Substrate cycle

Example of a substrate cycle: Simultaneous conversion of fructose-6-phosphate (F6P) into fructose-1,6-bisphosphate (F-1,6-bP) and vice versa.

Substrate cycles are exceptional cases in metabolism . At first glance, they seem pointless, since catabolic and anabolic reactions occur simultaneously. For this reason, they are also, especially in the English-language literature, as futile cycles (Engl. Futile = useless, useless), respectively.

meaning

Signal amplification

A substrate cycle is linked to the consumption of energy, but has no direct benefit. Opposing reactions such as the phosphorylation of fructose-6-phosphate (F-6P) to fructose-1,6-bisphosphate (F-1,6-bP; reaction of glycolysis ) or its reverse reaction (reaction of gluconeogenesis ) do not normally run simultaneously: both metabolic pathways are regulated separately.

However, there are some tissues for which such a phenomenon has been proven. Various reasons are considered for this, such as the amplification of metabolic signals. In the above example, the phosphorylation of F6P to F-1,6-bP (100 molecules per unit of time) only slightly exceeds the counter- hydrolysis of F-1,6-bP to F6P. By AMP, an energy deficiency signal , the enzyme of the forward reaction ( phosphofructokinase ) and that of the backward reaction ( fructose-1,6-bisphosphatase ) are counter-regulated (increase to 120 molecules for PFK, decrease to 72 molecules for FBPase). This increases the metabolite flow from 10 to 50 units, it increases fivefold due to an only approx. 20% change in the reaction rate in both directions.

Generation of heat

The substrate cycle shown here "destroys" (hydrolyses) ATP in the balance with heat generation

${\displaystyle \mathrm {{\text{Fructose-6-phosphat}}+ATP{\xrightarrow {PFK}}{\text{Fructose-1,6-bisphosphat}}+ADP} }$

${\displaystyle \mathrm {{\text{Fructose-1,6-bisphosphat}}+H_{2}O{\xrightarrow {FPBase}}{\text{Fructose-6-phosphat}}+P_{i}} }$

In the net balance, no new products are created, but ATP is hydrolyzed. The inherent energy is released as heat:

${\displaystyle \mathrm {ATP+H_{2}O\longrightarrow ADP+P_{i}+{\text{W}}{\ddot {a}}{\text{rme}}} }$

This mechanism has been proven for the flight muscles of the bumblebee . Bumblebees are the first insects to leave their burrows after the end of winter . Through the substrate cycle described, dormant bumblebees generate heat that they need to survive.

There is a rare hereditary disease in humans, malignant hyperthermia . Here a substrate cycle is triggered by anesthetic gases in a process in which calcium ions participate. The regular involvement of substrate cycles in heat generation is controversial in mammals. However, in rats with hypothyroidism, the survival rate at 5 ° C decreases in accordance with the fact that thyroid hormones stimulate metabolism in most tissues.

Individual evidence

1. ↑ EA Newsholme, B. Crabtree, SJ Higgins, SD Thornton, C. Start: The activities of fructose diphosphatase in flight muscles from the bumble-bee and the role of this enzyme in heat generation . In: The Biochemical journal. Volume 128, Number 1, June 1972, pp. 89-97, PMID 4343671 , PMC 1173573 (free full text).