Cycles, substrate

In liver and kidney cortex there are four enzymes, unique to glu-coneogenesis, which are required to reverse the sequence of reactions in glycolysis. These enzymes constitute a set of energy requiring reactions that permit circumvention of the energy barrier of the glycolytic pathway. 

Newsholme and Gevers (1967) have proposed that an additional form of amplification and control of a pathway may be obtained if a substrate cycle is operative in the pathway, e.g., a cycle, between fruc-tose-6-phosphate and fructose-1,6-diphosphate, which may participate in the regulation of glycolytic flux in muscle. A cycle between triglycerides and fatty acids, which appears to control the rate of fatty acid release from adipose tissue, may also occur (Newsholme and Crabtree, 1976). 

To be an effective form of regulation, substrate cycling requires that both enzymes respond to the same metabolites in opposite ways but that neither do so in an all-or-none fashion. Under circumstances 

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Newsholme, E., Challiss, R., and Crabtree, B., 1984. Substrate cycles Their role in improving sensitivity in metabolic control. Trends in Biochemical Sciences 9 277-280. 

Substrate Cycles Provide Metabolic Control Mechanisms... 

If fructose-1,6-bisphosphatase and phosphofructokinase acted simultaneously, they would constitute a substrate cycle in which fructose-1,6-bisphosphate and fructose-6-phosphate became interconverted with net consumption of ATP ... 

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. 

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. 

A totally different mechanism for improving sensitivity is known as the substrate cycle. It is possible for a reaction that is non-equilibrium in the forward direction of a pathway (i.e. A B, see below) to be opposed by a reaction... 

In some circumstances, substrate cycles may operate not only to regulate flux through biochemical pathways but to achieve the controlled conversion of chemical energy (i.e. ATP) into heat. This occurs in two conditions. 

The quantitive effect is examined when there is no substrate cycle and when there is substrate cycle. 

E represents the enzymes catalysing the reactions in the pathway. Simultaneous activities of E2 and E5 produce a substrate cycle between A and B. In the no cycling condition, enzyme E5 is absent (or inactive). 

Figure 6.24 The gluconeogenic pathway indicating the glycolytic and gluconeogenic non-equilibrium reactions. The non-equilibrium reactions provide for the substrate cycles. (See Chapter 3 for a discussion of substrate cycles and their role in regulation.)...

Gluconeogenesis is relatively energy expensive six molecules of ATP are hydrolysed for every two molecules of lactate converted to one of glucose, but, in addition, since substrate cycles are involved in three steps in the... 

Both glucose 6-phosphatase and glucokinase are simultaneously active, the result of which is a substrate cycle, the glucose/glucose 6-phosphate cycle (Figure 6.29(a)). 

However, if the heat produced is not sufficient to maintain the temperature, despite decreased heat loss, it can be produced by specific processes. These are shivering, substrate cycling or uncoupling of ATP formation from electron transfer in mitochondria. 

Examples of a substrate cycles are the glucose/glucose 6-phosphate, fructose 6-phosphate/fmctose 1,6-bisphosphate and fatty acid/triacylglycerol cycle. These are described in Chapters 3, 6, 7 and 11. One study has shown a direct role of a substrate cycle in heat generation (Appendix 9.11). 

The gland is situated in the neck across the front of the trachea. It secretes thyroxine (T4), which is converted to the active form of the hormone, triiodothyronine (T3), in peripheral tissues. It stimulates metabolic activity in tissues so that it increases heat production (for example, by stimulating protein turnover and substrate cycles). 

The channel within the SR membrane is inhibited by a compound known as ryanodine, so that it is known as the ryanodine-sensitive Ca -channel. A mutation in the ryanodine receptor is responsible for the sensitivity, in some individuals, to the anaesthetic halothane. This sensitivity results in severe hyperthermia, a condition known as malignant hyperthermia. The explanation is that the modified receptor allows a massive Ca ion release from the SR, which is then pumped back into the SR. Thus, the rates of both release and uptake are increased, i.e. the rate of the cycle is increased so that the rate of ATP hydrolysis is very high, resulting in heat generation, and hence hyperthermia. This is analogous to an increase in rate of substrate cycles which also leads to transfer of chemical energy from ATP to heat (Chapter 2). How halothane effects the receptor cause to this release of Ca ions is not known. 

Figure 13.15 A diagram representing the Ca ion cycle between the sarcoplasmic reticulum (SR) and the cytosol. The Ca ion release from the SR is down a concentration gradient of about 1000-fold. The re-uptake of Ca ions back into the SR, therefore, reguires ATP hydrolysis to provide the energy to overcome this gradient (i.e. active transport). This is a transport cycle, equivalent to a substrate cycle (Chapter 3). The release of Ca ions is via a Ca ion channel. See text for details of acb vab on of the...

Stimulation of the intra- and inter-tissue triacylglycerol/ fatty substrate cycles results in better control of the... 

Substrate cycling (e.g. the Cori cycle and the intra- and inter-cellular triacylglycerol/fatty acid cycles (Chapter 3)) in which there is no net metabolic change so that the energy from ATP hydrolysis is released as heat. 

SUBSTRATE-ASSISTED CATALYSIS SUBSTRATE CHANNELING Substrate contaminated with the enzyme, BASAL RATE Substrate cycling,... 

FIGURE 15-21 Regulation of fructose 1,6-bisphosphatase-1 (FBPase-1) and phosphofructokinase-1 (PFK-1). The important role of fructose 2,6-bisphosphate in the regulation of this substrate cycle is detailed in subsequent figures. 

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