Metabolic reactions classification

The previous chapter offered a broad overview of peptidases and esterases in terms of their classification, localization, and some physiological roles. Mention was made of the classification of hydrolases based on a characteristic functionality in their catalytic site, namely serine hydrolases, cysteine hydrolases, aspartic hydrolases, and metallopeptidases. What was left for the present chapter, however, is a detailed presentation of their catalytic site and mechanisms. As such, this chapter serves as a logical link between the preceding overview and the following chapters, whose focus is on metabolic reactions. 

Fig. 3.1 Classification of functional roles of subunit assembly and disassembly.4 a) The assembly of identical subunits is essential for the 9catalytic activity, b) The assembly of nonidentical subunits is essential for the catalytic activity, c) The assembly of active subunits enhances the catalytic activity, d) Sequential metabolic reactions are efficiently catalyzed by the assembly of subunits, e) The assembly of subunits is required for the expression of regulatory properties, f) The assembly of nonidentical subunits diminishes the catalytic activity. See text for details. (Reproduced with permission from S. Tokushige, Kagaku Zokan, 103, 41 (1984), in Japanese)).

Our objective in writing this chapter was to present structured data, namely, a reasoned classification of metabolic reactions and their enzymes. In this way, the vast diversity of metabolic reactions and of xenobiotic-metabolizing enzymes ceases to be a vague notion (a heap of stones) and can begin to be grasped as a structured whole made of many interacting parts. 

One is probably Richard Tecwyn Williams who introduced the Phase I and II classification of xenobiotics metabolism reactions. Although his emblematic book was called Detoxication mechanisms, he estimated that, in some cases, metabolism may increase toxicity. He also considered that this bioactivation may occur during the Phase II reactions (usually considered as detoxication reactions), and not only that of Phase I (functionalization reactions). 

Latino, A.R.S. and Aires-de-Sousa, J. (2006) Genome-scale classification of metabolic reactions a chemoinformatics approach. Angew. Chem. Int. Ed. Eng., 45, 2066-2069. 

This chapter is about both. Our first objective in writing it was obviously to supply as much useful information as would fit in the allocated pages. By useful information, mean structured data as exemplified by the classification of metabolic reactions (Sections 2 and 3) and biological factors affecting them (Section 4). 

An a priori classification of these various reactions as either toxification or detoxification is simply impossible, since each product from these various pathways may be toxic or not depending on its chemical properties and own products. Furthermore, the biological context plays a critical role [154], yet this role, best viewed as the influence of biological factors on the relative importance of competitive routes of metabolism, is often underplayed by those who venture to make predictions of metabolic outcome. Indeed, in the cascade of intertwined metabolic routes exemplified by haloalkenes, a small difference in pathway selectivity at an early metabolic crossroad may be amplified downstream, giving rise to major differences in relative levels of metabolites and overall toxicity. 

The true significance of ring opening and ring formation reactions in metabolism is not always recognized and, to the best of our knowledge, these two types of reaction have never been reviewed per se in a systematic manner. Here, we offer a preliminary classification of these reactions in an attempt to clarify this complex field. 

The above classification of detoxication reactions has been developed for the metabolism of synthetic pesticides In plants. However, the same reactions can occur with natural exocons, such as allelopathic compounds, that have the same functional groups as synthetic pesticides. Most allelopathic chemicals contain functional groups that can be conjugated by Phase II reactions. Thus, detoxication of allelopathic compounds can be expected to proceed by conjugation with the omission of Phase I reactions. The remainder of this review will be concerned with the conjugation of allelopathic compounds. 

Each PIR entry consists of Entry (entry ID), Title, Alternate names, Organism, Date, Accession (accession number), Reference, Function (description of protein function), Comment (e.g., enzyme specificity and reaction, etc.), Classification (superfamily), Keywords (e.g., dimer, alcohol metabolism, metalloprotein, etc.), Feature (lists of sequence positions for disulfide bonds, active site and binding site amino acid residues, etc.), Summary (number of amino acids and the molecular weight), and Sequence (in PIR format, Chapter 4). In addition, links to PDB, KEGG, BRENDA, WIT, alignments, and iProClass are provided. 

Classification of chemically induced hepatotoxicity is primarily based upon pattern of incidence and histopathological morphology. Intrinsic hepatotoxic drugs demonstrate a broad incidence, dose-response relationship and will usually give similar results in humans and experimental animals. The incidence of liver damage from idiosyncratic hepatotoxicants is limited to susceptible individuals and results from hypersensitivity reactions or unusual metabolic conversions that can occur due to polymorphisms in drug metabolism genes (see Chapters 11 and 13). 

The organophosphorus insecticides are all structurally related and undergo similar reactions. The chemical classification of the most widely used compounds of this type is given in Table V. These compounds can also be differentiated on the basis of whether they are largely effective per se or undergo oxidative conversions in plants or animals. All are inhibitors of the enzyme, cholinesterase. Their potency depends not only upon their intrinsic enzyme affinity but also on anticholinesterase properties acquired through in vivo metabolism. 

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