Glucose 6-Phosphate and Carbohydrate Interconversions

The biosynthetic origins of building blocks and coenzymes can be traced to relatively few precursors, called focal metabolites. Figures 1–4 illustrate how the respective focal metabolites glucose 6-phosphate (G6PD), phosphoenolpyruvate, oxaloacetate, and α-ketoglutarate give rise to most bio synthetic end products.

Fig1. Biosynthetic end products formed from glucose 6-phosphate. Carbohydrate phosphate esters of varying chain length serve as intermediates in the biosynthetic pathways.

Fig2. Biosynthetic end products formed from phosphoenolpyruvate.

Fig3. Biosynthetic end products formed from oxaloacetate. The end products aspartate, threonine, and pyrimidines serve as intermediates in the synthesis of additional compounds.

Fig4. Biosynthetic end products formed from α-ketoglutarate.

Figure 1 illustrates how G6PD is converted to a range of biosynthetic end products via phosphate esters of carbo hydrates with different chain lengths. Carbohydrates possess the empirical formula (CH₂O)n , and the primary objective of carbohydrate metabolism is to change n, the length of the carbon chain. Mechanisms by which the chain lengths of carbohydrate phosphates are interconverted are summarized in Figure 5. In one case, oxidative reactions are used to remove a single carbon from G6PD, producing the pentose derivative ribulose 5-phosphate. Isomerase and epimerase reactions interconvert the most common biochemical forms of the pentoses: ribulose 5-phosphate, ribose 5-phosphate, and xylulose 5-phosphate. Transketolases transfer a two carbon fragment from a donor to an acceptor molecule. These reactions allow pentoses to form or to be formed from carbo hydrates of varying chain lengths. As shown in Figure 5, two pentose 5-phosphates (n = 5) are interconvertible with triose 3-phosphate (n = 3) and heptose 7-phosphate (n = 7); pentose 5-phosphate (n = 5) and tetrose 4-phosphate (n = 4) are interconvertible with triose 3-phosphate (n = 3) and hexose 6-phosphate (n = 6).

Fig5. Biochemical mechanisms for changing the length of carbohydrate molecules. The general empirical formula for carbohydrate phosphate esters, (CnH2nOn )-N-phosphate, is abbreviated (Cn ) to emphasize changes in chain length.

The six-carbon hexose chain of fructose 6-phosphate can be converted to two three-carbon triose derivatives by the consecutive action of a kinase and an aldolase on fructose 6-phosphate. Alternatively, aldolases, acting in conjunction with phosphatases, can be used to lengthen carbohydrate molecules: Triose phosphates give rise to fructose 6-phosphate; a triose phosphate and tetrose 4-phosphate form heptose 7-phosphate. The final form of carbohydrate chain length interconversion is the transaldolase reaction, which interconverts heptose 7-phosphate and triose 3-phosphate with tetrose 4-phosphate and hexose 6-phosphate.

The coordination of different carbohydrate rearrangement reactions to achieve an overall metabolic goal is illustrated by the hexose monophosphate shunt (Figure 6). This metabolic cycle is used by cyanobacteria for the reduction of NAD+ (nicotinamide adenine dinucleotide) to NADH (reduced nicotinamide adenine dinucleotide), which serves as a reductant for respiration in the dark. Many organisms use the hexose monophosphate shunt to reduce NADP+ (nicotinamide adenine dinucleotide phosphate) to NADPH (reduced nicotinamide adenine dinucleotide phosphate), which is used for biosynthetic reduction reactions. The first steps in the hexose monophosphate shunt are the oxidative reactions that shorten six hexose 6-phosphates (abbreviated as six C6 in Figure 6) to six pentose 5-phosphates (abbreviated six C5 ). Carbohydrate rearrangement reactions convert the six C5 molecules to five C6 molecules so that the oxidative cycle may continue.

Fig6. The hexose monophosphate shunt. Oxidative reactions (see Figure 5) reduce NAD+ (nicotinamide adenine dinucleotide phosphate) and produce CO2 , resulting in the shortening of the six hexose phosphates (abbreviated C6 ) to six pentose phosphates (abbreviated C5 ). Carbohydrate rearrangements (see Figure 6-6) convert the pentose phosphates to hexose phosphates so that the oxidative cycle may continue.

Clearly, all reactions for interconversion of carbohydrate chain lengths are not called into play at the same time. Selection of specific sets of enzymes, essentially the determination of the metabolic pathway taken, is dictated by the source of carbon and the biosynthetic demands of the cell. For example, a cell given triose phosphate as a source of carbohydrate will use the aldolase–phosphatase combination to form fructose 6-phosphate; the kinase that acts on fructose 6-phosphate in its conversion to triose phosphate would not be expected to be active under these circumstances. If demands for pentose 5-phosphate are high, as in the case of photosynthetic carbon dioxide assimilation, transketolases that can give rise to pentose 5-phosphates are very active.

In sum, G6PD can be regarded as a focal metabolite because it serves both as a direct precursor for metabolic building blocks and as a source of carbohydrates of varying length that are used for biosynthetic purposes. G6PD itself may be generated from other phosphorylated carbohydrates by selection of pathways from a set of reactions for chain length interconversion. The reactions chosen are determined by the genetic potential of the cell, the primary carbon source, and the biosynthetic demands of the organism. Metabolic regulation is required to ensure that reactions that meet the requirements of the organism are selected.

Formation and Utilization of Phosphoenolpyruvate Triose phosphates, formed by the interconversion of carbohydrate phosphoesters, are converted to phosphoenolpyruvate by the series of reactions shown in Figure 7. Oxidation of glyceraldehyde 3-phosphate by NAD+ is accompanied by the formation of the acid anhydride bond on the one car bon of 1,3-diphosphoglycerate. This phosphate anhydride is transferred in a substrate phosphorylation to adenosine diphosphate (ADP), yielding an energy-rich bond in ATP. Another energy-rich phosphate bond is formed by dehydration of 2-phosphoglycerate to phosphoenolpyruvate; via another substrate phosphorylation, phosphoenolpyruvate can donate the energy-rich bond to ADP, yielding ATP and pyruvate. Thus, two energy-rich bonds in ATP can be obtained by the metabolic conversion of triose phosphate to pyruvate. This is an oxidative process, and in the absence of an exogenous electron acceptor, the NADH generated by oxidation of glyceraldehyde 3-phosphate must be oxidized to NAD+ by pyruvate or by metabolites derived from pyruvate. The products formed as a result of this process vary and, as described later in this chapter, can be used in the identification of clinically significant bacteria.

Fig7. Formation of phosphoenolpyruvate and pyruvate from triose phosphate. The figure draws attention to two sites of substrate phosphorylation and to the oxidative step that results in the reduction of NAD+ (nicotinamide adenine dinucleotide phosphate) to NADH (nicotinamide adenine dinucleotide hydride). Repetition of this energy-yielding pathway demands a mechanism for oxidizing NADH to NAD+. Fermentative organisms achieve this goal by using pyruvate or metabolites derived from pyruvate as oxidants.

Formation of phosphoenolpyruvate from pyruvate requires a substantial amount of metabolic energy, and two anhydride ATP bonds invariably are invested in the process. Some organisms—Escherichia coli, for example—directly phosphorylate pyruvate with ATP, yielding adenosine mono phosphate (AMP) and inorganic phosphate (Pi ). Other organisms use two metabolic steps: One ATP pyrophosphate bond is invested in the carboxylation of pyruvate to oxaloacetate, and a second pyrophosphate bond (often carried by guano sine triphosphate [GTP] rather than ATP) is used to generate phosphoenolpyruvate from oxaloacetate.

Formation and Utilization of Oxaloacetate As already described, many organisms form oxaloacetate by the ATP-dependent carboxylation of pyruvate. Other organisms, such as E. coli, which form phosphoenolpyruvate directly from pyruvate, synthesize oxaloacetate by carboxylation of phosphoenolpyruvate.

Succinyl-CoA is a required biosynthetic precursor for the synthesis of porphyrins and other essential compounds. Some organisms form succinyl-CoA by reduction of oxaloacetate via malate and fumarate. These reactions represent a reversal of the metabolic flow observed in the conventional tricarboxylic acid cycle .

Formation of α-Ketoglutarate From Pyruvate

 Conversion of pyruvate to α-ketoglutarate requires a metabolic pathway that diverges and then converges (Figure 8). In one branch, oxaloacetate is formed by carboxylation of pyruvate or phosphoenolpyruvate. In the other branch, pyruvate is oxidized to acetyl-CoA. It is noteworthy that, regardless of the enzymatic mechanism used for the formation of oxaloacetate, acetyl-CoA is required as a positive metabolic effector for this process. Thus, the syn thesis of oxaloacetate is balanced with the production of acetyl-CoA. Condensation of oxaloacetate with acetyl-CoA yields citrate. Isomerization of the citrate molecule pro duces isocitrate, which is oxidatively decarboxylated to α-ketoglutarate.

Fig8. Conversion of pyruvate to α-ketoglutarate. Pyruvate is converted to α-ketoglutarate by a branched biosynthetic pathway. In one branch, pyruvate is oxidized to acetyl-CoA; in the other, pyruvate is carboxylated to oxaloacetate.

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مواضيع ذات صلة

Relationship of Biocide Concentration and Time on Antimicrobial Killing

Specific Actions of Selected Biocides

Flow cytometry

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غشاء الخلية The cell membrane

مملكة البدائيات (Monera)

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