Futile cycles

Molybdate is also known as an inhibitor of the important enzyme ATP sulfurylase where ATP is adenosine triphosphate, which activates sulfate for participation in biosynthetic pathways (56). The tetrahedral molybdate dianion, MoO , substitutes for the tetrahedral sulfate dianion, SO , and leads to futile cycling of the enzyme and total inhibition of sulfate activation. Molybdate is also a co-effector in the receptor for steroids (qv) in mammalian systems, a biochemical finding that may also have physiological implications (57). 

Because substrate cycles such as this appear to operate with no net benefit to the cell, they were once regarded as metabolic quirks and were referred to as futile cycles. More recently, substrate cycles have been recognized as important devices for controlling metabolite concentrations. 

In rat liver mitochondria, in state 4, the AP was estimated to be about 220 mV, with the membrane potential representing about 90% of this (Nicholls, 1974 Appendix 3). Similar values have been reported for human and rat skeletal muscle mitochondria in state 4 (Stumpf et al., 1982). The control of the rate of electron transport is not only determined by the availability of ADP, but also of Pj oxidizable substrates, and oxygen. There is evidence for futile cycling of protons in intact normal rat hepatocytes (Brand et al., 1993). Recently, Porter and Brand (1993) found a correlation between the proton permeability of the inner membrane of liver mitochondria and body size in animals from the mouse (20 g) to horses (150 kg) with a decrease in permeability with increasing weight of several-fold at a constant... 

Substrate (Futile) Cycles Allow Fine Tuning... 

During catabolic and anabolic processes, a renovation of the molecular cellular components takes place. It should be emphasized that the catabolic and anabolic pathways are independent of each other. Be these pathways coincident and differing in the cycle direction only, the metabolism would have been side-tracked to the so-called useless, or futile, cycles. Such cycles arise in pathology, where a useless turnover of metabolites may occur. To avoid this undesirable contingency, the synthetic and degradative routes in the cell are most commonly separated in space. For example, the oxidation of fatty acids occurs in the mitochondria, while the synthesis thereof proceeds extramitochondrially, in the microsomes. 

A FUTILE CYCLE is set up when both synthetic and degradative pathways are operating at the same time. The net reaction of a futile cycle is just ATP hydrolysis. 

To minimize futile cycling, signals that turn on a synthetic pathway always turn off the opposing degradative pathway. 

Of course, superoxide may reduce ferric to ferrous ions and by this again catalyze hydroxyl radical formation. Thus, the oxidation of ferrous ions could be just a futile cycle, leading to the same Fenton reaction. However, the competition between the reduction of ferric ions by superoxide and the oxidation of ferrous ions by dioxygen depends on the one-electron reduction potential of the [Fe3+/Fe2+] pair, which varied from +0.6 to —0.4 V in biological systems [173] and which is difficult to predict.)... 

TRETHEWEY, R.N., REISMEIER, J.W., WILLMITZER, L., STITT, M GEIGENBERGER, P., Tuber specific expression of a yeast invertase and a bacterial glucokinase in potato leads to an activation of sucrose phosphate synthase and the creation of a futile cycle, Planta, 1999, 208, 227-238. 

Sallustio, B.C., Purdie, Y.J., Birkett, D.J. and Meffin, P.J. (1989). Effect of renal dysfunction on the individual components of the acyl-glucuronide futile cycle. J. Pharmacol. Exp. Ther. 25 288-294. 

However, FBA in itself is not sufficient to uniquely determine intracellular fluxes. In addition to the ambiguities with respect to the choice of the objective function, flux balance analysis is not able to deal with the following rather common scenarios [248] (i) Parallel metabolic routes cannot be resovled. For example, in the simplest case of two enzymes mediating the same reaction, the optimization procedure can only assign the sum of a flux of both routes, but not the flux of each route, (ii) Reversible reaction steps can not be resolved, only the sum of both directions, that is, the net flux, (iii) Cyclic fluxes cannot be resolved as they have no impact on the overall network flux, (iv) Futile cycles, which are common in many organisms, are not present in the FBA solution, because they are usually not optimal with respect to any optimization criterion. These shortcomings necessitate a direct experimental approach to metabolic fluxes, as detailed in the next section. 

Substrate cycling (also called futile cycles) illustrates the importance of keeping key enzymes in a low activity state. Here again, PFK in the liver provides a good example. 

The availability of both the cataboHc aldolase and the uniquely synthetic anabolic synthase made it possible to assemble a novel continuous assay for the determination of the metabolite N-acetylneuraminic acid [46]. A combination of both enzymes, in the presence of an excess of PEP, will start a cycle in which the determinant sialic acid will undergo a steady conversion of cleavage and re-syn-thesis as a futile cycle (Scheme 2.2.5.24). With each progression, however, 1 equiv of pyruvate is liberated simultaneously, which causes time-dependent signal amplification. Pyruvate is quantified spectrophotometrically by a corresponding NADH consumption when the system is coupled to the standard pyruvate dehy-... 

A somewhat different kind of futile cycle was obtained by Visedo-Gonzalez and Dixon (60). This arose from the fact that the incorporation of ethanolamine (i.e., 2-aminoethanol) into phospholipids starts with the reaction of its phosphate with CTP (Fig. 5). This forms the compound... 

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