How Enzymes Work:- Specific Catalytic Groups Contribute to Catalysis

In most enzymes, the binding energy used to form the ES complex is just one of several contributors to the overall catalytic mechanism. Once a substrate is bound to an enzyme, properly positioned catalytic functional groups aid in the cleavage and formation of bonds by a variety of mechanisms, including general acid-base catalysis, covalent catalysis, and metal ion catalysis. These are distinct from mechanisms based on binding energy, because they generally involve transient covalent interaction with a substrate or group transfer to or from a substrate.

General Acid-Base Catalysis Many biochemical reactions involve the formation of unstable charged intermediates that tend to break down rapidly to their constituent reactant species, thus impeding the reaction (Fig. 6–8). Charged intermediates can often be stabilized by the transfer of protons to or from the substrate or intermediate to form a species that breaks down more readily to products. For nonenzymatic reactions, the proton transfers can involve either the constituents of water alone or other weak proton donors or acceptors. Catalysis of this type that uses only the H⁺ (H₃O⁺) or OH^- ions present in water is referred to as specific acid-base catalysis. If protons are trans ferred between the intermediate and water faster than the intermediate breaks down to reactants, the inter mediate is effectively stabilized every time it forms. No additional catalysis mediated by other proton acceptors or donors will occur. In many cases, however, water is not enough. The term general acid-base catalysis refers to proton transfers mediated by other classes of molecules. For nonenzymatic reactions in aqueous solutions, this occurs only when the unstable reaction intermediate breaks down to reactants faster than protons can be transferred to or from water. Many weak organic acids can supplement water as proton donors in this situation, or weak organic bases can serve as proton acceptors.

In the active site of an enzyme, a number of amino acid side chains can similarly act as proton donors and acceptors (Fig. 6–9). These groups can be precisely positioned in an enzyme active site to allow proton transfers, providing rate enhancements of the order of 10² to 10⁵. This type of catalysis occurs on the vast majority of enzymes. In fact, proton transfers are the most common biochemical reactions.

Covalent Catalysis In covalent catalysis, a transient co valent bond is formed between the enzyme and the substrate. Consider the hydrolysis of a bond between groups A and B:

In the presence of a covalent catalyst (an enzyme with a nucleophilic group X:) the reaction becomes

This alters the pathway of the reaction, and it results in catalysis only when the new pathway has a lower activation energy than the uncatalyzed pathway. Both of the new steps must be faster than the uncatalyzed reaction.

FIGURE 6–8 How a catalyst circumvents unfavorable charge devel opment during cleavage of an amide. The hydrolysis of an amide bond, shown here, is the same reaction as that catalyzed by chymotrypsin and other proteases. Charge development is unfavorable and can be circumvented by donation of a proton by H₃O⁺ (specific acid catalysis) or HA (general acid catalysis), where HA represents any acid. Similarly, charge can be neutralized by proton abstraction by OH^- (specific base catalysis) or B (general base catalysis), where B rep resents any base.

A number of amino acid side chains, including all those in Figure 6–9, and the functional groups of some enzyme cofactors can serve as nucleophiles in the formation of covalent bonds with substrates. These covalent complexes always undergo further reaction to regenerate the free enzyme. The covalent bond formed between the enzyme and the substrate can activate a substrate for further reaction in a manner that is usually specific to the particular group or coenzyme.

Metal Ion Catalysis Metals, whether tightly bound to the enzyme or taken up from solution along with the substrate, can participate in catalysis in several ways. Ionic interactions between an enzyme-bound metal and a substrate can help orient the substrate for reaction or stabilize charged reaction transition states. This use of weak bonding interactions between metal and substrate is similar to some of the uses of enzyme-substrate binding energy described earlier. Metals can also mediate oxidation-reduction reactions by reversible changes in the metal ion’s oxidation state. Nearly a third of all known enzymes require one or more metal ions for catalytic activity.

Most enzymes employ a combination of several catalytic strategies to bring about a rate enhancement. A good example of the use of both covalent catalysis and general acid-base catalysis is the reaction catalyzed by chymotrypsin. The first step is cleavage of a peptide bond, which is accompanied by formation of a covalent linkage between a Ser residue on the enzyme and part of the substrate; the reaction is enhanced by general base catalysis by other groups on the enzyme (Fig. 6–10). The chymotrypsin reaction is described in more detail in Section 6.4.

FIGURE 6–9 Amino acids in general acid-base catalysis. Many organic reactions are promoted by proton donors (general acids) or proton acceptors (general bases). The active sites of some enzymes contain amino acid functional groups, such as those shown here, that can participate in the catalytic process as proton donors or proton acceptors.

FIGURE 6–10 Covalent and general acid-base catalysis. The first step in the reaction catalyzed by chymotrypsin is the acylation step. The hydroxyl group of Ser195is the nucleophile in a reaction aided by general base catalysis (the base is the side chain of His57). This provides a new pathway for the hydrolytic cleavage of a peptide bond. Catalysis occurs only if each step in the new pathway is faster than the un catalyzed reaction. The chymotrypsin reaction is described in more detail in Figure 6–21.

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قسم الشؤون الفكرية يهدي كتاب شرح دعاء أبي حمزة الثمالي إلى جامعة وارث الأنبياء (عليه السلام)

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مواضيع ذات صلة

Enzyme Kinetics as an Approach to Understanding Mechanism: -Kinetic Parameters Are Used to Compare Enzyme Activities

Enzyme Kinetics as an Approach to Understanding Mechanism: -The Relationship between Substrate Concentration and Reaction Rate Can Be Expressed Quantitatively

Enzyme Kinetics as an Approach to Understanding Mechanism: -Substrate Concentration Affects the Rate of Enzyme-Catalyzed Reactions

How Enzymes Work:- Binding Energy Contributes to Reaction Specificity and Catalysis

How Enzymes Work:- Weak Interactions between Enzyme and Substrate Are Optimized in the Transition State

Protein Interactions Modulated by Chemical Energy: Actin, Myosin, and Molecular Motors: -Additional Proteins Organize the Thin and Thick Filaments into Ordered Structures

Protein Interactions Modulated by Chemical Energy: Actin, Myosin, and Molecular Motors: - The Major Proteins of Muscle Are Myosin and Actin

Reversible Binding of a Protein to a Ligand: Oxygen-Binding Proteins: -The Antibody-Antigen Interaction Is the Basis for a Variety of Important Analytical Procedures

Reversible Binding of a Protein to a Ligand: Oxygen-Binding Proteins: -Antibodies Bind Tightly and Specifically to Antigen

Complementary Interactions between Proteins and Ligands: The Immune System and Immunoglobulins: -Antibodies Have Two Identical Antigen-Binding Sites

Complementary Interactions between Proteins and Ligands: The Immune System and Immunoglobulins: -Self Is Distinguished from Nonself by the Display of Peptides on Cell Surfaces

Complementary Interactions between Proteins and Ligands: The Immune System and Immunoglobulins: -The Immune Response Features a Specialized Array of Cells and Proteins