Enzyme catalysis covalent bond

Many enzymes form covalent bonds with their substrates to form true intermediates. Enzyme-bound coenzymes (prosthetic groups) can also form covalent bonds with the substrate. Enzyme effects involving such formation of covalent bonds with the substrate are referred to as covalent catalysis. The enzyme-bound or coenzyme-bound substrate is more reactive than the original substrate. An example is transamination (Chapter 20), where the amino acid... 

Fluorodeoxyuridine monophosphate (FdUMP) is a molecule that is a mechanism-based inhibitor. Irreversible binding of FdUMP to thymidylate synthase occurs only in the presence of 5,10-methyl enetetrahydrofolate. Crystallographic analysis of thymidylate synthase with dUMP and an analog of 5,10-methylenetetrahydrofolate (that could not be acted on by the enzyme) reveals that thymidylate synthase normally makes a transient covalent bond in the process of catalysis of the reaction. Apparently FdUMP s structure traps the enzyme-substrate covalent bond and prevents it from breaking down. 

Many enzymes form covalent bonds with their substrates during catalysis, such as the acyl-enzyme intermediate in carboxyl ester hydrolysis (Scheme 2.1) or the glycol monoester intermediate in epoxide hydrolysis (Scheme 2.85). Despite the covalent enzyme-substrate bond, such species are metastable and should be regarded as activated intermediates . Some enzymes utilize cofactors, such as... 

Affinity Labels. Active site-directed, irreversible inhibitors or affinity labels are usually substrate analogues that contain a reactive electrophilic functional group. In the first step, they bind to the active site of the target enzyme in a reversible fashion. Subsequentiy, an active site nucleophile in close proximity reacts with the electrophilic group on the substrate to form a covalent bond between the enzyme and the inhibitor, typically via S 2 alkylation or acylation. Affinity labels do not require activation by the catalysis of the enzyme, as in the case of a mechanism-based inhibitor. 

Catalysis by enzymes that proceeds via a unique reaction mechanism typically occurs when the transition state intermediate forms a covalent bond with the enzyme (covalent catalysis). The catalytic mechanism of the serine protease chymotrypsin (Figure 7-7) illustrates how an enzyme utilizes covalent catalysis to provide a unique reaction pathway. 

Another alternative is for the enzyme to actually form a covalent bond between the enzyme and the substrate. This direct, covalent participation of the enzyme in the chemical reaction is termed covalent catalysis. The enzyme uses one of its functional groups to react with the substrate. This enzyme-substrate bond must form fast, and the intermediates must be reasonably reactive if this kind of catalysis is going to give a rate acceleration. 

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

In addition to participating in acid-base catalysis, some amino acid side chains may enter into covalent bond formation with substrate molecules, a phenomenon that is often referred to as covalent catalysis.174 When basic groups participate this may be called nucleophilic catalysis. Covalent catalysis occurs frequently with enzymes catalyzing nucleophilic displacement reactions and examples will be considered in Chapter 12. They include the formation of an acyl-enzyme intermediate by chymotrypsin (Fig. 12-11). Several of the coenzymes discussed in Chapters 14 and 15 also participate in covalent catalysis. These coenzymes combine with substrates to form reactive intermediate compounds whose structures allow them to be converted rapidly to the final products. 

There are a growing number of asymmetric organocatalytic reactions, which are accelerated by weak interactions. This type of catalysis includes neutral host-guest complexation, or acid-base associations between catalyst and substrate. The former case is highly reminiscent of the way that many enzymes effect reactions, by bringing together reactants at an active site and without the formation of covalent bonds. The chemistry of this organocatalysis is discussed in Chapter 13. 

L. E. Scriven Yes, and not only for covalent bonding but also for molecular conformation and, I believe, for structured aggregates of molecules. I would say not just enzyme catalysis in the biochemical setting, but also in its... 

The side chains of amino acids present a number of nucleophilic groups for catalysis these include RCOO-, R—NH2, aromatic—OH, histidyl, R—OH, and RS. These groups attack electrophilic (electron-deficient) parts of substrates to form a covalent bond between the substrate and the enzyme, thus forming a reaction intermediate. This type of process is particularly evident in the group-transfer enzymes (EC Class 2 see Table 8.1). In the formation of a covalently bonded intermediate, attack by the enzyme nudeophile (Enz-X in Example 8.10) on the substrate can result in acylation, phosphorylation, or glycosylation of the nucleophile. 

---