The latter option is inherently a long-term one and will be discussed later. In contrast,
there are several mechanisms by which the activity of an enzyme can be altered almost
instantaneously:- Product inhibition:Here the product produced by the enzyme acts as an inhibitor of the
reaction so that unless the product is removed by further metabolism the reaction will
cease. An example is the inhibition of hexokinase by glucose-6-phosphate. Hexokinase
exists in four isoenzyme forms I, II, III and IV. The first three isoforms all have a lowKm
for glucose (about 10–100mM) and are inhibited by glucose-6-phosphate, whereas
isoform IV has a higherKm(10mM) and is not inhibited by glucose-6-phosphate.
Isoform IV is confined to the liver where its higherKmallows it to deal with high glucose
concentrations following a carbohydrate-rich meal. The other three isoforms are
distributed widely and do not encounter such high glucose concentrations as those found
in the liver. Thus their lowerKmvalues allow them to work optimally under their
prevailing physiological conditions. - Allosteric regulation:Here a small molecule that may be a substrate, product or
key metabolic intermediate such as ATP or AMP alters the conformation of the
catalytic site as a result of its binding to an allosteric site. A good example is the
regulation of 6-phosphofructokinase discussed earlier. - Reversible covalent modification:This may involve adenylation of a Tyr residue by
ATP (e.g. glutamine synthase), the ADP-ribosylation of an arginine residue by NADþ
(e.g. nitrogenase) but most frequently involves the phosphorylation of specific Tyr, Ser
or Thr residues by a protein kinase. Most significantly, phosphorylation is reversible by
the action of a phosphatase. Phosphorylation introduces the highly polarg-phosphate
group of ATP that is capable of inducing conformational changes in the enzyme structure
such as to either activate or deactivate the enzyme. Reversible covalent modification is
quantitatively the most important of the three mechanisms. A characteristic feature of
many of these kinases is that they are involved in a cascade of enzyme reactions such
as glycogenolysis and glycogenesis that will be discussed in the following section.
Such cascades offer the opportunity for fine metabolic control and a large amplification
of the original signal received by the membrane receptor.
15.5.2 Control of metabolic pathways
A large proportion of the thousands of enzymes in a cell are involved in the promotion
of coordinated chemical pathways such as glycolysis, the citric acid cycle and the
biosynthesis of fatty acids and steroids. Enzymes linked in a coordinated pathway are
frequently clustered in one of three ways namely:- by being located in the same compartment of the cell;
- by being physically associated as a multienzyme complex such as that of the fatty acid
synthase ofE. coli; - by being membrane-bound such as the enzymes of electron transport.
This clustering facilitates the transport of the product of one enzyme to the next
enzyme in the pathway.616 Enzymes