Metabolic pathways intermediary

The ways in which energy in the form of ATP is produced and utilized constitute bioenergetics, and will be discussed in greater detail at the end of this chapter. However, before turning to a selection of metabolic pathways, we outline some fundamental notions concerning redox reactions followed by a brief description of the central role of ATP in metabolism as an acceptor and donor of phosphoryl groups, and finally a summary of the types of reactions that we will encounter as we wend our way along a sample of some of the pathways of intermediary metabolism. 

The term intermediary metabolism is used to emphasize the fact that metabolic processes occur via a series of individual chemical reactions. Such chemical reactions are usually under the control of enzymes which act upon a substrate molecule (or molecules) and produce a product molecule (or molecules) as shown in Figure 1.1. The substrates and products are referred to collectively as intermediates or metabolites . The product of one reaction becomes the substrate for another reaction and so the concept of a metabolic pathway is created. 

Wilson and Madsen [152] used the metabolic pathway for bacterial naphthalene oxidation as a guide for selecting l,2-dihydroxy-l,2-dihydronaphthalene as a unique transient intermediary metabolite whose presence in samples from a contaminated field site would indicate active in situ naphthalene biodegradation (Fig. 26). Naphthalene is a component of a variety of pollutant mixtures. It is the major constituent of coal tar [345], the pure compound was commonly used as a moth repellant and insecticide [345], and it is a predominant constituent of the fraction of crude oil used to produce diesel and jet fuels [346]. Prior studies at a coal tar-contaminated field site have focused upon contaminant transport [10,347], the presence of naphthalene catabolic genes [348, 349], and non-metabolite-based in situ contaminant biodegradation [343]. 

To elucidate the metabolic pathway of phenylmalonic acid, the incubation broth of A. bronchisepticus on phenylmalonic acid was examined at the early stage of cultivation. After a one-day incubation period, phenylmalonic acid was recovered in 80% yield. It is worthy of note that the supposed intermediate, mandelic acid, was obtained in 1.4% yield, as shown in Eq. (8). The absolute configuration of this oxidation product was revealed to be S. After 2 days, no metabolite was recovered from the broth. It is highly probable that the intermediary mandelic acid is further oxidized via benzoylformic acid. As the isolated mandelic acid is optically active, the enzyme responsible for the oxidation of the acid is assumed to be S-specific. If this assumption is correct, the enzyme should leave the intact l -enantiomer behind when a racemic mixture of mandelic acid is subjected to the reaction. This expectation was nicely realized by adding the racemate of mandelic acid to a suspension of A. bronchisepticus after a 4-day incubation [4]. 

A number of central metabolic pathways are common to most cells and organisms. These pathways, which serve for synthesis, degradation, and interconversion of important metabolites, and also for energy conservation, are referred to as the intermediary metabolism. 

The enzymes specifically involved in the metabolism of foreign compounds are necessarily often flexible, and the substrate specificity is generally broad. However, it follows from the above two conditions that if the structure of a foreign compound is similar to a normal endogenous molecule, then the foreign compound may be a suitable substrate for an enzyme primarily involved in intermediary metabolic pathways if the enzyme is present in the exposed tissue. Thus, foreign compounds are not exclusively metabolized by specific enzymes. 

The liver also has an extensive role in intermediary metabolism and synthesis, and consequently, interference with endogenous metabolic pathways may lead to toxic effects, as discussed in chapter 7 (see sects. 7,8.2 and 7.8.3). 

Enzymes are organised into metabolic pathways which collectively constitute metabolism. Two types of metabolism are found in cells, catabolism (breakdown pathways) and anabolism (synthetic pathways). Linking these two types of metabolic reactions are the intermediary reactions of central metabolism. Cells, which contain many complex polymers, thus have the means to generate and convert monomeric materials into the complex biological structure. The sources of these materials are the simpler components from the cell s environment, such as inorganic salts and glucose (Fig. 5.9). 

I n this and the next 14 chapters we consider the synthesis and degradation of small molecules in the living cell. These aspects of biochemistry are collectively referred to as intermediary metabolism because they focus on the small-molecule intermediates in metabolic pathways. In this chapter the principles governing the intermediary metabolism are discussed. 

Branchpoints in metabolic pathways sometimes occur at locations where an intermediary, S, can follow a catabolic sequence or an anabolic sequence. The first reactions after the branchpoints are catalyzed by enzymes B and A, respectively. Once the first step after the branchpoint has been taken, the metabolic intermediate is irreversibly committed to follow that pathway. 

The network operates through a series of enzyme-catalyzed reactions that constitute the metabolism. Each of the consecutive steps in a metabolic pathway brings about a specific chemical change, usually the removal, transfer, or addition of a particular atom or functional group. The precursor is converted into a product through a series of metabolic intermediates called metabolites. The term intermediary metabolism is often applied to the combined activities of all the metabolic pathways that interconvert precursors, metabolites, and products of low molecular weight. 

Table 21.1 Hormone Effects on Intermediary Metabolic Pathways...

Most such metabolic pathways are linear, that is, they begin with a specific substrate and end with a specific product. However, some pathways, such as the Krebs cycle, are cyclic. Often, metabolic pathways also have branches that feed into or out of them. The specific sequences of intermediates in the pathways of cell metabolism are called intermediary metabolism. 

S-adenosyl-L-methionine (SAM)-dependent methyl-ation was briefly discussed under Thiomethylation (see Figure 14). Other functional groups that are methylated by this mechanism include aliphatic and aromatic amines, N-heterocyclics, monophenols, and polyphenols. The most important enzymes involved in these methylation reactions with xenobiotics are catechol O-methyltransferase, histamine N-methylt-ransferase, and indolethylamine N-methyltransferase - each catalyzes the transfer of a methyl group from SAM to phenolic or amine substrates (O- and N-methyltransferases, respectively). Methylation is not a quantitatively important metabolic pathway for xenobiotics, but it is an important pathway in the intermediary metabolism of both N- and O-contain-ing catechol and amine endobiotics. 

The second metabolic pathway which we have chosen to describe is the tricarboxylic acid cycle, often referred to as the Krebs cycle. This represents the biochemical hub of intermediary metabolism, not only in the oxidative catabolism of carbohydrates, lipids, and amino acids in aerobic eukaryotes and prokaryotes, but also as a source of numerous biosynthetic precursors. Pyruvate, formed in the cytosol by glycolysis, is transported into the matrix of the mitochondria where it is converted to acetyl CoA by the multi-enzyme complex, pyruvate dehydrogenase. Acetyl CoA is also produced by the mitochondrial S-oxidation of fatty acids and by the oxidative metabolism of a number of amino acids. The first reaction of the cycle (Figure 5.12) involves the condensation of acetyl Co and oxaloacetate to form citrate (1), a Claisen ester condensation. Citrate is then converted to the more easily oxidised secondary alcohol, isocitrate (2), by the iron-sulfur centre of the enzyme aconitase (described in Chapter 13). This reaction involves successive dehydration of citrate, producing enzyme-bound cis-aconitate, followed by rehydration, to give isocitrate. In this reaction, the enzyme distinguishes between the two external carboxyl groups... 

Mitz MA, Aldrich FL, Vasta BM. 1962. Study of intermediary metabolic pathways of 1,1-... 

The initial step of amino acid catabolism frequently involves the loss of the amine nitrogen to yield a carbon skeleton in the form of a keto acid, either as a result o transamination or by deamination. In general, energy is derived from amino acids bj the oxidation of the carbon skeletons after entry into the intermediary metabolic pathways. 

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