Regulation by isoenzymes
Definition: multiple forms of enzymes
Enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These
enzymes usually display different kinetic parameters (e.g. different KM values), or different
regulatory properties. The existence of isozymes permits the fine-tuning of metabolism to meet
the particular needs of a given tissue or developmental stage. In biochemistry, isozymes (or
isoenzymes) are isoforms(closely related variants) of enzymes. In many cases, they are coded for
by homologous genes that have diverged over time.
An example of an isozyme is glucokinase, a variant of hexokinase which is not inhibited
by glucose 6-phosphate.
The enzyme lactate dehydrogenase is a tetramer made of two different sub-units, the H-form and
the M-form.
The existence of these isozymes was first recognized byUmbarger and his associates as a
consequence of their studies on the feedback regulation of isoleucine' and valine2 biosynthetic
pathways.
Regulatory isozymes may be grouped in the following four arbitrary categories: (1) enzymes that
catalyze common steps in a branched biosynthetic pathway leading to the formation of two or
more end products; (2) enzymes that catalyze a step that is common to biosynthetic and to
degradative metabolic pathways; (3) enzymes that catalyze a common step in two separate
degradative pathways; and (4) enzymes that catalyze the same overall reaction but which differ
with respect to their cofactor specificities.
Isoenzymes in branched biosynthetic pathway
Effective regulation of branched biosynthetic pathways can be achieved by tight metabolic
control of the first common step in the pathway and also of the first divergent steps uniquely
concerned with the formation of each ultimate end product. However, if the first common step is
catalyzed by a single enzyme, problems may arise if its control involves feedback inhibition or
repression of enzyme synthesis by one of the ultimate end products. Then, an over-supply of one
end product could theoretically curtail the synthesis of intermediates needed also for the
formation of other end products.
These studies disclose the existence of several novel mechanisms for effective feedback control.
One of the most effective mechanisms involves the elaboration of multiple enzymes catalyzing
the first common step, these enzymes differing from each other with respect to their
susceptibility to, and specificity of, end-product control. One of the most effective mechanisms
involves the elaboration of multiple enzymes catalyzing the first common step, these enzymes
differing from each other with respect to their susceptibility to, and specificity of, end-product
control
In this mechanism, which is illustrated in Fig. , the first common step (step a) in the pathway is catalyzed
by two different enzymes, one of which is under specific feedback control by the end product E and the
other is specifically controlled by compowd G. An excess of compound E can therefore inhibit only that
fraction of step a activity that is catalyzed by the E-sensitive enzyme. The residual step a activity
resulting from the G-sensitive enzyme would still be available for the production of compounds B and C
needed for the continued synthesis of compound G. In order to prevent further utilization of B and C for
the synthesis of E, there is a, second feedback control of step c by the end product. This latter
represents a simple case of feedback inhibition of the first committed step in the biosynthetic pathway
by the ultimate end product. As illustrated by Fig. a parallel set of feedback controls of the G-sensitivc
step a activity and of step d limits the synthesis of intermediates that are common to both end products
but assures normal production of E in the presence of an excess of G. Finally, when both end products
are in excess the entire pathway becomes inoperative.
Fig: Enzyme multiltiplicity in the regulation of branched pathways
Multiple Enzymes in the Regulation of Aspartate Metabolism
Multiple enzymes form the basis of effective regulatory patterns for a number of biosynthetic
pathways. The first branched biosynthetic pathway shown to be under multiple enzyme control is
that concerned with the biosynthesis of lysine, methionine, and threonin.
These amino acids are all derived from aspartate by a branched pathway in which the
phosphorylation of aspartate, catalyzed by aspartokinase
Thus, in E. coli three different aspartokinases and two different homoserine dehydrogenases are
involved in the feedback control of the highly branched pathway by which aspartate is utilized
for the synthesis of lysine, threonine, methionine and and isoleucine. One of the aspirate kinase
enzymes is selectively inhibited and repressed by lysine, while another is specifically inhibited
by threonine