ATP utilization

The mechanism of action proposed is based on a direct binding to the channel and the following partial block of the ATP-binding pocket of CFTR (French et al., 1997), a mechanism similar to that used by genistein to inhibit the activity of other ATP-utilizing enzymes such as protein kinases and topoisomerase II (Polkowski and Mazurek, 2000 and refs therein). The selection of flavonoid compounds or the development of synthetic drugs reasonably selective for CFTR activation might be an area for future clinical trials. 

Effects of Allelochemlcals on ATP Supply. Allelochemlcals might decrease the ATP content of tissue by either increasing ATP utilization or decreasing ATP production. Some allelochemlcals that inhibit mineral absorption decrease ATP content of plant tissues. Salicylic acid decreased the ATP content of oat roots in a pH dependent manner (Figure 3). This result suggested that mitochondrial production of ATP was decreased in the tissue. On the other hand, Tillberg (38) found that salicylic acid and cinnamic acid increased the ATP content of Scenedesmus. Various flavonoids inhibited ATP production by mitochondria Isolated from cucumber (Cucumls satlvus L.) hypocotyls (54). Flavones such as kaempferol were more inhibitory than the corresponding flavanones. Substituted cinnamic acids such as caffeic acid were not inhibitory. 

This results in the extrusion of three positive charges for every two that enter the cell, resulting in a transmembrane potential of 50-70 mV, and has enormous physiological significance. More than one-third of the ATP utilized by resting mammalian cells is used to maintain the intracellular Na+-K+ gradient (in nerve cells this can rise up to 70%), which controls cell volume, allows neurons and muscle cells to be electrically excitable, and also drives the active transport of sugars and amino acids (see later). 

The first reaction vi (Gx. ATP) describes the upper part of glycolysis, converting one (external) molecule of glucose (Gx) into two molecules of triosephosphate (TP), using two molecules of ATP. The second reaction v2 (TP, ADP) describes the synthesis of two molecules ATP from each molecule of TP. The third reaction v3 (ATP) describes a (lumped) overall ATP utilization. To obtain a minimal kinetic model for the glycolytic pathway, we adopt rate function similar to [96], using... 

Similar to Eq. (67), the first reaction (incorporating the enzyme phosphofructo-kinase) exhibits a Hill-type inhibition by its substrate ATP [126]. The overall ATP utilization v3 (ATP) is modeled by a saturable Michaelis Menten function. The system is specified by five kinetic parameters (with Gx lumped into Vm ), the Hill coefficient n, and the total concentration, 4 / = [ATP] + [ADP]. Note that the model is not intended to capture biological realism, rather it serves as a paradigmatic example to identify dynamic behavior in metabolic pathways. 

Figure 22. The nullclines corresponding to the minimal model of glycolysis. Depending on the value of the maximal ATP utilization Vm3, the pathway either exhibits a unique steady state or allows for a bistable solution. Note that the nullcline for TP does not depend on VThe corresponding steady states are shown in Fig. 23. Parameters are Vm 3.1, K 0.57, ki 4.0, K i 0.06, and n 4 (the values do not correspond to a specific biological situation).

Figure 23. The steady state ATP concentration as a function of maximal ATP utilization Vmi for the minimal model of glycolysis. The letters denoted on the x axis correspond to the different scenarios shown in Fig. 22A D. Bold lines indicate stable steady states. Note that the physiologically feasible region is confined to the interval ATP0 e [0,Ar]. For low ATP usage (Vm3 small), there are three steady states, two of which are stable. However, both stable states are outside the feasible interval.

Note that this expression also provides a conceptual foundation to approximate complex processes, like ATP utilization, by a single reaction with a single saturation parameter sampled randomly from a specified interval. 

Doring HJ. 1975. Reversible and irreversible forms of contractile failure caused by disturbances by general anesthetics in myocardial ATP utilization. In Fleckenstein A, DhallaNS, eds. Recent Advances in Studies on Cardiac Structure and Metabolism, vol. 5 Basic functions of cations in myocardial activity. Baltimore, MD University Park Press, 395-403. 

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 model has numerous short-comings . Chiefly, it fails to account for the fact that U- and R-enzymes frequently have other phosphoryl-acceptor and -donor substrates, and the model does not explain how fluctuations in these cosubstrate concentrations may alter the so-called responsiveness of enzymes. Moreover, the concentration of orthophosphate is wholly omitted from the model, despite the fact that key regulatory steps in ATP utilization and regeneration are exquisitely sensitive to changes in orthophosphate concentration. The energy-charge model also fails to consider magnesium ion com-... 

Periodic acid oxidation has proved to be a very useful tool in enzymology since a wide variety of biochemicals contain hydroxyl groups on adjacent carbon atoms. For example, periodate-oxidized ATP (also called adenosine 5 -triphosphate 2, 3 -dialdehyde) has often been used as an alternative substrate or an irreversible inhibitor for a wide variety of ATP-utilizing enzymes. This compound, and many others, are now commercially available, even though they are readily synthesized e.g., periodic acid oxidized ADP, AMP, adenosine, P, P -di(adenosine-5 )pentaphosphate, P, P -di(adenosine-5 )tetraphos-phate, GTP, GDP, GMP, guanosine, CTP, CDP, CMP, etc. In the case of the nucleosides, commercial sources also can supply the dialcohol form of the nucleoside i.e., the nucleoside has first been oxidized with periodic acid and then reduced to the dialcohol with borohydride. 

Magnesium is bound in the active site of D-xylose isomerase (Carrell et al., 1984, 1989 Farber et al., 1987 Key etal., 1988 Henrick a/., 1989). Here, the site at which two metals [from among Mg(II), Mn(ll), and Co(II)] bind is similar to that found for Fe(ll) in ribonucleotide reductase (Nordlund et al., 1990). The active site of xylose isomerase is shown in Fig. 28. Magnesium ions are preferred in ATP-utilizing enzyme reactions (Mildvan, 1987). 

Mildvan, A. S. (1987). Role of magnesium and other divalent cations in ATP-utilizing... 

Nucleotide Base Conformation. Using NMR data, a relationship between the degree of specificity and the conformation of bound ATP at the active site has been shown for a number of ATP utilizing enzymes. Two examples of these are cAMP-dependent protein kinase and pyruvate kinase (18,19) It appears that enzymes that exhibit higher nucleotide triphosphate specificity bind ATP so... 

Thyroid hormones are intimately involved in regulating the basal metabolic rate. Liver tissue of animals given excess thyroxine shows an increased rate of 02 consumption and increased heat output (thermogenesis), but the ATP concentration in the tissue is normal. Different explanations have been offered for the thermogenic effect of thyroxine. One is that excess thryroxine causes uncoupling of oxidative phosphorylation in mitochondria. How could such an effect account for the observations Another explanation suggests that the thermogenesis is due to an increased rate of ATP utilization by the thyroxine-stimulated tissue. Is this a reasonable explanation Why ... 

A quantitative description of oxidative phosphorylation within the cellular environment can be obtained on the basis of nonequilibrium thermodynamics. For this we consider the simple and purely phenomenological scheme depicted in Fig. 1. The input potential X0 applied to the converter is the redox potential of the respiratory substrates produced in intermediary metabolism. The input flow J0 conjugate to the input force X0 is the net rate of oxygen consumption. The input potential is converted into the output potential Xp which is the phosphate potential Xp = -[AG hoS -I- RT ln(ATP/ADP P,)]. The output flow Jp conjugate to the output force Xp is the net rate of ATP synthesis. The ATP produced by the converter is used to drive the ATP-utilizing reactions in the cell which are summarized by the load conductance L,. Since the net flows of ATP are large in comparison to the total adenine nucleotide pool to be turned over in the cell, the flow Jp is essentially conservative. 

In order to obtain a more intuitive insight into the mechanism of thermodynamic buffering we calculated the effects of thermodynamic buffering on the entropy production of the system. The entropy production of oxidative phosphorylation with an attached load is given in equation (8). A convenient way to introduce the contribution of the adenylate kinase reaction to this system is to consider L/ as an overall load conductance embracing the effects of the adenylate kinase reaction as well as the effects of the true extrinsic load conductance of the irreversible ATP utilizing... 

This pioneering work showed that the sodium pump was not confined to the plasma membrane of excitable cells (the pump is in fact found in virtually all animal cells) it also paved the way for an avalanche of mechanistic studies examining very many aspects of the function of the sodium pump. These included partial reactions, kinetic affinities for the three substrates at both sides of the membrane and their mutual interdependence, ATP utilization and its stoichiometric relationship to cation fluxes. Such experiments were readily performed on the red cell since these are available in large quantities and the development of simple technical procedures such as red cell ghost formation by transient hypotonic shock allowed ready access to, and control of, the intra- as well as extra-cellular face of the pump. 

Ehrlich I, Elmslie KS (1995) Neurotransmitters acting via different G proteins inhibit N-type calcium current by an identical mechanism in rat sympathetic neurons. J Neurophysiol 74 2251-7 Esser L, Wang CR, Hosaka M et al (1998) Synapsin I is structurally similar to ATP-utilizing enzymes. EMBO J 17 977-84... 

The Role of Histidine Residues and the Conformation of Bound ATP on ATP-Utilizing Enzymes... 

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