Biology Reference
In-Depth Information
1956), that is, the frequent occurrence of the end metabolite of a pathway acting
as inhibitor of one of the earlier enzymes in its production. Great significance
was attached to the discovery of a control mechanism that was a common
motif in man-made devices. Again, however, there was no detailed theory of
the operation of feedback inhibition; it was assumed to control the rate of a
metabolic pathway by analogy with known control mechanisms. These different
strands came together into the generalisation that metabolic pathways began
with a committed step (an irreversible reaction) that was often controlled by
feedback inhibition and which was the rate-limiting step of the pathway. The best
attempts to systematise these beliefs were by Rolleston (1972) and Newsholme
and colleagues (Crabtree & Newsholme, 1985; Newsholme and Start, 1973).
These ideas were also presented as criteria for the identification of the rate-
limiting step in a pathway. As so often in biology, teleological explanation had
come to the fore: the features of the pathways were explained in terms of the
function of controlling metabolic rates.
Needless to say, a number of shortcomings with these ideas began to emerge.
First, on occasions different groups would examine the evidence and nominate
different steps as the rate-limiting step of a pathway. For example, there were
conflicting claims for the site of control of mitochondrial respiration, as sum-
marized by Groen et al. (1982). The traditional axioms of metabolic control
were not so specific as to be able to decide between competing interpretations.
Secondly, the representation of pathways was sometimes made to fit the gen-
eralisations rather than the other way round. For example, it is rare to see the
pathway for synthesis of the amino acid threonine drawn correctly in any topic.
The first step, aspartate kinase, uses ATP and is represented as an irreversible
committed step, further underlined by the fact that the enzyme is feedback
inhibited (by threonine, and usually lysine, depending on the organism). As
it happens, the equilibrium constant of the aspartate kinase reaction does not
favour the direction of threonine synthesis (Black & Wright, 1955; Chassagnole
et al., 2001); the reaction is a close analogue of that of phosphoglycerate kinase
from glycolysis when working in the gluconeogenic direction. Hence we have
a first pathway step that counters the principles because, although it converts
ATP to ADP, it is reversible and is catalysed by a feedback-inhibited enzyme;
recent evidence suggests it is far from being a rate-limiting step, which probably
does not exist in the threonine synthesis pathway (Chassagnole et al., 2001).
Another counter-example to the generalisations is mammalian serine synthesis;
this three-enzyme pathway has two reversible steps at the beginning, followed by
an irreversible step that is product-inhibited (through non-cooperative, uncom-
petitive inhibition) by serine. Most control of the pathway is in the last enzyme
(Fell & Snell, 1988). This different control pattern is not the result of some
chemical or thermodynamic imperative, as the bacterial pathway begins more
conventionally with a serine-inhibited enzyme (Pizer, 1963).
