Control of glycolysis and gluconeogenesis

The first point of regulation is the interconversion of fructose phosphate to fructose 1,6-bisphosphate (Fig. 3.8). 6-Phosphofructokinase has been purified from liver and from breast muscle of domestic fowl (Kono Uyeda, 1973) and crystallised from the former. It is an oligomeric enzyme comprising identical subunits of 60 kDa The important features 

6-Phosphofrudo-2-kinase adivity is inhibited by dtrate and by PEP. A difference between this bifunctional enzyme in liver and in muscle is that the former is pho horylated by cAMP-depaident protein kinase, causing inadivation of the kinase adivity and adivation of the phosphatase. The pigeon muscle enzyme, however, is not phosphorylated by cAMP-dqrendent protein kinase but, nevertheless, its activities 

The mechanisms involved are still imclear but may involve protein kinase C. 

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Newsholme, E. A., and Gevers, W., 1967, Control of glycolysis and gluconeogenesis in liver and kidney cortex, Vitam. Horm. 25 1. 

Having now considered the principles of metabolic regulation, we can turn our attention to some real pathways and study how the theory is put into practice. Further details of the control reactions of glycolysis and gluconeogenesis are given in Section 6.4.2. 

We begin our examination of the coordinated regulation of glycolysis and gluconeogenesis by considering the regulatory patterns seen at the three main control... 

Pyruvate carboxylase - This enzyme is found only in the mitochondrial matrix, apart from the other enzymes of glycolysis and gluconeogenesis. It can be activated by acetyl-CoA, but it is not clear what role it has in the overall control of the enzyme, since cellular levels of acetyl-CoA are far higher, under most conditions, than the concentration giving half-maximal stimulation. 

The interconversion of fructose-6-phosphate and fructose-1,6 bis phosphate is a control point in glycolysis and gluconeogenesis. Gluconeogenesis is a pathway which allows carbon atoms from substrates such as lactate, glycerol and some amino acids to be used for the synthesis of glucose, so it is in effect physiologically the opposite of... 

To limit futile cycling between glycolysis and gluconeogenesis, the two pathways are under reciprocal allosteric control, mainly achieved by the opposite effects of fructose 2,6-bisphosphate on PFK-1 and FBPase-1. 

As we have seen in glycolysis and gluconeogenesis, biosynthetic and degradative pathways rarely operate by precisely the same reactions in the forward and reverse directions. Glycogen metabolism provided the first known example of this important principle. Separate pathways afford much greater flexibility, both in energetics and in control. 

As was the case with glycolysis and gluconeogenesis, it would be futile for the cell to carry out glycogen synthesis and degradation simultaneously. The results achieved by the action of one pathway would be imdone by the other. This problem is avoided by a series of hormonal controls that activate the enzymes of one pathway while inactivating the enzymes of the other pathway. 

Now that we know something about the effects of hormones in triggering responses within the cell, we can return to and expand on some earlier points about metabolic control. In Section 18.3, we discussed some points about control mechanisms in carbohydrate metabolism. We saw at that time how glycolysis and gluconeogenesis can be regulated and how glycogen synthesis and breakdown can respond to the body s needs. Phosphorylation and dephosphorylation of the appropriate enzymes played a large role there, and that whole scheme is subject to hormonal action. 

Describe the coordinated control of the enzymes in glycolysis and gluconeogenesis. Include a discussion of the effects of the hormones insulin and glucagon. 

Activity of phosphofructokinase and fructose 1,6-diphosphatase in mammals can be finely controlled within the cell to regulate glycolysis and gluconeogenesis, and there is some evidence to suggest a similar control mechanism in seedling tissues [53a]. 

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