Phosphoenolpyruvate catabolism

Inhibition of PK In liver, pyruvate kinase is inhibited by alanine and cyclic AMP (which is produced under the influence of glucagon). Glucagon is present during fasting, as is the gluconeogenic precursor alanine, which is derived from muscle protein (Chapter 44). Inhibition of PK restricts phosphoenolpyruvate catabolism and favours gluco-neogenesis (Fig. 46.2). 

Synthetic studies for sialic acid and its modifications have extensively used the catabolic enzyme N-acetylneuraminic acid aldolase (NeuA E.C. 4.1.3.3), which catalyzes the reversible addition of pyruvate (70) to N-acetyl-D-mannosamine (ManNAc, 11) to form the parent sialic acid N-acetylneuraminic acid (NeuSNAc, 12 Scheme 2.2.5.23) [1, 2, 45]. In contrast, the N-acetylneuraminic acid synthase (NeuS E.C. 4.1.3.19) has practically been ignored, although it holds considerable synthetic potential in that the enzyme utilizes phosphoenolpyruvate (PEP, 71) as a preformed enol nucleophile from which release of inorganic phosphate during... 

The glucocorticoids have important dose-related effects on carbohydrate, protein, and fat metabolism. The same effects are responsible for some of the serious adverse effects associated with their use in therapeutic doses. Glucocorticoids stimulate and are required for gluconeogenesis and glycogen synthesis in the fasting state. They stimulate phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and glycogen synthase and the release of amino acids in the course of muscle catabolism. 

Calmes, R. 1978. Involvement of phosphoenolpyruvate in the catabolism of caries-conducive disaccharides by Streptococcus mutans Lactose transport. Infect. Immun. 19, 934-942. 

Pyruvate-dependent aldolases have catabolic activity in vivo, whereas their counterparts utilizing phosphoenolpyruvate as the donor substrate are involved in the biosynthesis of keto acids. Both classes of enzymes have been used in synthesis to prepare similar a-keto acids. The enzymes catalzye this type of reaction in vivo and their stereoselectivity are presented together in this section (Schemes 5.27, 5.28). 

Mammals produce sialic acid by aldolic condensation of phosphoenolpyruvate and Ai-acetylmannosamine 6-phosphate (reaction 12.1). A kinase enzyme catalyses the phosphorylation of A -acetylmannosamine and a phosphatase catalyses the hydrolysis of the phosphate of sialic acid. These phosphorylation and dephosphorylation steps are irreversible, such that the synthesis can be total even with low concentrations of the substrate. A variation of reaction (12.1), observed with the bacterium Neisseria meningitidis, uses non-phosphated /-acetylmannosamine. However, these were not the enzymes used in the preparative synthesis, which used instead a microbial aldolase which catalyses equilibrium (12.2). This enzyme probably plays a catabolic role in these organisms, but it functions in the synthetic sense in the presence of an excess of pyruvate. 

The aldolases which have been investigated for their synthetic utility can be classified on the basis of the donor substrate accepted by the enzyme. For the synthesis of 3-deoxy-2-ulosonic acids pyruvate- and phosphoenolpyruvate dependent aldolases are the most desirable enzymes as they are involved in the metabolism of sialic acids (or structurally related ones) in vivo. They use pyruvate or phosphoenolpyruvate as a donor to form 3-deoxy-2-keto acids (Table 1). Both of them add a three-carbons ketone fragment onto a carbonyl group of an aldehyde. The pyruvate dependent aldolases have a catabolic function in vivo, whereas the phosphoenolpyruvate dependent aldolases are involved in the biosynthesis of the keto acids. For synthetic purpose the equilibrium of the pyruvate dependent aldolases is shifted toward the condensation products through the use of an excess of pyruvate. 

FIGURE 19.10 a summary of catabolism, showing the central role of the citric acid cycle. Note that the end products of the catabolism of carbohydrates, lipids, and amino acids all appear. (PEP is phosphoenolpyruvate a-KG is a-ketoglutarate TA is transamination > > > is a multistep pathway.)... 

Elucidation of the metabolic pathway repertoire of C, glutamicum was initiated soon after its discovery [4-6], related to the high importance of the central metabolism for amino acid fermentation. Evidence on the presence of the major catabolic routes, such as the Embden-Meyerhof-Parnas (EMP) pathway, the pentose phosphate (PP) pathway, the tricarboxylic acid (TCA) cycle, and the glyoxylate shunt had already been provided by the end of the 1950s [4, 5, 7] (Figure 6.1). However, it took more than 30 years for a more detailed resolution of the central metabolic network mainly related to the complex structure of the phosphoenolpyruvate/pyruvate - oxaloacetate/malate node [8-11]. Altogether,... 

In this manner the phosphoenolpyruvate and the acetylphosphate can transfer their phosphate group to the ADP in the same type of reaction. The two intermediary molecules in the catabolism of sugar are therefore very important from an energetic viewpoint... 

Figure 2. Diagram representing anaplerotic (solid lines and shapes) and cataplerotic (dashed lines and shapes) sequences connecting the Krebs cycle to gluconeogenesis, fatty acid metabolism, and dispensible AA synthesis. Some sequences can serve both anaplerotic and cataplerotic roles, thus linked metabolites (bold) can be catabolized or synthesized. a-KG, a-ketoglutarate OAA, oxaloacetate PEP, phosphoenolpyruvate.

All of the steps in the breakdown of phosphoenolpyruvate carboxy-kinase in vitro occur at neutral pH and are not accelerated either by intact or by disrupted lysosomes. Yet a role for lysosomes cannot be eliminated, especially in the latter stages of enzyme catabolism, since the "denatured" enzyme might be selectively translocated into lysosomes after being attached to their outer surfaces. Nevertheless, it is most unlikely that lysosomes initiate the degradation process. Initiation is reduced by a combination of the ability of enzyme to maintain a stable conformation and by the high ratio of reduced to oxidized glutathione in cells. 

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