Allosteric and feedback regulation

Allosteric and feedback regulation

1. ALLOSTERIC AND FEEDBACK REGULATION Presented by Akshaya Anil M.Phil Biochemistry Kerala University

2. History The term allosteric has been introduced by the two Noble laureates, MONOD AND JACOB , to denote an enzyme site, different from the active site ,which non competitively bands molecule other than the substrate and may influence the enzyme activity. Allosteric Enzyme: Enzymes having allosteric sites (Greek; allo-other) besides the active site. The allosteric sites are unique places on the enzyme molecules; allosteric enzymes have one or more allosteric site.

3. Properties of allosteric regulation Their kinetics do not obey the Michaelis–Menten equation. Inhibition of a regulatory enzyme by a feedback inhibitor does not conform to any normal inhibition Positively or negatively affect enzyme activity Have an oligomeric organization. Regulatory effects exerted on the enzyme’s activity are achieved by conformational changes occurring in the protein when effector metabolites bind.

4. Sigmoid curve M echanism responsible for the S-shaped curves is that binding of one S to a protein molecule makes it easier for additional substrate molecules to bind to the same protein molecule. In the jargon of allostery, substrate binding is cooperative.

5. MODELS OF ALLOSTERIC REGULATION Two main model have been proposed to describe the mechnastic basis of enzyme allostery: Symmetrical model :Given by MONOD,WYMAN AND CHANGEUX . Sequential model : Given by KOSHLAND, NEMETHY AND ALLOUS

6. Symmetrical model

7. Sequential model:

8. TYPES OF ALLOSTERIC EFFECTORS Homotropic : •A homotropic allosteric modulator is a substrate for its target enzyme,which regulate enzyme's activity. It is typically an activator of the enzyme. Heterotropic : •A heterotropic allosteric modulator is a regulatory molecule other than enzyme's substrate. It may be either an activator or an inhibitor of the enzyme. Positive heterotrophic effectors - Postive heterotrophic effectors/Allosteric activators Negative heterotrophic effectors - Negative heterotrophic effector/Allosteric inhibitors

9. Allosteric regulation of glycogen phosphorylase

10. Feedback inhibition Feedback inhibition is the phenomenon where the output of a process is used as an input to control the behavior of the process itself, oftentimes limiting the production of more product.

11. Feedback inhibition

12. Applications Recently, the combined use of physical techniques (for example, x-ray crystallography and solution small angle x-ray scattering or SAXS) and genetic techniques (site-directed mutagenesis or SDM) has enabled researchers to investigate more deeply the molecular basis of allostery. The Escherichia coli enzyme aspartate carbamoyltransferase (ATCase) has established itself as one of the model system's for allosteric regulation. However, it is irrefutable that the canonical allosteric system that has shaped our current understanding of allostery is tetrameric vertebrate Hemoglobin. Long-range allostery is especially important in cell signaling. Pharmacology