Enzyme-Catalyzed Metabolic Pathways

Aerobic glycolysis first involves a ten-step conversion of glucose to pyruvic acid or pyruvate, called the Embden-Meyerhoff-Pamas pathway, followed by its further conversion to carbon dioxide and water via what is variously called the tricarboxylic acid cycle, or citric acid cycle, or Krebs cycle after its discoverer. The net products discharged from the cycle are carbon dioxide and water, with recycle of a further product called oxaloacetic acid or oxaloacetate. Successive organic acids that contain three carboxyl groups (-COOH), are initially involved in the cycle starting with citric acid or a neutral salt of citric acid (citrate). Hence the designator tricarboxylic. 

What we call anaerobic glycolysis also involves the same ten-step conversion of glucose to pyruvic acid or pyruvate. However, the pyruvic acid is instead further converted to lactic acid or lactate in a single step catalyzed by an enzyme called lactate dehydrogenase (and sometimes called lactic acid dehydrogenase). 

Although the carbohydrate glucose or its polymer glycogen is regarded as the fundamental fuel or nutrient, other carbohydrates may be involved, even nitrogen-containing amines, or amino acids. Thus, for example, there is the role of glutamine, 

Glycolysis, the ten-step sequence producing pyruvic acid or pyruvate, which occurs in all cells, normal or cancerous. 

Anaerobic conversion of pyruvate to lactate, as occurs in cancer cells. 

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Moriya, Y., Shigemizu, D., Hattori, M., Tokimatsu, T. et al (2010) PathPred an enzyme-catalyzed metabolic pathway prediction server. Nucleic Acids Res.,... 

Feedback can also be positive. Since AMP is a product of the hydrolysis of ATP, its accumulation is a signal to activate key enzymes in metabolic pathways that generate ATP. For example, AMP causes allosteric activation of glycogen phosphorylase, which catalyzes the first step in the catabolism of glycogen. As is shown in Fig. 11-5, the allosteric site for AMP or IMP binding is more than 3 nm away from the active site. Only a... 

A number of enzymes and metabolic pathways have been identified by scientists. PHA synthases are the key enzymes of PHA biosynthesis in all of these pathways. These enzymes catalyze the covalent linkage between the hydroxyl group of one and the carboxyl group of another hydroxyalkanoic acid. The substrates of PHA synthases are the coen me A thioesters of hydroxyalkanoic acids. There is no evidence that PHA synthases can utilize either free hydroxyalkanoic acids or other derivatives. Most PHA synthases incorporate either short carbon chain length hydroxyalkanoic acids with 3-5 carbon atoms or medium carbon chain length hydroxyalkanoic acids with 6-16 carbon atoms. There are only a few PHA synthases which can incorporate both short chain and medium chain monomers. Examples are the PHA synthases of T. pfennigii and Aeromonas caviae ([Pg.256]

FIGURE 14.2 The breakdown of glucose by glycolysis provides a prime example of a metabolic pathway. Ten enzymes mediate the reactions of glycolysis. Enzyme A, fructose 1,6, hiphos-phate aldolase, catalyzes the C—C bondbreaking reaction in this pathway. 

Allosteric regulation acts to modulate enzymes situated at key steps in metabolic pathways. Consider as an illustration the following pathway, where A is the precursor for formation of an end product, F, in a sequence of five enzyme-catalyzed reactions ... 

In nature, aminotransferases participate in a number of metabolic pathways [4[. They catalyze the transfer of an amino group originating from an amino acid donor to a 2-ketoacid acceptor by a simple mechanism. First, an amino group from the donor is transferred to the cofactor pyridoxal phosphate with formation of a 2-keto add and an enzyme-bound pyridoxamine phosphate intermediate. Second, this intermediate transfers the amino group to the 2-keto add acceptor. The readion is reversible, shows ping-pong kinetics, and has been used industrially in the production ofamino acids [69]. It can be driven in one direction by the appropriate choice of conditions (e.g. substrate concentration). Some of the aminotransferases accept simple amines instead of amino acids as amine donors, and highly enantioselective cases have been reported [70]. 

Controlling an Enzyme That Catalyzes a Rate-Limiting Reaction Regulates an Entire Metabolic Pathway... 

Such a pathway has both flow and direction. The enzymes catalyzing nonequilibrium reactions are usually present in low concentrations and are subject to a variety of regulatory mechanisms. However, many of the reactions in metabolic pathways cannot be classified as equilibrium or nonequilibrium but fall somewhere between the two extremes. 

Studies of a network of metabolic pathways and their disorders. A metabolic disorder occurs when there is a blockage in one of the pathways because the enzyme required to catalyze the reaction is malfunctioning or missing. This results in an accumulation of metabolites on one side of the block and a dehciency of essential chemicals on the other. In many metabolic disorders, early diagnosis may prevent permanent functional damage or death. 

A common characteristic of metabolic pathways is that the product of one enzyme in sequence is the substrate for the next enzyme and so forth. In vivo, biocatalysis takes place in compartmentalized cellular structure as highly organized particle and membrane systems. This allows control of enzyme-catalyzed reactions. Several multienzyme systems have been studied by many researchers. They consist essentially of membrane- [104] and matrix- [105,106] bound enzymes or coupled enzymes in low water media [107]. 

Biochemical reactions. As discussed previously, there are two broad classes of biochemical reactions reactions that exploit the metabolic pathways in selected microorganisms and those catalyzed by enzymes. Consider microbial biochemical reactive of the type ... 

Reactions can be catalyzed using the metabolic pathways in microorganisms or the direct use of enzymes in biochemical reactors. The use of enzymes directly can have... 

Shukla s et al. work [321,322] has been mentioned (Section 3.2.3) and the metabolic pathways his group proposed have been described, as well. Although, there was no enzyme identified in that work, the strain studied shows evidence that the underlying reactions are catalyzed by oxygenases. 

Oxidation is intimately linked to the activation of polycyclic aromatic hydrocarbons (PAH) to carcinogens (1-3). Oxidation of PAH in animals and man is enzyme-catalyzed and is a response to the introduction of foreign compounds into the cellular environment. The most intensively studied enzyme of PAH oxidation is cytochrome P-450, which is a mixed-function oxidase that receives its electrons from NADPH via a one or two component electron transport chain (10. Some forms of this enzyme play a major role in systemic metabolism of PAH (4 ). However, there are numerous examples of carcinogens that require metabolic activation, including PAH, that induce cancer in tissues with low mixed-function oxidase activity ( 5). In order to comprehensively evaluate the metabolic activation of PAH, one must consider all cellular pathways for their oxidative activation. 

In addition, it has been discovered that there are naturally occurring enzymes that facilitate Diels-Alder type reactions within certain metabolic pathways and that enzymes are also instrumental in forming polyketides, isoprenoids, phenylpropanoids, and alkaloids (de Araujo et al., 2006). Agresti et al. (2005) identified ribozymes from RNA oligo libraries that catalyzed multiple-turnover Diels-Alder cycloaddition reactions. 

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