Electrophilic agents Enzymes

The Michael reaction involves conjugate addition of a nucleophile onto an a,P-unsaturated carbonyl compound, or similar system. Such reactions take place in nature as well, and some can be potentially dangerous to us. For example, the a,P-unsaturated ester ethyl acrylate is a cancer suspect agent. This electrophile can react with biological nucleophiles and, in so doing, bind irreversibly to the nucleophile, rendering it unable to carry out its normal functions. A particularly important enzyme that can act as a nucleophile is DNA polymerase, which is responsible for the synthesis of strands of DNA, especially as part of a DNA repair mechanism (see Section 14.2.2). The nucleophilic centre is a thiol grouping, and this may react with ethyl acrylate as shown. 

Irreversible inhibitors act by covalently modifying the enzyme, generally at the active site. The active site is then blocked, and the enzyme is permanently rendered inactive. Because functional groups in the active site tend to be electron rich and nucleophilic, irreversible inhibitors tend to be electrophiles. Acylation agents are especially common. 

The phosphonic amino acids are also an important class of compounds with applications as antibiotics, antiviral agents, and enzyme inhibitors. The first example of electrophilic amination of a-cuprophosphonates 14 was reported by Genet and co-workers [5a]. This route has opened new access to N-protected a-amino phosphonic derivates 15 from the corresponding phosphonates 13 (Scheme 5). 

Enzymatic activity is dependent upon several variables, such as enzyme and substrate concentrations, pH, salt concentration of the buffer milieu, temperature and light. Many enzymes also possess non proteinaceous chemical portions termed prosthetic groups. Typical prosthetic groups are the iron protoporphyrin of peroxidase, and biotin of carboxy transferases. In addition, many enzymes require the presence of metal ions such as Mg++, Mn++, and Zn++, which function as electrophilic (electron attracting) agents. 

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