Glycolysis in hepatocytes

Glycolysis could be justly considered as one of the main and most studied biochemical pathways in the cell. Historically, the research of cell metabolism began exactly from this pathway. However, in spite of this it plays the main role not in all types of cells, because the rate of this process and loading on it significantly depends on carbon source in the medium and presence of oxygen. The object of our research is glycolysis it mammalian liver cells, where load on it is big enough. Moreover, this process has two significant differences in comparison with analogical ones in the others organisms.

  • First from them is connected with colossal hormone load on the glycolysis. In the liver cells this metabolic pathway is influenced directly by some very important hormones (insulin, glucagons, etc). It significantly complicates the nets of gene and metabolic regulation, adding into them new elements and systems. Moreover, derangements in hormone control during the several diseases (for example, diabetes) seriously influence the metabolism in such cellular systems, research of that allows making some conclusions about mechanisms of pathological alterations.

  • The second feature consists in the fact that glycolysis in mammalian cells associated with apoptotic processes, i.e. with programming cell death. Exactly on the mammalian liver cells the connection of apoptosis directly with central cellular metabolism was found. It is very important step in the research of this phenomenon, because it have been earlier believed that only special special extracellular signal factors (TNF) or intramitochondrial regulatory processes (Bcl-like protens) can start the processes of cell suicide.

HKII_engSuch connection was found while only for one step of glycolisis, its first reaction - glucose phosphorylation. It occurs by such way (see the figure). This reaction in the liver cells is catalyzed by three enzyme isoforms - hexokinase type I, III and IV. The last two represent ordinary cytoplasmic enzymes without essential regulation and with moderate glucose affinity. The first hexokinase isoform has a number of differences from its analogs. Firstly, high glucose affinity; secondly, strong inhibition by product – glucose-6-phosphate. Third, the most essential difference - this enzyme is able to connect with mitochondrion, the enzyme properties essentially change at that. Moreover, connection with mitochondrion realizes in the definitely place of external membrane – on the transmembrane proteins VDAC. In that way complex from mitochondrial transporters ANT, VDAC and hexokinase I (primordial cytoplasmic enzyme) form. After formation of such complex VDAC lose the ability to connect with Bcl-like proteins and consequently, to start apoptotic cascades. In other words, connection of hexokinase I with mitochondrion has antiapoptotic effect and is able to block programming cell death. It should be add that this process directly depends on physiological conditions in the cell, i.e. on the concentration of some primary intermediates of cell metabolism.

It is early to say about of this research results now, because we only began it and were limited by development of some detailed model of individual enzymes and mechanism of hexokinase I binding with mitochondrion. However, taking into account the interest which this research causes in the scientific circles, it is possible to say that this project will have great future.

 

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