ADP3 - in the intermembrane space and transports it into the matrix in exchange for an ATP4 molecule simultaneously transported outward (see Fig. 13-1 for the ionic forms of ATP and ADP). Because this antiporter moves four negative charges out for every three moved in, its activity is favored by the... 

The combined effect of exchanging extramitochon-drial ADP-3 and H2P04 for mitochondrial ATP-4 and OH is to move one proton into the mitochondrial matrix for every molecule of ATP that the mitochondrion releases into the cytosol. This proton translocation must be considered, along with the movement of protons through the ATP synthase, to account for the P-to-O ratio of oxidative phosphorylation. If three protons pass through the ATP synthase, and the adenine nucleotide and Pj transport systems move one additional proton, then four protons in total move into the matrix for each ATP molecule provided to the cytosol. 

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