Biology Reference
In-Depth Information
1.
INTRODUCTION
The implied promise that drove the rise of genome sequencing was that, once
we had the genetic blueprint of an organism, we would understand the basis of
its attributes and its vulnerabilities, first for an average member of the species,
but ultimately for specific individuals. If this is realisable at all, then it should
surely be possible for an organism's metabolism, because this is an aspect of
the phenotype that we know is coded in the genome in a very simple way:
genes specify enzymes and transporters, these proteins catalyse chemical and
transport reactions, and the resulting network of transformations constitutes the
metabolism. Indeed, by the time genome sequencing got under way, metabolism
was widely regarded as a problem that had been solved. If that were really true,
then there should be little difficulty in designing the changes in metabolism nec-
essary to make cells produce more of a desired product (metabolic engineering)
or in selecting a step in metabolism to inhibit so that a pathogenic organism
dies whilst the host is unaffected (target selection in drug development). But
in neither field is it the norm to be able to accurately predict beforehand the
consequences of an intervention. In this chapter, I will consider how our modes
of explanation of metabolic phenomena are changing with the rise of systems
biology, and whether we are becoming better placed to claim that we understand
metabolism. Although I will draw examples from metabolism, other cellular
processes such as signal transduction and the cell cycle show essentially similar
attributes.
2. TRADITIONAL PRINCIPLES OF METABOLISM
Biochemistry textbooks have almost always contained a section called 'principles
of metabolism' that was until recently largely based on the ideas prevalent
in the 1960s and 1970s. The distinction between reversible and irreversible
reactions and the need to bypass irreversible reactions by one or more different
reactions to reverse a pathway (as in the case of glycolysis and gluconeogenesis)
were underpinned by arguments from classical thermodynamics. Other concepts
seemed to have no stronger foundations other than being claims about recurrent
features in metabolism or statements of opinion. The concept of the control of
a metabolic pathway by a single rate-limiting step was strongly promoted by
Krebs (1957), having originated with Blackman (1905) in the context of the
response of plant photosynthesis to environmental factors. There was no real
theoretical underpinning of the concept, to the extent that Denton & Pogson
(1976) justified it as a truism.
However, the rate-limiting step concept was strengthened by the discovery of
feedback inhibition in metabolic pathways (Umbarger, 1956; Yates & Pardee,
