Anaerobic Metabolism of Pyruvate

How does the conversion of pyruvate to lactate take place in muscle  

The final reaction of anaerobic glycolysis is the reduction of pyruvate to lactate. 

This reaction is also exergonic (AG° = -25.1 moH = -6.0 kcal moH) as before, we need to multiply this value by 2 to hnd the energy yield for each molecule of glucose that enters the pathway. Lactate is a dead end in muscle metabolism, but it can be recycled in the liver to form pyruvate and even glucose by a pathway called gluconeogenesis ( new synthesis of glucose ), which we will discuss in Section 18.2. 

At this point, one might ask why the reduction of pyruvate to lactate (a waste product in aerobic organisms) is the last step in anaerobic glycolysis, a pathway that provides energy for the organism by oxidation of nutrients. There is another point to consider about the reaction, one that involves the relative amounts of NAD+ and NADH in a cell. The half reaction of reduction can be written 

I ACTIVE FIGURE 17.11 Therecycling of NAD and NADH in anaerobic glycolysis. Sign in at www.thomsonedu.com/login to see an animated version of this figure. 

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The majority of microbial hydrogen production is driven by the anaerobic metabolism of pyruvate, formed during the catabolism of various substrates. The breakdown of pyruvate is catalyzed by one of two enzyme systems ... 

It is interesting to note that the dihydroxybenzoyl nucleus arises from chorismic acid which, in turn, is derived from erythrose phosphate and phosphoenol pyruvate, both of these substances being intermediates in the anaerobic metabolism of carbohydrate (74). Accordingly, the biogenesis of the catechol type ligand is independent of the presence of oxygen gas. 

C. In cells that are unable to transfer electrons to oxygen due to lack of mitochondria, eg, RBCs, or in vigorously exercising muscle cells (anaerobic conditions), NAD" is regenerated by further metabolism of pyruvate. 

The best-studied enzymes to date that contain glycyl radicals are pyruvate formate-lyase (PFL) and a ribonucleoside triphosphate reductase (ARR), both isolated from anaerobically growing E. coli. These enzymes play central roles in the anaerobic metabolism of the bacterium. The first catalyzes the reversible formation of acetyl-CoA and formate from pyruvate and coenzyme A, while the second is responsible for synthesizing the deoxyribonucleotide monomers of the polymer DNA. It is intriguing to note that formate, a product of the PFL reaction, is a substrate for the ARR. It supplies the reducing equivalents needed for each round of deoxynucleotide synthesis. ... 

TCA cycle. (tricarboxylic acid cycle Krebs cycle citric acid cycle). A series of enzymatic reactions occurring in living cells of aerobic organisms, the net result of which is the conversion of pyruvic acid, formed by anaerobic metabolism of carbohydrates, into carbon dioxide and water. The metabolic intermediates are degraded by a combination of decarboxylation and dehydrogenation. It is the major terminal pathway of oxidation in animal, bacterial, and plant cells. Recent research indicates that the TCA cycle may have predated life on earth and may have provided the pathway for formation of amino acids. 

Lactic acidosis is one of the most common canses of high SAG metabolic acidosis. Lactic acid is the end prodnct of anaerobic metabolism of glucose (glycolysis). In normal individnals, lactic acid derived from pyruvate enters the circulation in small amonnts and is promptly removed by the liver. In the liver, and to a lesser extent in the kidney, lactic acid is reoxidized to pyruvic acid, which is then metabolized to CO2 and H2O. The normal plasma lactate concentration in healthy subjects is approximately 1 rnEq/L. " The diagnosis of lactic acidosis should be considered in aU patients with metabolic acidosis... 

Fermentation Anaerobic metabolism of the pyruvic acid produced in glycolysis. 

The metabolism of pyruvate, which may be either an anaerobic or an aerobic breakdown. The aerobic breakdown leads into the citric acid cycle and the respiratory chain in the anaerobic breakdown the coenzyme NAD is regenerated in a hydrogenation step which produces lactate in the muscle, and ethyl alcohol in yeast. 

Glucose is metabolized to pyruvate by the pathway of glycolysis, which can occur anaerobically (in the absence of oxygen), when the end product is lactate. Aerobic tissues metabolize pyruvate to acetyl-CoA, which can enter the citric acid cycle for complete oxidation to CO2 and HjO, linked to the formation of ATP in the process of oxidative phosphorylation (Figure 16-2). Glucose is the major fuel of most tissues. 

Lactate is the end product of glycolysis under anaerobic conditions (eg, in exercising muscle) or when the metabolic machinery is absent for the further oxidation of pyruvate (eg, in erythrocytes). 

This chapter focuses on the developmental regulation of the pyruvate dehydrogenase complex (PDC). The PDC plays diverse and pivotal roles in the entry of glycolytically generated carbon into the TCA cycle in aerobic stages and the metabolism of mitochondrially generated pyruvate in anaerobic stages (Fig. 14.1). 

Similarly, the regulation of PDK activity is modified in adult muscle PDC. For example, PDK activity is inhibited by pyruvate and propionate (metabolites elevated during anaerobic metabolism) and is less sensitive to stimulation by elevated NADH/NAD+ and acetyl CoA/CoA ratios (Fig. 14.2) (Thissen et al, 1986 Chen et al, 1998). The effects of NADH and acetyl CoA on PDK activity are mediated by the degree of E3-catalysed oxidation and E2-catalysed acetylation of the inner lipoyl domain of E2 (Roche and Cate, 1977 Rahmatullah and Roche, 1985, 1987 Ravindran et al, 1996 Yang et al, 1998), so that the regulation of this phenomenon is complex and involves multiple interacting components. 

The glycolytic pathway, or glycolysis, is a metabolic sequence in which glucose is broken down to pyruvic acid. The subsequent fate of pyruvate then depends upon whether or not the organism is aerobic or anaerobic Under aerobic conditions, pyruvate is oxidized via oxidative phosphorylation under anaerobic conditions, pyruvate is converted further into compounds such as lactate or ethanol, depending upon the organism. 

Different abortives may be formed with alternative products or substrates. Such procedures can be useful in helping to distinguish Theorell-Chance mechanisms from ordered systems with abortive complexes . In the case of lactate dehydrogenase, the E-pyruvate-NAD+ and E-lactate-NADH abortive complexes may play a regulatory roles in aerobic versus anaerobic metabolism. 

Accumulation of metformin can occur in patients with renal insufficiency, and interference with pyruvate metabolism can lead to severe lactic acidosis. Lactic acidosis is more likely in situations associated with anaerobic metabolism, and metformin should not be given to patients with renal disease, liver disease, or severe pulmonary or cardiac disease predisposing to hypoxia. It is recommended to switch patients taking metformin to another oral hypoglycaemic prior to cardiac or other major surgery. 

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