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Gly synthase via nase via nase


Further regulation is brought about by glucose itself. Glucose binds to a specific site on phosphorylase a, causing a conformational change that makes the enzyme a better substrate for dephosphorylation by protein phosphatase-1G. Thus, in the liver, an increase in the intracellular glucose concentration will itself lead to inactivation of phosphorylase.

Glycogen synthesis

Insulin acts via PKB to phosphorylate and inactivate glycogen synthase kinase-3 (GSK-3: see Fig. 2.4.1, Box 2.4). It also activates protein phosphatase-lG, bringing about the dephosphorylation (and thus activation) of glycogen synthase, by conversion from its inactive, phosphorylated form (shown as gly synthase b) to its active, dephosphorylated form (gly synthase a). Insulin also inhibits glycogenolysis as described above. Thus, there is coordinated control of glycogen synthesis and breakdown: when one process is stimulated, the other is inhibited.

The pathways are similar in muscle although there are differences in regulation (see Fig. 8.8). For instance, in muscle glycogen breakdown is more susceptible to allosteric effects of AMP (activation) and glucose 6-phosphate (inhibition). Liver glycogen breakdown seems - very reasonably - to respond more to stimuli from outside the cell (i.e. hormones and the glucose concentration). Glycogen synthase in muscle is also phosphorylated by PKA, whereas liver glycogen synthase lacks the relevant phosphorylation sites. Therefore, in muscle adrenaline may also act via PKA to inhibit glycogen synthesis.

Information for this box taken from (amongst others) Cohen (1999); Bollen et al. (1998).

the pathway of gluconeogenesis is like glycolysis in reverse, but there are some essential differences in the enzymatic steps, and these are the points at which regulation occurs (Box 4.2). The substrates for gluconeogenesis are smaller molecules: usually, in order of importance, lactate, alanine, glycerol. Other amino acids can also serve as gluconeogenic precursors, although alanine is by far the most important, for reasons that will be discussed in Section 6.4.2.

The pathway of gluconeogenesis is controlled by two major factors: by the rate of supply of substrate, and by hormonal regulation of the enzymes concerned (discussed in detail in Box 4.2). As in the case of glycolysis, hormonal control involves both acute effects and effects on gene expression. As Table 2.5 shows, the expression of some enzymes of gluconeogenesis is down-regulated by insulin.

Overall, gluconeogenesis is stimulated by glucagon and inhibited by insulin whilst glycolysis is favoured under the opposite conditions. The stimulation of gluconeogenesis by glucagon also occurs in part because of direct stimulation of the transporters for uptake of substrates (particularly alanine) from the

Box 4.2 The pathways of glycolysis and gluconeogenesis and their hormonal regulation

Pathways and abbreviations

The pathways are shown as they occur in the liver. Fine-dashed arrows in pathways indicate multiple enzymatic steps. Dashed arrows indicate regulation. The dotted ellipse is the mitochondrial membrane. Co-substrates including ATP, ADP, P, GTP and CO2 are not shown, for simplicity. Substrates: G 6-P, glucose 6-phosphate; F 6-P, fructose 6-phosphate; F 1,6-P2, fructose 1,6 bisphosphate; F 2,6-P2, fructose 2,6-bisphosphate; Glyc 3-P, glyceraldehyde 3-phosphate; DHAP, dihydroxyacetone phosphate; PEP, phosphoenolpyruvate. Enzymes: GK, glucokinase; G-6-Pase, glucose-6-phosphatase; PFK, phos-phofructokinase; FBP, fructose-1,6 bisphosphatase; PK, pyruvate kinase; PC, pyruvate carboxylase; PEPCK, phosphoenolpyruvate carboxykinase; Glyc-K, glycerol kinase; LDH, lactate dehydrogenase; AAT, alanine aminotransferase. The enzyme marked BFE is a single, bifunctional enzyme known as 6-phos-phofructo-2-kinase/fructose-2,6-bisphosphatase, responsible for formation and breakdown of F 2,6-P2, a compound with a crucial role in regulation of these pathways.

Glucose A GLUT2

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