Lecture 14. Enzyme regulation
Thursday 7 March 2019
Control of enzyme activity. Aspartate transcarbamoylase (ATCase) and allosteric control in enzymes. Control by covalent modification: Phosphorylation, kinases, and phosphatases.
Reading: Lehninger - Ch.6, pp.225-236.
Summary
Reading summary. §6.5 Regulatory enzymes. Allosteric enzymes undergo conformational changes in response to modulator binding. The kinetic properties of allosteric enzymes diverge from Michaelis-Menten behavior. Some enzymes are regulated by reversible covalent modification. Phosphoryl groups affect the structure and catalytic activity of enzymes. Multiple phosphorylations allow exquisite regulatory control. Some enzymes and other proteins are regulated by proteolytic cleavage of an enzyme precursor. A cascade of proteolytically activated zymogens leads to blood coagulation. Some regulatory enzymes use several regulatory mechanisms.
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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 (Primary example: phosphorylation and dephosphorylation by kinases and phosphatases, respectively. The text discusses the example of glycogen phosphorylase, which is activated by phosphorylation).
4. Proteolytic activation (Examples: processing of proenzyme forms of digestive enzymes; blood clotting cascade - see zymogens)
Loss of feedback inhibition: How beets became red.
A kinase is an enzyme that transfers a phosphate group - typically from the γ-phosphate from ATP - to a substrate molecule. If the substrate is a protein, the enzyme is referred to as a protein kinase. Kinases are ubiquitous metabolic and regulatory enzymes, and mediate links of signal transduction pathways. Of the many protein kinases in eukaryotic cells, some of the most important regulate key cellular processes such as the cell division cycle (Cyclins are a family of cell-cycle (external link to information on the cell cycle) regulatory proteins that are required by CDK (cyclin-dependent kinase) proteins for their activity. Entry into and transit through the cell cycle is a highly regulated process, to a large degree controlled by the phosphorylating activity of cyclin-cdk complexes. The cyclins themselves are regulated in a cell-cycle dependent manner. The cyclin-cdk complexes activate proteolytic pathways that lead to cyclin degradation, thus forming an autoregulatory feedback loop. In mammalian cells, progression through G1 requires cyclin D (in combination with cdk 4 or 6); the G1-S transition is dependent on cyclin E + cdk 2; the completion of S phase requires cyclin A + cdk 2; and cyclins A and B in combination with cdc 2 is required for the entry into G2 and the G2-M transition.) The most common amino acid residues targeted by protein kinases for modification are serine, threonine, and tyrosine. The actions of kinases are reversed by hydrolytic enzymes known as phosphatases. Edwin Krebs and Edmond Fischer won the 1992 Nobel Prize for Physiology or Medicine for their discoveries of "reversible protein phosphorylation as a biological regulatory mechanism".