The 1992 Nobel
Prize for physiology and medicine was awarded to
Prof. Edwin G. Krebs and
Prof. Edmond H. Fisher, both of University of Washington, Seattle, U.S.A. for their pioneering work on 'reversible protein phosphorylation as a biological regulatiory mechanism'. Phosphorylation of proteins has been shown to affect transcription, translation, cell division, cell growth, cell differentiation, cell transformation and many other cellular processes. Regulation of enzyme activity by reversible phosphorylation has several advantages over
de novo synthesis of enzyme. The response is fast and the signal gets amplified. One molecule of kinase can phosphorylate several molecules of an enzyme. Activity of several non-enzymatic proteins like transcription factors is also regulated by reversible phosphorylation. It is estimated that a eukaryotic cell has about 1000 genes for different
protein kinases (for phosphorylation) and perhaps same number of genes for
protein phosphatases (for dephosphorylation).
Fig. 37.21. Reversible phosphorylation of phosphorylase enzyme at serine residue causing conformational changes in the enzyme.
The first protein (enzyme in this case), whose activity was shown to be regulated by phosphorylation was
glycogen phosphorylase (involved in breakdown of glycogen in muscle and liver). This enzyme exists in two forms,
phosphorylase a (not dependent on AMP for its activity) and
phosphorylase b (dependent on AMP for its activity). Reversible phosphorylation leading to interconversion of these two forms has been shown. Almost all of the enzyme is in an inactive 'b' form in resting muscle, which gets converted to the active 'a' form, when the level of hormone,
epinephrine, increases in the blood (Fig. 37.21).
Fig. 37.21. Reversible phosphorylation of phosphorylase enzyme at serine residue causing conformational changes in the enzyme.
Phosphorylation of protein occurs on many residues, but mainly
serine (Ser; 90-95%),
threonine (Thr; 5-10%) and
tyrosine (Tyr; <10%) are phosphorylated. Phosphorylation does not always lead to increase in enzyme activity, and in some cases may actually lead to decrease in activity (e.g. glycogen synthase). Sometimes positive and negative regulatory phosphorylation sites are present in the same enzyme, so that same enzyme may need two kinases and two phosphatases.
