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The EMP pathway is present in organisms from every branch of the bacteria, archaea, and eukarya. Clearly, this is an early evolutionary adaptation, probably present in the ancestor of all current life forms. This suggests that the EMP pathway evolved in an anaerobic, fermentative world. However, the pathway also functions efficiently as the basis for aerobic respiration of glucose. The differences between fermentation and respiration lie largely in the differing fates of the pyruvate produced (see later). For simplicity, this discussion focuses on the EMP pathway in the well-known bacterium Escherichia coli, though the basic features of the pathway are nearly universal. Before glucose metabolism begins, it must be transported into the cell and phosphorylated. In E. coli, these two processes are intimately coupled such that the glucose is phosphorylated by the phosphotransferase system (PTS) as it passes into the cell. Since glucose-6-phosphate (G-6-P), like most if not all sugar phosphates, is toxic at high cellular concentrations, this transport process is tightly regulated. Transcription of the glucose-specific transporter gene, ptsG, is maximal only when cyclic adenosine monophosphate (cAMP) (signaling energy limitation) accumulates. Moreover, translation of ptsG messenger RNA (mRNA) is inhibited by the small RNA sgrS, which is produced when G-6-P accumulates. Thus, the import and concomitant phosphorylation to G-6-P is reduced whenever the demand for more energy is low or the concentration of G-6-P is dangerously high. In the absence of a PtsG protein, other PTS-linked transporters, especially the mannose-specific transporter, ManXYZ, can also transport and phosphorylate glucose. However, ptsG mutants grow more slowly on glucose than on wild-type strains. Free glucose can also accumulate intracellularly from the degradation of glucose-containing oligosaccharides such as lactose or maltose. Entry of intracellular glucose into the EMP pathway occurs via a hexokinase encoded by the glk gene. The next two steps in the EMP pathway prepare the G-6-P for cleavage into two triose phosphates. First, a reversible phosphoglucose isomerase (pgi gene) converts G-6-P to fructose-6-phosphate. A pgi mutant can still grow slowly on glucose by using other glycolytic pathways (see later), but the EMP pathway is blocked in a pgi mutant. The resulting fructose-6-phosphate is further phosphorylated at the C1 position to fructose-1,6,-bisphosphate at the expense of adenosine triphosphate (ATP) by a phosphofructokinase encoded by pfkA. A second minor isozyme of phosphofructokinase encoded by pfkB allows slow growth of pfkA mutants. A potentially competing set of phosphatases that remove the C1 phosphate from fructose-1,6,-bisphosphate function during gluconeogenesis but are controlled during glycolysis by a variety of feedback mechanisms to prevent futile cycling. The next reaction in the pathway is the cleavage of fructose-1,6-bisphosphate to two triose phosphates that gives the pathway its name (glycolysis = sugar breakage). This reversible reaction is carried out by fructose bisphosphate aldolase (fbaA gene) and yields dihydroxyacetone phosphate (DHAP) and glyceraldehyde phosphate (GAP) as products. A second, unrelated aldolase (fbaB gene) is made only during gluconeogenesis and thus plays no role in glycolysis. The two triose phosphates are freely interconvertible via triosephosphate isomerase (tpi gene). DHAP is a key substrate for lipid biosynthesis. GAP is an important node in glycolysis; two other common glycolytic pathways (see below) join the EMP pathway at GAP. Up to this point, the EMP pathway can be regarded as a biosynthetic pathway since it yields three key biosynthetic building blocks (G-6-P, fructose-6-phosphate, and DHAP) at the expense of ATP and without any oxidative steps. The next step is the oxidative phosphorylation of GAP to 1,3-diphosphoglyceric acid, a high-energy compound. The incorporation of inorganic phosphate by GAP dehydrogenase (gapA gene) is coupled to the reduction of NAD+ to NADH. Under aerobic conditions, this NADH is reoxidized using the respiratory chain to yield ATP. Under anaerobic conditions, this NADH is reoxidized by coupling to the reduction of products derived from pyruvate or other EMP pathway intermediates. The enzyme phosphoglycerate kinase (pgk gene) then phosphorylates adenosine diphosphate (ADP) to ATP at the expense of the C1 phosphate of 1,3-diphosphoglycerate. This is the first of two substrate-level phosphorylations where phosphate is transferred from a highly reactive substrate directly to ADP without the involvement of the membrane ATP synthase. The next two steps rearrange the resulting 3-phosphoglycerate to the last high-energy intermediate of the pathway, phosphoenolpyruvate (PEP). First, the phosphate is transferred from the C3 position to the C2 position by a phosphoglycerate mutase. There are two evolutionarily unrelated isozymes, one of which (encoded by the gpmA gene) requires a 2,3-bisphosphoglycerate as a cofactor and the other (gpmM gene) does not. Although E. coli, Bacillus subtilis, and some other bacteria have both isozymes, many organisms have only one or the other. For example, the yeast Saccharomyces cerevisiae, the bacterium Mycobacterium tuberculosis, and all vertebrates have only the cofactor-dependent enzyme, whereas higher plants, the archaea, and the bacterium Pseudomonas syringae have only the cofactor-independent enzyme. A third isozyme (ytjC gene) appears to exist in E. coli, though its role is less clear. The rearranged 2-phosphoglycerate is then dehydrated by an enolase (eno gene) to yield the key intermediate, PEP. Although pyruvate is generally considered to be the end product of the EMP pathway, it can be argued that PEP shares that honor. PEP is the ultimate source of phosphate for the PtsG-mediated transport/phosphorylation of glucose that initiates the pathway. In addition, the enzyme enolase is a required part of the degradasome that functions with the small RNA sgrS (described earlier) to inhibit translation of ptsG mRNA and stimulate degradation of ptsG mRNA. This reduces the generation of the otherwise toxic accumulation of G-6-P. It is worth noting that PEP is a branch point under both aerobic and anaerobic conditions. The carboxylation of PEP by PEP carboxylase (ppc gene) provides oxaloacetate, which condenses with the acetyl-CoA derived from pyruvate to form citrate for running both the tricarboxylic acid (TCA) cycle and glyoxylate shunt aerobically. During fermentation, this same oxaloacetate is an intermediate in the reductive (NAD regenerating) pathway to succinate. In addition, the PEP-derived oxaloacetate is used (via a portion of the TCA cycle) for the biosynthesis of glutamic acid even under anaerobic conditions. The last reaction is a substrate-level phosphorylation of ADP to ATP at the expense of PEP to yield pyruvate. The two isozymes of pyruvate kinase (pykA and pykF genes) are activated by sugar phosphates and the product of the pykF gene shows positive cooperativity with respect to the substrate PEP, again tending to prevent accumulation of this phosphorylated intermediate and thus preventing the generation of more G-6-P via the PEP-dependent PtsG transport mechanism. At the end of the EMP pathway, 1 mol of glucose is converted to 2 mol of pyruvate, which can be used for further catabolism or for biosynthesis. It also yields 2 mol of ATP and 2 mol of NADH (which must be reoxidized for the pathway to continue operating). Since the pathway generates several toxic intermediates, it is not surprising that the flux through the pathway is tightly regulated. The enzymes of the pathway respond rapidly to variations in supply and demand by feedback inhibition and substrate activation of enzyme activities. They also respond (more slowly) by transcriptional regulation of gene expression in response to global regulators that vary from organism to organism. The EMP pathway functions to generate both biosynthetic intermediates and catabolic energy from glucose. However, it also serves as a central trunk line into which many other catabolic pathways feed. G-6-P, fructose-6-phosphate, DHAP, and GAP are common junction points where catabolic pathways for sugars, alcohols, fats, and organic acids feed into the EMP pathway. View chapterPurchase book Read full chapter URL: https://www.sciencedirect.com/science/article/pii/B9780123749840006598 Inborn Errors of Metabolism and the Nervous SystemJoseph Jankovic MD, in Bradley and Daroff's Neurology in Clinical Practice, 2022 Disorders of Glycolysis and GluconeogenesisDeficiency of glycolytic enzyme in muscle can associate with myopathy and hemolytic anemia (Berardo et al., 2010; Naini et al., 2009). Characteristic disorders include PGK, phosphoglycerate mutase, and α-enolase deficiencies, all of which are inherited as autosomal-recessive traits with the exception of X-linked PGK deficiency (Chiarelli et al., 2012; Salameh et al., 2013). Neurological morbidity in PGK deficiency encompasses intellectual deficiency, behavioral abnormalities, and seizures. Defects of gluconeogenesis result in recurrent combined hypoglycemia and lactic acidosis, with or without ketosis. Neurodegenerative features occur in PC and phosphoenolpyruvate carboxykinase (PEPCK) deficiencies. In the severe neonatal form of PC deficiency, there is congenital lactic acidosis along with citrullinemia and hyperammonemia. Citrullinemia can be highly suggestive, the result of the absent conversion of pyruvate to oxaloacetate, which leads to lowered aspartic acid (transamination product of oxaloacetate). Aspartate is a co-reactant in the condensation of citrulline to form argininosuccinic acid in the urea cycle. The integrity of glycogenolysis and gluconeogenesis can be examined with the glucagon stimulation test. In patients with glycogenosis type I (von Gierke disease), the glucose curve following glucagon administration (0.5 g intramuscularly) is usually flat, or there may be a decline associated with an increase in lactate and alanine levels. GlycolysisF.K. Zimmermann, in Encyclopedia of Genetics, 2001 Glycolysis in HumansThe genetics of glycolysis in humans is complicated (1) by the presence of tissue and cell type-specific isoenzymes and (2) because several glycolytic enzymes and their genes have additional functions beyond a strictly catalytic role. The expression of the glycolytic enzymes is stimulated by glucose in several cell types via glucose-6-phosphate and a hypoxia-inducible helix–loop–helix transcription factor. Numerous genetic diseases are caused by enzyme deficiencies in the glycolytic pathway (Table 1). Deficiency in hexokinase type I causes hemolytic anemia. Hexokinase II is a leading enzyme and glucose ‘sensor’ in insulin-sensitive tissues, and a defect causes type 2 diabetes. Many tumor cells have increased rates of glucose catabolism, which can promote cell proliferation. Certain tumor-associated p53 mutant proteins cause a significant activation of the type II hexokinase promoter. Glucokinase is the glucose sensor, and low-activity and low-stability mutants can explain in part the maturity-onset diabetes of the young (MODY), because glucose metabolism of the β-cells controls insulin secretion, and amino acid substitutions have been associated with this syndrome. Different amino acid substitutions of the muscle phosphofructokinase cause an exertional myopathy and hemolytic syndrome (Tarui disease). A stop codon in position 145 of the triosephosphate isomerase locus has been associated with neurological disorders. Glyceraldehyde-3-phosphate dehydrogenase has a subunit that participates in RNA export and DNA replication and repair. Mutant forms of this enzyme could be involved in several disease syndromes. Phosphoglycerate kinase deficiency has been found in patients with myoglobinuria. The gene coding for the α-enolase isoenzyme is transcribed into a single mRNA species which, when translated from the first initiation codon, yields enolase. Another AUG codon 400 bp downstream starts the translation of a protein, MBP-1, binding and thus downregulating the promoter of the c-myc gene which, when overexpressed, causes cancer. Thus the human eno1 gene could be a tumor suppressor gene. Many well-defined mutations affecting erythrocyte pyruvate kinase enzymic parameters cause severe hemolytic anemia. Table 1. Human enzyme deficiencies and genetic disease Glycolytic enzymeMutation-associated demonstrated or possible defectsHexokinase INonspherocytic hemolytic anemiaHexokinase IINonspherocytic hemolytic anemia; insulin resistance; possible cause of increased glycolysis in cancer cellsGlucokinaseGestational diabetes; hyperinsulinism of the newborn; maturity-onset diabetes of the youngPhosphoglucose isomeraseNonspherocytic hemolytic anemiaPhosphofructokinaseExercise intolerance and compensated hemolysis (Tarui disease)Aldolase BHereditary fructose intoleranceTriosephosphate isomeraseMultisystem disease, lethality in early childhoodGlyceraldehyde-3-phosphate dehydrogenaseDiverse nonglycolytic functions, could be involved in, e.g., prostate cancer, age-related neurodegenerative diseasePhosphoglycerokinaseChronic hemolytic anemiaPhosphoglycerate mutaseExercise intoleranceEnolase IDeregulation of c-myc oncogenePyruvate kinaseα-Hereditary hemolytic anemia Recent findings support the view that nuclear genes for the enzymes of glycolysis in eukaryotes were acquired from mitochondrial genomes (Liaud et al., 2000). View chapterPurchase book Read full chapter URL: https://www.sciencedirect.com/science/article/pii/B012227080000570X Carbohydrate MetabolismAntonio Blanco, Gustavo Blanco, in Medical Biochemistry, 2017 Glucose Oxidation Energy BalanceGlycolysis. Anaerobically, each mole of glucose produces 2 moles of ATP. When there is adequate supply of oxygen, NAD reduced during oxidation of glyceraldehyde-3-phosphate transfers reducing equivalents from the cytosol to the respiratory chain by one of the shuttle systems (p. 199). Through this mechanism, the energy yield is either two (glycerophosphate shuttle) or three ATP (malate–aspartate shuttle). Two molecules of triose-phosphate produced per molecule of glucose yields 4–6 ATP. These, in addition to the 2 ATP made from glycolysis, gives a total of 6–8 molecules of ATP per glucose molecule. Decarboxylation of pyruvate. Three ATPs are generated in the respiratory chain by transfer of reducing equivalents from reduced NAD. Each glucose molecule generates two molecules of pyruvate; thus ATP gain is 6 moles per mole of glucose. Citric acid cycle. Oxidation of acetate yields a total of 12 ATP. One mole of glucose results in 2 moles of acetate, yielding a total of 24 moles of ATP. Table 14.5 summarizes the total ATP production of 1 mole of glucose in oxidative catabolism. Table 14.5. Energy Yield by Oxidation of 1 Mole of Glucose Glycolysis6–8 mol ATPaPyruvate oxidative decarboxylation6 mol ATPCitric acid cycle24 mol ATPTotal yield36–38 mol ATP aAccording to the shuttle used to transfer H from cytosol to mitochondria.Free energy of ATP hydrolysis is 7.3 kcal/mol (30.5 kJ/mol); therefore, the total energy captured in the form of ATP per mole of glucose is around 277 kcal (1159 kJ). Combustion of 1 mole of glucose releases 686 kcal (2870 kJ). The efficiency of the oxidative pathway (percentage of the energy contained in the fuel utilized for work) in terms of energy obtained from glucose is approximately 40%. This is a remarkable difference when compared to a common combustion engine. Most engines barely reach 30% efficiency and lose energy as heat or useless frictions. This highlights how efficient living organisms are in utilizing fuel (Fig. 14.8).  Figure 14.8. Glucose oxidative catabolism. View chapterPurchase book Read full chapter URL: https://www.sciencedirect.com/science/article/pii/B9780128035504000148 Glycolysis OverviewR.A. Harris, in Encyclopedia of Biological Chemistry (Second Edition), 2013 AbstractGlycolysis is a linear metabolic pathway of enzyme-catalyzed reactions that convert glucose into two molecules of pyruvate in the presence of oxygen or into two molecules of lactate in the absence of oxygen. The latter pathway, anaerobic glycolysis, is believed to be the first process to have evolved in nature to produce adenosine triphosphate (ATP). In most cells glycolysis converts glucose to pyruvate which is subsequently oxidized to carbon dioxide and water by mitochondrial enzymes. However, in some cells, most notably mature red blood cells, glycolysis is the only means of ATP production because of the lack of mitochondria. In the absence of oxygen, glycolysis is the only option that cells have for the production of ATP from glucose. Overproduction of lactic acid by anaerobic glycolysis leads to lactic acidosis, a life-threatening condition. Many cancer cells have an exceptionally high enzymatic capacity for glycolysis. Even when oxygen is available, cancer cells produce much of their ATP by glycolysis. The ability to produce sufficient ATP by a pathway that does not require oxygen gives cancer cells a selective advantage over normal cells. View chapterPurchase book Read full chapter URL: https://www.sciencedirect.com/science/article/pii/B978012378630200044X Cell Injury, Cellular Responses to Injury, and Cell DeathThomas C. King MD, PhD, in Elsevier's Integrated Pathology, 2007 HypoxiaHypoxic injury implies damage to cells resulting only from decreased oxygen tension. This is a relatively unusual pattern of injury in its pure form. Hypoxia can result from decreased atmospheric oxygen concentration, abnormal lung function, and decreased oxygen-carrying capacity in the blood (e.g., severe anemia). Acute hypoxia results in depletion of ATP in cells that triggers a switch to anaerobic glycolysis. Since the energy yield from glycolysis is much less than from oxidative phosphorylation, energy demands are not met and the continuing decrease in ATP levels results in additional cellular dysfunction. Increased lactic acid produced by glycolysis also decreases intracellular pH, resulting in additional dysfunction. As discussed above, different types of cells have markedly different metabolic rates and cells with high metabolic rates tend to be injured or killed very rapidly by hypoxia. For example, proximal tubular cells in the kidney may undergo necrosis (acute tubular necrosis, ATN) as a result of even transient hypoxia (Fig. 1-3). The light microscopic changes associated with necrosis include condensation and shrinking (pyknosis) or disappearance (karyolysis) of cell nuclei, which is evident in the necrotic renal tubular cells in Figure 1-3. These cells also show increased eosin staining (hypereosinophilia) of their cytoplasm as a result of the degradation of cellular proteins and loss of cytoplasmic RNA. Other cell types (e.g., neurons) may initiate apoptosis in response to hypoxic injury (see Apoptosis section). Chronic, sublethal hypoxia can activate transcription of genes that can initiate angiogenesis (new blood vessel formation), resulting in neovascularization of the affected tissue. BIOCHEMISTRY Glycolysis metabolizes glucose and rapidly produces a small amount of ATP as well as acid, pyruvate, and NADH that can feed into the Krebs cycle. The overall reaction is Glucose + 2 ADP + 2 Pi + 2 NAD+ → 2 pyruvate + 2 ATP + 2 NADH + 2 H+ + 2 H2O Metabolism of glycolysis end products in the Krebs cycle produces much larger amounts of ATP than glycolysis does. In the absence of oxygen, the Krebs cycle is not active and acid and pyruvate can quickly accumulate. Since the amount of ATP produced from glucose by glycolysis is quite small relative to oxidative phosphorylation, energy charge declines rapidly in most hypoxic cells even if large glucose stores are available. |
Where does glycolysis occur in the body
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