Lecture 23. Enzyme regulation
Wednesday 2 November 2016
Control of enzyme activity. Aspartate transcarbamoylase (ATCase) and allosteric control in enzymes. Control by covalent modification: Phosphorylation, kinases, and phosphatases. Drug design. Cytochromes P450.
Reading: VVP4e - Ch.12, pp.376-391.
Summary
There are numerous ways in which the activity of enzymes are regulated. More generally, the regulation of protein function by specific ligand interactions (including interactions with other proteins) and covalent modifications are key features in the organizational and control mechanisms of living organisms. The regulatory strategies we will consider are the following:
1. Allosteric control. Examples: Hemoglobin and aspartate transcarbamoylase (ATCase).
2. Multiple forms of enzymes - "isozymes"
3. Reversible covalent modification. There are a great many types of posttranslational modifications that affect the functional properties of proteins. The primary example of this general regulatory mechanism is phosphorylation and dephosphorylation by kinases and phosphatases, respectively. The example of glycogen phosphorylase [EC 2.4.1.1], the enzyme responsible for liberating glucose from storage in glycogen and which is activated by phosphorylation, illustrates how the action of kinases and phosphatases exerts regulatory effects on carbohydrate metabolism.
4. Proteolytic activation (Examples: processing of proenzyme (zymogen) forms of digestive enzymes; blood coagulation cascade.
Drug design
Historically, pharmacology has relied on empirical observations. More recently, as knowledge about biological function at the molecular level has accumulated, it has fostered attempts to exploit understanding of molecular mechanisms in development of therapeutic interventions (see Ref 1, Ch.12, pp.394-400).