Coenzymes in Metabolic Pathways

LEARNING GOAL Give the sites and products of digestion for carbohydrates, triacylglycerols, and proteins. 

7 What is the general type of reaction that occnrs dnring the digestion of carbohydrates  

9 What is the role of bile salts in lipid digestion  

11 Where do dietary proteins undergo digestion in the body  

An oxidation reaction involves the loss of hydrogen or electrons by a substance, or an increase in the number of bonds to oxygen. Reduction is the gain of hydrogen ions and electrons or a decrease in the number of bonds to oxygen. When hydrogen ions and electrons are picked up by a coenzyme, it is reduced. Table 18.2 summarizes the characteristics of oxidation and reduction. 

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Coenzymes in Metabolic Pathways LEARNING GOAL Describe the components and functions of the coenzymes NAD, FAD, and coenzyme A. 

Riboflavin (vitamin B2) is a component of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), coenzymes that play a major role in oxidation-reduction reactions (see Section 15.1.1). Many key enzymes involved in metabolic pathways are actually covalently bound to riboflavin, and are thus termed flavoproteins. 

SHELLEY D. COPLEY is a professor of molecular, cellular and developmental biology at the University of Colorado at Boulder. Her research interests center on the molecular evolution of enzymes and metabolic pathways and protein structure-function relationships. Dr. Copley is a member of the Council of Fellows of the University of Colorado s Cooperative Institute for Research in Environmental Sciences. Dr. Copley served on the NSF Molecular Biochemistry Panel (1999-2003), was co-chair for the Gordon Conference on Enzymes, Coenzymes, and Metabolic Pathways (2004), and currently serves on the National Institutes of Health Genetic Variation and Evolution Study Section. 

A substantial number of pharmaceutically and clinically related problems require the detection and determination of small amounts of metal ions and other inorganic constituents of biological and xenobiotic substances (1-3). Some obvious examples are the detections of heavy metals and lithium in biological fluids and tissue samples in cases of suspected intoxication and the determination of potassium for purposes of quality control in intravenous solutions to be given to cardiac patients. Trace amounts of nonmetals such as selenium and iodine, which are associated with the functions of coenzymes or hormones, also must be analyzed in order to determine their roles in metabolic pathways. 

ATP, ADP and AMP are coenzymes influencing the direction of flow in metabolic pathways. In addition ATP often functions as a donor of a phosphate to other molecules in reactions catalysed by kinases. 

The conversion of serine to glycine involves the transfer of a one-carbon unit from serine to an acceptor. This reaction is catalyzed by senne hydroxymethylase, with pyridoxal phosphate as a coenzyme. The acceptor in this reaction is tetra-hydrofolate, a derivative of folic acid and a frequently encountered carrier of one-carbon units in metabolic pathways. Its structure has three parts a substituted pteridine ring, /(-aminobenzoic acid, and glutamic acid (Figure 23.11). Folic acid is a vitamin that has been identified as essential in preventing birth defects consequently, it is now a recommended supplement for all women of... 

Vitamins are involved in metabolic pathways as coenzymes, and some act as protectors in antioxidant and immune systems. The sources and functions of individual vitamins, and the disorders caused by their deficiencies, are summarised below. 

Many of the enzymes involved in metabolic pathways require coenzymes to act as carriers of electrons, atoms or groups of atoms. The coenzymes act alternately as acceptors and donors and exist in alternative states, e.g. NAD /NADH, NADP /NADPH, pyridoxal/pyridoxamine, CoA/acetyl-CoA. Since coenzymes are in effect cosubstrates that react with the substrate in stoichiometric proportions, the question of which of the two forms predominates may be decisive in determining the direction of reactions occurring at or near equilibrium. Specific portions of some metabolic pathways may be controlled in this way, e.g. the conversion of pyruvate to lactate in muscles during physical exertion. 

Describe the reactive part of each of the following coenzymes and the way each participates in metabolic pathways ... 

Several p-amino acids occur naturally as free metabolites in metabolic pathways or as key intermediates in biosynthetic products. p-Alanine is the simplest p-amino acid that appears in pantothenic acid, a precursor of the coenzyme A. Further examples are (2R,3S)-N-benzoyl-3-phenylisoserine derived from (R)-p-phenylalanine, a compound in the antitumor agent paclitaxel from Taxus brevifolia [89], or as building blocks for p-lactam antibiotics [90] and in jasplakinolide, an antifungal compound [91] (Scheme 29.12). 

Divalent sulfur compounds are achiral, but trivalent sulfur compounds called sulfonium stilts (R3S+) can be chiral. Like phosphines, sulfonium salts undergo relatively slow inversion, so chiral sulfonium salts are configurationally stable and can be isolated. The best known example is the coenzyme 5-adenosylmethionine, the so-called biological methyl donor, which is involved in many metabolic pathways as a source of CH3 groups. (The S" in the name S-adenosylmethionine stands for sulfur and means that the adeno-syl group is attached to the sulfur atom of methionine.) The molecule has S stereochemistry at sulfur ana is configurationally stable for several days at room temperature. Jts R enantiomer is also known but has no biological activity. 

Nicotinic acid derivatives occur in biologic materials as the free acid, as nicotinamide, and in two coenzymatic forms nicotinamide adenine dinucleotide (NAD), and nicotinamide adenine dinucleotide phosphate (NADP). These coenzymes act in series with flavoprotein enzymes and, like them, are hydrogen acceptors or, when reduced, donors. Several plants and bacteria use a metabolic pathway for the formation of nicotinic acid that is different from the tryptophan pathway used by animals and man (B39). 

The conversion of glucose proceeds via its splitting into pyruvic acid and hydrogen, which is bound as NADPH. Pyruvic acid is subsequently decarboxylated to C02 and acetaldehyde (bound to the coenzyme-A), which is subsequently rehydrogenated to ethanol. The overall reaction delivers therefore two molecules of ethanol and two C02 for every glucose unit. Notice that such a simplified metabolic pathway does not display the energy fluxes, e.g., in the form of ATP/ADP interconversion. 

Coenzyme M was shown to function as the central cofactor of aliphatic epoxide carboxylation in Xanthobacter strain Py2, an aerobe from the Bacteria domain (AUen et al. 1999). The organism metabolizes short-chain aliphatic alkenes via oxidation to epoxyalkanes, followed by carboxylation to p-ketoacids. An enzyme in the pathway catalyzes the addition of coenzyme M to epoxypropane to form 2-(2-hydroxypropylthio)ethanesulfonate. This intermediate is oxidized to 2-(2-ketopropylthio)ethanesulfonate, followed by a NADPH-dependent cleavage and carboxylation of the P-ketothioether to form acetoacetate and coenzyme M. This is the only known function for coenzyme M outside the methanoarchaea. 

Ferredoxins (Fds) are widespread in the three domains of life and an abundance of sequence data and structural information are available for Fds isolated from several sources. In particular, the bacterial type Fds are small electron-transfer proteins that posses cubane xFe-yS clusters attached to the protein matrix by Fe ligation of Cys via a conserved consensus ligating sequence. The archaeal type ferredoxins are water-soluble electron acceptors for the acyl-coenzyme A forming 2-oxoacid/ferredoxin oxidoreductase, a key enzyme involved in the central archaeal metabolic pathways. Fds have been distinguished according to the number of iron and inorganic sulphur atoms, 2Fe-2S, 4Fe-4S/3Fe-4S (Fig. Ib-d) and Zn-containing Fds. 

The oxidation/reduction reactions that require one of the nicotinamide coenzymes are everywhere in metabolism in the glycolytic pathway, the citric acid cycle, the synthesis and degradation of fatty acids, the synthesis of steroids, and so on. Certain of... 

The next part presents the reactions involved in the interconversion of these compounds—the part of biochemistry that is commonly referred to as metabolism (pp. 88-195). The section starts with a discussion of the enzymes and coenzymes, and discusses the mechanisms of metabolic regulation and the so-called energy metabolism. After this, the central metabolic pathways are presented, once again arranged according to the class of metabolite (pp. 150-195). 

Finally, the activity of key enzymes can be regulated by ligands (substrates, products, coenzymes, or other effectors), which as allosteric effectors do not bind at the active center itself, but at another site in the enzyme, thereby modulating enzyme activity (6 see p. 116). Key enzymes are often inhibited by immediate reaction products, by end products of the reaction chain concerned feedback inhibition), or by metabolites from completely different metabolic pathways. The precursors for a reaction chain can stimulate their own utilization through enzyme activation. 

The most important process in the degradation of fatty acids is p-oxidation—a metabolic pathway in the mitochondrial matrix (see p. 164). initially, the fatty acids in the cytoplasm are activated by binding to coenzyme A into acyl CoA [3]. Then, with the help of a transport system (the carnitine shuttle [4] see p. 164), the activated fatty acids enter the mitochondrial matrix, where they are broken down into acetyl CoA. The resulting acetyl residues can be oxidized to CO2 in the tricarboxylic acid cycle, producing reduced... 

Any process by which there is direct transfer of noncova-lently bound substrate(s) or coenzyme from the active site of the enzyme producing the metabolite to the active site of an enzyme catalyzing a succeeding step in a metabolic pathway or to another enzyme utilizing the coenzyme product. 

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