Pyruvate metabolism pathways

Fig. 1.4.1 Lactate and pyruvate metabolic pathway. (P Phosphate, PEP phosphoenolpyruvate)...

Compounds called carboxylic acids, which contain the -C02H grouping, occur abundantly in all living organisms and are involved in almost all metabolic pathways. Acetic acid, pyruvic acid, and citric acid are examples. 

Take glycolysis, for example, the metabolic pathway by which organisms convert glucose to pyruvate as the first step in extracting energy from carbohydrates. 

The metabolic pathway for bacterial sugar fermentation proceeds through the Embden-Meyerhof-Paranas (EMP) pathway. The pathway involves many catalysed enzyme reactions which start with glucose, a six-carbon carbohydrate, and end with two moles of three carbon intermediates, pyruvate. The end pyruvate may go to lactate or be converted to acetyl CoA for the tricarboxylic acid (TCA) cycle. The fermentation pathways from pyruvate and the resulting end products are shown in Figures 9.7 and 9.8. 

Fig. 1. Modification of plant metabolic pathways for the synthesis of poly(3HB) and poly(3HB-co-3HV). The pathways created or enhanced by the expression of transgenes are highlighted in bold, while endogenous plant pathways are in plain letters. The various transgenes expressed in plants are indicated in italics. The ilvA gene encodes a threonine deaminase from E. coli. The phaARe, phaBRe, and phaCRe genes encode a 3-ketothiolase, an aceto-acetyl-CoA reductase, and a PHA synthase from R. eutropha, respectively. The btkBRe gene encodes a second 3-ketothiolase isolated from R. eutropha which shows high affinity for both propionyl-CoA and acetyl-CoA [40]. PDC refers to the endogenous plant pyruvate dehydrogenase complex...

The metabolism of cyanide has been studied in animals. The proposed metabolic pathways shown in Figure 2-3 are (1) the major pathway, conversion to thiocyanate by either rhodanese or 3-mercapto-pyruvate sulfur transferase (2) conversion to 2-aminothiazoline-4-carboxylic acid (Wood and Cooley 1956) (3) incorporation into a 1-carbon metabolic pool (Boxer and Richards 1952) or (4) combining with hydroxocobalamin to form cyanocobalamin (vitamin B12) (Ansell and Lewis 1970). Thiocyanate has been shown to account for 60-80% of an administered cyanide dose (Blakley and Coop 1949 Wood and Cooley 1956) while 2-aminothiazoline-4-carboxylic acid accounts for about 15% of the dose (Wood and Cooley 1956). The conversion of cyanide to thiocyanate was first demonstrated in 1894. Conversion of cyanide to thiocyanate is enhanced when cyanide poisoning is treated by intravenous administration of a sulfur donor (Smith 1996 Way 1984). The sulfur donor must have a sulfane sulfur, a sulfur bonded to another sulfur (e.g., sodium thiosulfate). During conversion by rhodanese, a sulfur atom is transferred from the donor to the enzyme, forming a persulfide intermediate. The persulfide sulfur is then transferred... 

H. G. Holzhtitter, G. Jacobasch, and A. Bisdorff, Mathematical modeling of metabolic pathways affected by an enzyme deficiency. A mathematical model of glycolysis in normal and pyruvate kinase deficient red blood cells. Eur. J. Biochem. 149(1), 101 111 (1985). 

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. 

The metabolic pathways can be diverted to other products, however. For instance, the pyruvic acid can be rehydrogenated to lactic acid. Accordingly, glucose is converted into two molecules of lactic acid, which is the building block for Cargill s polylacate polymer [65],... 

Glycolysis the metabolic pathway leading from glucose to pyruvate and lactate. 

The fate of the oxoacid is either (i) formation of a common intermediate of metabolism, i.e. an intermediate within a well-established metabolic pathway (e.g. oxaloacetate or pyruvate, in the above examples), or (ii) conversion to a common intermediate , e.g. oxoisocaproate is converted to acetyl-CoA (see Appendix 8.3). 

Scheme 23.5 Metabolic pathways of lactic acid bacteria leading from pyruvate to a-acetolactate and acetoin and chemical diacetyl formation. ALS a-acetolactate synthase, ALDB a-acetolactate decarboxylase, DDH diacetyl dehydrogenase. (Adapted from [72])...

The reaction involves biotin as a carrier of activated HCO3 (Fig. 14-18). The reaction mechanism is shown in Figure 16-16. Pyruvate carboxylase is the first regulatory enzyme in the gluconeogenic pathway, requiring acetyl-CoA as a positive effector. (Acetyl-CoA is produced by fatty acid oxidation (Chapter 17), and its accumulation signals the availability of fatty acids as fuel.) As we shall see in Chapter 16 (see Fig. 16-15), the pyruvate carboxylase reaction can replenish intermediates in another central metabolic pathway, the citric acid cycle. 

Figure 13.3 Alternative pathways of pyruvate metabolism by homofer-mentative lactic streptococci. CoA = coenzyme A TPP = thiamine pyrophosphate. (Adapted from Thomas et at. 1979.)...

A small number of other biosynthetic pathways, which are used by both photosynthetic and nonphotosynthetic organisms, are indicated in Fig. 10-1. For example, pyruvate is converted readily to the amino acid t-alanine and oxaloacetate to L-aspartic acid the latter, in turn, may be utilized in the biosynthesis of pyrimidines. Other amino acids, purines, and additional compounds needed for construction of cells are formed in pathways, most of which branch from some compound shown in Fig. 10-1 or from a point on one of the pathways shown in the figure. In virtually every instance biosynthesis is dependent upon a supply of energy furnished by the cleavage to ATP. In many cases it also requires one of the hydrogen carriers in a reduced form. While Fig. 10-1 outlines in briefest form a minute fraction of the metabolic pathways known, the ones shown are of central importance. 

Linked oxidation and decarboxylation. Metabolic pathways often make use of oxidation of a (3-hydroxy acid to a (3-oxoacid followed by decarboxylation in the active site of the same enzyme. An example is conversion of L-malate to pyruvate (Eq. 13-45). The Mg2+ or Mn2+-dependent decarboxylating malic dehydrogenase that catalyzes the reaction is usually called the malic enzyme. It is found in most organisms.237-240 While a concerted decarboxylation and dehydrogenation may sometimes occur,241-242 the enzymes of this group appear usually to operate with bound oxoacid intermediates as in Eq. 13-45. 

Most known thiamin diphosphate-dependent reactions (Table 14-2) can be derived from the five halfreactions, a through e, shown in Fig. 14-3. Each halfreaction is an a cleavage which leads to a thiamin- bound enamine (center, Fig. 14-3) The decarboxylation of an a-oxo acid to an aldehyde is represented by step b followed by a in reverse. The most studied enzyme catalyzing a reaction of this type is yeast pyruvate decarboxylase, an enzyme essential to alcoholic fermentation (Fig. 10-3). There are two 250-kDa isoenzyme forms, one an a4 tetramer and one with an ( P)2 quaternary structure. The isolation of ohydroxyethylthiamin diphosphate from reaction mixtures of this enzyme with pyruvate52 provided important verification of the mechanisms of Eqs. 14-14,14-15. Other decarboxylases produce aldehydes in specialized metabolic pathways indolepyruvate decarboxylase126 in the biosynthesis of the plant hormone indoIe-3-acetate and ben-zoylformate decarboxylase in the mandelate pathway of bacterial metabolism (Chapter 25).1243/127... 

It is important not to confuse the reactions of Eq. 17-42 as they occur in an aerobic cell with the tightly coupled pair of redox reactions in the homolactate fermentation (Fig. 10-3 Eq. 17-19). Tire reactions of steps a and c of Eq. 17-42 are essentially at equilibrium, but the reaction of step b may be relatively slow. Furthermore, pyruvate is utilized in many other metabolic pathways and ATP is hydrolyzed and converted to ADP through innumerable processes taking place within the cell. Reduced NAD does not cycle between the two enzymes in a stoichiometric way and the "reducing equivalents" of NADH formed are, in large measure, transferred to the mitochondria. The proper view of the reactions of Eq. 17-42 is that the redox pairs represent a kind of redox buffer system that poises the NAD+/NADH couple at a ratio appropriate for its metabolic function. 

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