Lactate favours the dissociation of skeletal muscle 6-phosphofructo-1-kinase tetramers down-regulating the enzyme and muscle glycolysis

Abstract

For a long period lactate was considered as a dead-end product of glycolysis in many cells and its accumulation correlated with acidosis and cellular and tissue damage. At present, the role of lactate in several physiological processes has been investigated based on its properties as an energy source, a signalling molecule and as essential for tissue repair. It is noteworthy that lactate accumulation alters glycolytic flux independently from medium acidification, thereby this compound can regulate glucose metabolism within cells. PFK (6-phosphofructo-1-kinase) is the key regulatory glycolytic enzyme which is regulated by diverse molecules and signals. PFK activity is directly correlated with cellular glucose consumption. The present study shows the property of lactate to down-regulate PFK activity in a specific manner which is not dependent on acidification of the medium. Lactate reduces the affinity of the enzyme for its substrates, ATP and fructose 6-phosphate, as well as reducing the affinity for ATP at its allosteric inhibitory site at the enzyme. Moreover, we demonstrated that lactate inhibits PFK favouring the dissociation of enzyme active tetramers into less active dimers. This effect can be prevented by tetramer-stabilizing conditions such as the presence of fructose 2,6-bisphosphate, the binding of PFK to f-actin and phosphorylation of the enzyme by protein kinase A. In conclusion, our results support evidence that lactate regulates the glycolytic flux through modulating PFK due to its effects on the enzyme quaternary structure.

Lactic Acid and Acidification Inhibit TNF Secretion and Glycolysis of Human Monocytes

“…It is known that lactate inhibits PFK-1, a key regulatory enzyme of glycolysis, and favors the dissociation of active PFK-1 tetramers into less active dimers (42). In the light of our findings, intracellular lactate accumulation could suppress PFK-1 and thereby reduce the glycolytic flux in monocytes.…”

Bistability in Glycolysis Pathway as a Physiological Switch in Energy Metabolism

“…In those cases, the high levels of lactate accumulated in culture causes inhibition of PFK [54], [55] and induces a shift in the metabolism to lactate consumption (Mulukutla et al, in preparation). The extended model includes the pentose phosphate pathway (PPP) and the TCA cycle.…”

Proteomic changes to the sarcoplasmic fraction of predominantly red or white muscle following acute heat stress

“…Muscle phosphofructokinase can be phosphorylated at several sites by several protein kinases, which are dependent on what hormones (insulin, epinephrine, or others) are regulating the phosphorylation [44]. Phosphorylation decreases the inhibitory effect of ATP or lactate on phosphofructokinase by stabilizing the tetrameric form of the enzyme [45,46]. Indeed, many studies have shown an increase in circulating insulin in response to heat stress when compared to pair fed counterparts [11,12].…”