Inhibitors and Effectors

A procedure that utilizes quantitative structure-activity relationships to assist in the characterization and design of enzyme alternative substrates, inhibitors, and effectors. In this procedure, the inhibition (or activity) results of a series of structurally related compounds are analyzed to determine the coefficients in an equation of the form ... 

Sono M, Cady SG (1989) Enzyme kinetic and spectroscopic studies of inhibitor and effector interactions with indoleamine 2, 3-dioxygenase. 1. Norharman and 4-phenylimidazole binding to the enzyme as inhibitors and heme ligands. Biochemistry 28 5392-5399... 

Zhu LL, Lynch VM, Anslyn EV (2004) FRET Induced by an allosteric cycloaddition reaction regulated with exogenous inhibitor and effectors. Tetrahedron 60 7267-7275... 

Sorafenib is a multitargeted cancer therapy that inhibits VEGFR, PDGFR, KIT, fetal liver tyrosine kinase 3 (FLT-3), and the serine/threonine kinase RAF. RAF kinase is a key downstream effector of Ras in the MAPK/Ras signal-transduction pathway that has been linked to various cancers. Sorafenib is both a tyrosine kinase inhibitor and serine/threonine signal-transduction inhibitor. Sorafenib has been approved in renal cancer. 

The lack of structural similarity between a feedback inhibitor and the substrate for the enzyme whose activity it regulates suggests that these effectors are not isosteric with a substrate but allosteric ( occupy another space ). Jacques Monod therefore proposed the existence of allosteric sites that are physically distinct from the catalytic site. Allosteric enzymes thus are those whose activity at the active site may be modulated by the presence of effectors at an allosteric site. This hypothesis has been confirmed by many lines of evidence, including x-ray crystallography and site-directed mutagenesis, demonstrating the existence of spatially distinct active and allosteric sites on a variety of enzymes. 

Enzyme-specific inhibitor and activator proteins can be considered as a type of effector molecules. 

Malonyl CoA is an allosteric effector of carnitine acyl transferase. What kind of effector is it, i.e., activator or inhibitor, and what is the logic behind the interaction ... 

Just as the auto mechanic sometimes has parts left over, electron-density maps occasionally show clear, empty density after all known contents of the crystal have been located. Apparent density can appear as an artifact of missing Fourier terms, but this density disappears when a more complete set of data is obtained. Among the possible explanations for density that is not artifactual are ions like phosphate and sulfate from the mother liquor reagents like mercaptoethanol, dithiothreitol, or detergents used in purification or crystallization or cofactors, inhibitors, allosteric effectors, or other small molecules that survived the protein purification. Later discovery of previously unknown but important ligands has sometimes resulted in subsequent interpretation of empty density. 

If the metabolism of both substrate and effector are measured, the validity of treating the two processes independently can be tested. For example, we reported that 7,8-benzoflavone dramatically increases the Vm of phenanthrene metabolism by CYP3A4 and that phenanthrene is a partial inhibitor of... 

Which of the caspases must be inhibited in order to achieve reduced tissue damage One approach is to inhibit initiator caspases such as caspase-8 and -9. However, inhibiting the initiator caspase of the extrinsic or intrinsic pathways may not be sufficient since in many instances both pathways may be activated. Another approach is to inhibit the effector caspases since the both extrinsic and intrinsic pathways converge in these caspases. This approach has been successful in sepsis [184], However, the most commonly used approach is combination of both and is targeting initiator and effector caspases, using broad-spectrum (nonselective) inhibitors [185],... 

Compounds which exhibit specific interactions with a particular site of an enzyme other than an active site are called cofactors and allosteric effectors. These compounds are not considered in this review. Specific compounds which interact with the active site itself will be classified into two types. One of them include simple competitive inhibitors and photoaffinity labeling reagents. Compounds of this type exhibit a specific interaction only with the binding site (specificity site) of the enzyme. 

Structural models of protein and nucleic acid molecules derived by X-ray crystallography are exttemely interesting in themselves, each being a representative member of some architectural class of macromolecule shaped by evolutionary time and process toward the optimal completion of a specific cellular or metabolic task. They are nevertheless static objects. Because the catalytic functions they perform depend on dynamic events involving the interaction of the macromolecules with substrates, effectors, inhibitors, and other cellular components, we are constantly searching for techniques that will allow us to visualize the macromolecules in some intermediate stages of a biochemical or physiological activity. 

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