Structural Biochemistry, Enzyme, Group Specific Reagent

Definition

Irreversible enzyme inhibitor that is for covalent modification that inactivates enzyme; or chemical that modifies by reaction with functional groups of enzyme.

Group specific reagents are enzyme inhibitors that can covalently bond to a particular amino acid residue on the enzyme and irreversibly modify it.It is less specific compared with affinity label and suicide inhibitor. It reacts with side chain of amino acid.

Two examples of group-specific reagents are diisppropylphosphoflouridate (modifies a serine residue) and iodoacetamide (modifies cystein residue)

(Image: Mlinht at English Wikibooks, Public domain)

(Image: Tinojasontran at English Wikibooks, Public domain)

Applications

Group-specific reagent (Image: Irynagutman at English Wikibooks, Public domain)

Group specific reagents are not only used to inhibit enzymes, but are also used to deduce if certain amino acid residues are very reactive and actually take on an important role in the catalysis of the product. For example, diisopropylphosphofluoridate (DIPF) modifies only one serine residue out of all the amino acid residues on the enzyme, chymotrypsin. By measuring the turnover rate before and after inhibition, one can determine if that serine residue is essential to the catalytic power of the enzyme. (The pink x in the figure has no meaning and should be ignored.)

(Image: Melowdeeh at English Wikibooks, Public domain)

Transition State Inhibitors

Transition state inhibitors, much like group specific reagents, resemble the substrate of the enzyme. Transitions state inhibitors are molecules which are originally derived from the substrate of the enzyme. They very much resemble the transition state of the substrate but are not 100% identical. Because of this, the transition state inhibitor is able to bind to the active site. However because of its subtle difference that makes it unique from the original substrate, the enzyme is unable to carry out its catalytic effects. An example of a transition state inhibitor is the transition-state analog pyrrole-2-carboxylic acid. This substance mimics the binding properties of D-proline; however, unlike D-proline, pyrrole-2-carboxylic acid is a trigonal molecule, whereas D-proline is tetrahedral. This difference makes pyrrole-2-carboxylic acid an inhibitor that is bound 160 times more tightly to racemase than is D-proline. The ability of transition-state analogs to bind so well to enzymes draws attention to the fundamental nature of catalysis: selective binding of the transition state[1].

One use of transition state inhibitors is the ability to create antibodies from them. By experimentally injecting transition state analogs in a rabbits, these rabbits were able to produce antibodies to the transition state analog as well as its intended converted substrate. These antibodies, however, were found to be not as efficient those antibodies which actually were created as a result of being injected with the actual substrate.

References

[1] Berg, Jeremy M., Tymoczko, John L., and Stryer, Lubert. Biochemistry. 6th ed. New York, N.Y.: W.H. Freeman and Company, 2007: 231, 232.

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