Discussion of Specific Enzymes

We begin with descriptions of the properties of enzymes and the principles underlying their catalytic power, then introduce enzyme kinetics, a discipline that provides much of the framework for any discussion of enzymes. Specific examples of enzyme mechanisms are then provided, illustrating principles introduced earlier in the chapter. We end with a discussion of how enzyme activity is regulated. 

Certain therapeutic effects can be attributed to the inhibition of specific enzymic reactions. The inhibition of cholinesterase (Section 1.06.3), orotidylate pyrophosphorylase (Section 1.06.5) and of dihydrofolate reductase (Section 1.06.6.3) have already been discussed. They illustrate two modes of action, chemical alteration of the enzyme and competition with a substrate for the active site. 

In this chapter we introduced some of the basic principles that govern protein structure. The discussion of protein structures begun in this chapter is continued in many other chapters in this text in which we consider structures designed for specific purposes. In chapter 5 we examine the protein structures for two systems the protein that transports oxygen in the blood and the proteins that constitute muscle tissue. In chapters 8 and 9 we discuss structures of specific enzymes. In chapters 17 and 24 we consider proteins that interact with membranes. In chapters 30 and 31 we study regulatory proteins that interact with specific sites on the DNA. And finally, in supplement 3 we examine the structures of immuno-globin molecules. 

Discuss the inhibition of specific enzymes, enzyme synthesis induction, stress proteins, DNA and chromosomal damage, immunological endpoints, and nutritional state as biomarkers of exposure to xenobiotics. 

In contrast to UGTlA-related irinotecan toxicity, where low enzyme activity results in prolonged exposure to a toxic metabolite, another common chemotherapeutic agent, tamoxifen, has received recent attention for the role of specific enzymes in conversion of this prodrug to its active metabolites. The second part of this article discusses the elfects of CYP variants on tamoxifen therapy. 

The intact animal can be improved for experimental purposes if it is rendered abnormal in some way, by genetic malfunction, by illness, or by operation. Genetic defects, or mutations, are used widely in the study of bacterial metabolism, where they can be read ily induced, for example through irradiation by X-rays or from a radioactive source. Genetic defects frequently reveal themselves in the form of the absence of one specific enzyme, and metabolic studies with such enzymically defective preparations are of the same type as those made possible by the use of a specific enzymic inhibitor which we discussed above. Genetic defects in animals are rarer, but classic cases of the absence of specific enzymes and hence the accumulation of abnormal metabolites are provided in humans by the genetically carried diseases of phenylketonuria and alkaptonuria. In both, unusual substances are excreted in the urine, and the analysis of the reasons for their appearance has led to valuable information about the mechanism of amino acid metabolism in the body. 

It seems to follow that tocopherol, and possibly the other naturally occurring (juinonoid substances, act in close connection with sensitive sulfhydryl sites of specific enzymes necessary for maintenance of normal respiration. Two theoretically possible mechanisms, namely oxidation-reduction and formation of addition products of sulfhydryl groups with quinones, are discussed. 

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