INTRODUCTION

Glucose occupies a central position in the metabolism of plants, animals, and many microorganisms. It is relatively rich in potential energy, and thus a good fuel; the complete oxidation of glucose to carbon dioxide and water proceeds with a standard free-energy change of −2,840 kJ/mol. By storing glucose as a high molecular weight polymer such as starch or glycogen, a cell can stockpile large quantities of hexose units while maintaining a relatively low cytosolic osmolarity. When energy demands increase, glucose can be released from these intracellular storage polymers and used to produce ATP either aerobically or anaerobically.

Glucose is not only an excellent fuel; it is also a remarkably versatile precursor, capable of supplying a huge array of metabolic intermediates for biosynthetic reactions. A bacterium such as Escherichia coli can obtain from glucose the carbon skeletons for every amino acid, nucleotide, coenzyme, fatty acid, or other metabolic intermediate it needs for growth. A comprehensive study of the metabolic fates of glucose would encompass hundreds or thousands of transformations. In animals and vascular plants, glucose has four major fates: it may be

  • Used in the synthesis of complex polysaccharides destined for the extracellular space
  • Stored in cells (as a polysaccharide or as sucrose)
  • oxidized to a three-carbon compound (pyruvate) via glycolysis to provide ATP and metabolic intermediates
  • oxidized via the pentose phosphate (phosphogluconate) pathway to yield ribose 5-phosphate for nucleic acid synthesis and NADPH for reductive biosynthetic  processes.
  • Nonphotosynthetic cells make glucose from simpler three- and four-carbon precursors by the process of gluconeogenesis, effectively reversing glycolysis in a pathway that uses many of the glycolytic enzymes
GLYCOLYSIS AND GLUCONEOGENESIS
FIGURE DEPICTING :- Major pathway of glucose utilization.

In glycolysis (from the Greek glykys, “sweet” or “sugar,” and lysis, “splitting”), a molecule of glucose is degraded in a series of enzymecatalyzed reactions to yield two molecules of the three-carbon compound pyruvate. During the sequential reactions of glycolysis, some of the free energy released from glucose is conserved in the form of ATP and NADH. Glycolysis was the first metabolic pathway to be elucidated and is probably the best understood. From Eduard Buchner’s discovery in 1897 of fermentation in cell-free extracts of yeast until the elucidation of the whole pathway in yeast (by Otto Warburg and Hans von Euler-Chelpin) and in muscle (by Gustav Embden and Otto Meyerhof) in the 1930s.

TWO PHASES OF GLYCOLYSIS

The breakdown of the six-carbon glucose into two molecules of the threecarbon pyruvate occurs in 10 steps, the first 5 of which constitute the preparatory phase.

  • In these reactions, glucose is first phosphorylated at the hydroxyl group on C-6.
  • The D-glucose 6- phosphate thus formed is converted to D-fructose 6-phosphate,
  • Which is again phosphorylated, this time at C-1, to yield D-fructose 1,6- bisphosphate (step 3 ). For both phosphorylations, ATP is the phosphoryl group donor.
  • Fructose 1,6-bisphosphate is split to yield two three-carbon molecules, dihydroxyacetone phosphate and glyceraldehyde 3-phosphate.
  • this is the “lysis” step that gives the pathway its name. The dihydroxyacetone phosphate is isomerized to a second molecule of glyceraldehyde 3-phosphate.

ending the first phase of glycolysis. Note that two molecules of ATP are invested before the cleavage of glucose into two three-carbon pieces; there will be a good return on this investment. To summarize: in the preparatory phase of glycolysis the energy of ATP is invested, raising the free-energy content of the intermediates, and the carbon chains of all the metabolized hexoses are converted to a common product, glyceraldehyde 3- phosphate. The energy gain comes in the payof phase of glycolysis .

  • Each molecule of glyceraldehyde 3-phosphate is oxidized and phosphorylated by inorganic phosphate (not by ATP) to form 1,3- bisphosphoglycerate.
  • Energy is then released as the two molecules of 1,3-bisphosphoglycerate are converted to two molecules of pyruvate.

Much of this energy is conserved by the coupled phosphorylation of four molecules of ADP to ATP. The net yield is two molecules of ATP per molecule of glucose used, because two molecules of ATP were invested in the preparatory phase.

Overall equation of glycolysis is :-

GLYCOLYSIS AND GLUCONEOGENESIS

Energy is also conserved in the payoff phase in the formation of two molecules of the electron carrier NADH per molecule of glucose. In the sequential reactions of glycolysis, three types of chemical transformations are particularly noteworthy:

  • degradation of the carbon skeleton of glucose to yield pyruvate
  • phosphorylation of ADP to ATP by compounds with high phosphoryl group transfer potential, formed during glycolysis
  • transfer of a hydride ion to NAD+ , forming NADH.
FIGURE DEPICTING Steps of glycolysis
FIGURE DEPICTING :- Steps of glycolysis

FATES OF THE PYRUVATE

  • Pyruvate is oxidized, with loss of its carboxyl group as CO2 , to yield the acetyl group of acetyl-coenzyme A; the acetyl group is then oxidized completely to CO2 by the citric acid cycle.
  • The second route for pyruvate is its reduction to lactate via lactic acid fermentation. When vigorously contracting skeletal muscle must function under low-oxygen conditions (hypoxia), NADH cannot be reoxidized to NAD+, but NAD+ is required as an electron acceptor for the further oxidation of pyruvate. Under these conditions pyruvate is reduced to lactate, accepting electrons from NADH and thereby regenerating the NAD+ necessary for glycolysis to continue. Certain tissues and cell types (retina and erythrocytes, for example) convert glucose to lactate even under aerobic conditions, and lactate is also the product of glycolysis under anaerobic conditions in some microorganisms.
  • The third major route of pyruvate catabolism leads to ethanol. In some plant tissues and in certain invertebrates, protists, and microorganisms such as brewer’s or baker’s yeast, pyruvate is converted under hypoxic or anaerobic conditions to ethanol and CO2 , a process called ethanol (alcohol) fermentation.
FIGURE DEPICTING Fate of pyruvate
FIGURE DEPICTING :- Fate of pyruvate

CHEMICAL REACTIONS OF GLYCOLYSIS

  • 1ST Phosphorylation of Glucose In the first step of glycolysis, glucose is activated for subsequent reactions by its phosphorylation at C-6 to yield glucose 6-phosphate, with ATP as the phosphoryl donor: This reaction, which is irreversible under intracellular conditions, is catalyzed by hexokinase. Hexokinase, like many other kinases, requires Mg 2+ for its activity, because the true substrate of the enzyme is not ATP 4− but the MgATP 2− complex.

GLYCOLYSIS AND GLUCONEOGENESIS
  • 2ND Conversion of Glucose 6-Phosphate to Fructose 6- Phosphate The enzyme phosphohexose isomerase (phosphoglucose isomerase) catalyzes the reversible isomerization of glucose 6-phosphate, an aldose, to fructose 6-phosphate, a ketose

GLYCOLYSIS
  • 3RD Phosphorylation of Fructose 6-Phosphate to Fructose 1,6-Bisphosphate In the second of the two priming reactions of glycolysis, phosphofructokinase-1 (PFK-1) catalyzes the transfer of a phosphoryl group from ATP to fructose 6-phosphate to yield fructose 1,6- bisphosphate.

GLYCOLYSIS

Phosphofructokinase-1 is subject to complex allosteric regulation; its activity is increased whenever the cell’s ATP supply is depleted or when the ATP breakdown products, ADP and AMP (particularly the latter), accumulate. The enzyme is inhibited whenever the cell has ample ATP and is well supplied by other fuels such as fatty acids. In some organisms, fructose 2,6-bisphosphate (not to be confused with the PFK-1 reaction product, fructose 1,6-bisphosphate) is a potent allosteric activator of PFK-1. Ribulose 5-phosphate, an intermediate in the pentose phosphate pathway discussed later in this chapter, also activates phosphofructokinase indirectly.

  • 4TH Cleavage of Fructose 1,6-Bisphosphate The enzyme fructose 1,6-bisphosphate aldolase, often called simply aldolase, catalyzes a reversible aldol condensation (see Fig. 13-4). Fructose 1,6-bisphosphate is cleaved to yield two different triose phosphates, glyceraldehyde 3- phosphate, an aldose, and dihydroxyacetone phosphate, a ketose.
GLYCOLYSIS
  • 5TH Interconversion of the Triose Phosphates Only one of the two triose phosphates formed by aldolase, glyceraldehyde 3-phosphate, can be directly degraded in the subsequent steps of glycolysis. The other product, dihydroxyacetone phosphate, is rapidly and reversibly converted to glyceraldehyde 3-phosphate by the fifth enzyme of the glycolytic sequence, triose phosphate isomerase.

GLYCOLYSIS
  • 6TH Oxidation of Glyceraldehyde 3-Phosphate to 1,3- Bisphosphoglycerate The first step in the payoff phase is the oxidation of glyceraldehyde 3-phosphate to 1,3-bisphosphoglycerate, catalyzed by glyceraldehyde 3-phosphate dehydrogenase.

    This is the first of the two energy-conserving reactions of glycolysis that eventually lead to the formation of ATP. The aldehyde group of glyceraldehyde 3-phosphate is oxidized, not to a free carboxyl group but to a carboxylic acid anhydride with phosphoric acid. This type of anhydride, called an acyl phosphate, has a very high standard free energy of hydrolysis (ΔG′° = −49.3 kJ/mol).

GLYCOLYSIS
  • 7TH Phosphoryl Transfer from 1,3-Bisphosphoglycerate to ADP The enzyme phosphoglycerate kinase transfers the high-energy phosphoryl group from the carboxyl group of 1,3-bisphosphoglycerate to ADP, forming ATP and 3-phosphoglycerate.

    This is the first of the two energy-conserving reactions of glycolysis that eventually lead to the formation of ATP. The aldehyde group of glyceraldehyde 3-phosphate is oxidized, not to a free carboxyl group but to a carboxylic acid anhydride with phosphoric acid. This type of anhydride, called an acyl phosphate, has a very high standard free energy of hydrolysis (ΔG′° = −49.3 kJ/mol).

GLYCOLYSIS
  • 8TH Conversion of 3-Phosphoglycerate to 2- Phosphoglycerate The enzyme phosphoglycerate mutase catalyzes a reversible shift of the phosphoryl group between C-2 and C-3 of glycerate; Mg 2+ is essential for this reaction: The reaction occurs in two steps.

     A phosphoryl group initially attached to a His residue of the mutase is transferred to the hydroxyl group at C-2 of 3-phosphoglycerate, forming 2,3-bisphosphoglycerate (2,3-BPG). The phosphoryl group at C-3 of 2,3-BPG is then transferred to the same His residue, producing 2-phosphoglycerate and regenerating the phosphorylated enzyme. Phosphoglycerate mutase is initially phosphorylated by phosphoryl transfer from 2,3-BPG, which is required in small quantities to initiate the catalytic cycle and is continuously regenerated by that cycle.

    This is the first of the two energy-conserving reactions of glycolysis that eventually lead to the formation of ATP. The aldehyde group of glyceraldehyde 3-phosphate is oxidized, not to a free carboxyl group but to a carboxylic acid anhydride with phosphoric acid. This type of anhydride, called an acyl phosphate, has a very high standard free energy of hydrolysis (ΔG′° = −49.3 kJ/mol).

GLYCOLYSIS
  • 9TH Dehydration of 2-Phosphoglycerate to Phosphoenolpyruvate In the second glycolytic reaction that generates a compound with high phosphoryl group transfer potential (the first was step 6 ), enolase promotes reversible removal of a molecule of water from 2- phosphoglycerate to yield phosphoenolpyruvate (PEP): The mechanism of the enolase reaction involves an enolic intermediate stabilized by Mg 2+. The reaction converts a compound with a relatively low phosphoryl group transfer potential (ΔG′° for hydrolysis of 2- phosphoglycerate is −17.6 kJ/mol) to one with high phosphoryl group transfer potential (ΔG′° for PEP hydrolysis is −61.9 kJ/mol).

     A phosphoryl group initially attached to a His residue of the mutase is transferred to the hydroxyl group at C-2 of 3-phosphoglycerate, forming 2,3-bisphosphoglycerate (2,3-BPG). The phosphoryl group at C-3 of 2,3-BPG is then transferred to the same His residue, producing 2-phosphoglycerate and regenerating the phosphorylated enzyme. Phosphoglycerate mutase is initially phosphorylated by phosphoryl transfer from 2,3-BPG, which is required in small quantities to initiate the catalytic cycle and is continuously regenerated by that cycle.

    This is the first of the two energy-conserving reactions of glycolysis that eventually lead to the formation of ATP. The aldehyde group of glyceraldehyde 3-phosphate is oxidized, not to a free carboxyl group but to a carboxylic acid anhydride with phosphoric acid. This type of anhydride, called an acyl phosphate, has a very high standard free energy of hydrolysis (ΔG′° = −49.3 kJ/mol).

GLYCOLYSIS
  • 10TH Transfer of the Phosphoryl Group from Phosphoenolpyruvate to ADP The last step in glycolysis is the transfer of the phosphoryl group from phosphoenolpyruvate to ADP, catalyzed by pyruvate kinase, which requires K+ and either Mg 2+ or Mn 2+ : In this substrate-level phosphorylation, the product pyruvate first appears in its enol form, then tautomerizes rapidly and nonenzymatically to its keto form, which predominates at pH 7.

     A phosphoryl group initially attached to a His residue of the mutase is transferred to the hydroxyl group at C-2 of 3-phosphoglycerate, forming 2,3-bisphosphoglycerate (2,3-BPG). The phosphoryl group at C-3 of 2,3-BPG is then transferred to the same His residue, producing 2-phosphoglycerate and regenerating the phosphorylated enzyme. Phosphoglycerate mutase is initially phosphorylated by phosphoryl transfer from 2,3-BPG, which is required in small quantities to initiate the catalytic cycle and is continuously regenerated by that cycle.

    This is the first of the two energy-conserving reactions of glycolysis that eventually lead to the formation of ATP. The aldehyde group of glyceraldehyde 3-phosphate is oxidized, not to a free carboxyl group but to a carboxylic acid anhydride with phosphoric acid. This type of anhydride, called an acyl phosphate, has a very high standard free energy of hydrolysis (ΔG′° = −49.3 kJ/mol).

GLYCOLYSIS

REGULATION OF GLYCOLYSIS

  • The flux of glucose through the glycolytic pathway is regulated to maintain nearly constant ATP levels (as well as adequate supplies of glycolytic intermediates that serve biosynthetic roles). The required adjustment in the rate of glycolysis is achieved by a complex interplay among ATP consumption, NADH regeneration, and allosteric regulation of several glycolytic enzymes—including hexokinase, PFK-1, and pyruvate kinase— and by second-to-second fluctuations in the concentration of key metabolites that reflect the cellular balance between ATP production and consumption.

  • On a slightly longer time scale, glycolysis is regulated by the hormones glucagon, epinephrine, and insulin, and by changes in the expression of the genes for several glycolytic enzymes. An especially interesting case is the aerobic glycolysis in tumors. The German biochemist Otto Warburg first observed in 1928 that tumors of nearly all types carry out glycolysis at a much higher rate than normal tissue, even when oxygen is available.

CONCLUSION

  • Glycolysis is a near-universal pathway by which a glucose molecule is oxidized to two molecules of pyruvate, with energy conserved as ATP and NADH.
  • All 10 glycolytic enzymes are in the cytosol, and all 10 intermediates are phosphorylated compounds of three or six carbons.
  • In the preparatory phase of glycolysis, ATP is invested to convert glucose to fructose 1,6-bisphosphate. The bond between C-3 and C-4 is then broken to yield two molecules of triose phosphate.
  • In the payoff phase, each of the two molecules of glyceraldehyde 3- phosphate derived from glucose undergoes oxidation at C-1; the energy of this oxidation reaction is conserved in the form of one NADH and two ATP per triose phosphate oxidized.
  • Glycolysis is tightly regulated in coordination with other energy-yielding pathways to ensure a steady supply of ATP.
  • In type 1 diabetes, defective uptake of glucose by muscle and adipose tissue has profound effects on the metabolism of carbohydrates and fats.
  • Three irreversible steps in glycolysis are bypassed by reactions catalyzed by gluconeogenic enzymes: (1) conversion of pyruvate to PEP via oxaloacetate, catalyzed by pyruvate carboxylase and PEP carboxykinase; (2) dephosphorylation of fructose 1,6-bisphosphate by FBPase-1; and (3) dephosphorylation of glucose 6-phosphate by glucose 6-phosphatase.

REFERENCES

  • Lehninger  principles of biochemistry seventh edition By  David L. Nelson and Michael M. Cox
  • voets and voets biochemistry 4th edition
  • Life sciences  fundamental and practices sixth edition, pathfinder publication By Pranav Kumar and Usha Mina
  • Essential cell biology (fourth edition) by ALBERTS, BRAY, HOPKIN, JOHNSON, LEWIS, RAFF, ROBERTS, WALTER

:- Article Written By Zahra Madraswala

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