7 Glycolysis and Gluconeogenesis - Minificciones Glycolysis and Gluconeogenesis. Because glucose is such a precious fuel, the end products of biochemical pathways are salvaged to synthesize

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Text of 7 Glycolysis and Gluconeogenesis - Minificciones Glycolysis and Gluconeogenesis. Because glucose is...

  • Learning Objectives How is ATP generated in glycolysis?

    Why is the regeneration of NAD crucial to fermentations?

    How is gluconeogenesis powered in the cell?

    How are glycolysis and gluconeogenesis coordinated?

    We begin our study of metabolism by focusing on the processing of glucose,a fundamental fuel molecule for virtually all life forms. The first metabolicpathway that we encounter is glycolysis, an ancient pathway employed by a hostof organisms. Glycolysis is the sequence of reactions that converts one moleculeof glucose into two molecules of pyruvate while generating ATP. Glycolysis servestwo major functions in the cell. First, this set of reactions generates ATP. Indeed,some tissues, such as the brain and red blood cells, rely solely on glucose as a fuel;consequently, glycolysis is especially important in these tissues. The second majorfunction of glycolysis is to provide building blocks for biosynthesis. For instance,the molecules formed in the metabolism of glucose in glycolysis are used as pre-cursors for amino acid and fatty acid synthesis.

    SECTION

    7Glycolysis and Gluconeogenesis

  • Because glucose is such a precious fuel, the end products of biochemicalpathways are salvaged to synthesize glucose in the process of gluconeogenesis.Gluconeogenesis is vital for ensuring that the brain and red blood cells haveadequate supplies of glucose even during a fast, such as during a nights sleep.Although glycolysis and gluconeogenesis have some enzymes in common, thetwo pathways are not simply the reverse of each other. In particular, the highlyexergonic, irreversible steps of glycolysis are bypassed in gluconeogenesis. Thetwo pathways are reciprocally regulated so that glycolysis and gluconeogene-sis do not take place simultaneously in the same cell at the same time to asignificant extent, thereby preventing the waste in energy that would resultif glucose were being broken down at the same instant as it is being synthesized.

    We start this section with glycolysis, paying special attention to the regulationof this pathway. We proceed to gluconeogenesis, again with a focus on regu-lation. We end this section by noting how glycolysis and gluconeogenesis areregulated within a cell as well as between tissues.

    Chapter 15: Glycolysis

    Chapter 16: Gluconeogenesis

  • 226

    CHAPTER

    15 Glycolysis

    15.1 Glycolysis Is an Energy-Conversion Pathway

    15.2 NAD Is Regenerated from theMetabolism of Pyruvate

    15.3 Fructose and Galactose AreConverted into GlycolyticIntermediates

    15.4 The Glycolytic Pathway Is TightlyControlled

    15.5 Metabolism in Context:Glycolysis Helps Pancreatic Cells Sense Glucose

    Earlier, we looked at how carbohydrates are digested to biochemically usefulmolecules, such as glucose (Chapter 13). Glucose is the principal carbohydratein living systems and an important fuel. In mammals, glucose is the only fuel thatthe brain uses under nonstarvation conditions and the only fuel that red bloodcells can use at all. Indeed, almost all organisms use glucose, and most process itin a similar fashion. Recall from Chapter 9 that there are many carbohydrates.Why is glucose such a prominent fuel, rather than some other monosaccharide?We can speculate on the reasons. First, glucose is one of several monosaccharidesformed from formaldehyde under prebiotic conditions, and so it may have beenavailable as a fuel source for primitive biochemical systems. Second, glucose has alow tendency, relative to other monosaccharides, to nonenzymatically glycosylateproteins. In their open-chain forms, monosaccharides contain carbonyl groupsthat can covalently modify the amino groups of proteins. Such nonspecificallymodified proteins often do not function effectively. Glucose has a strong tendencyto exist in the ring formation and, consequently, relatively little tendency tomodify proteins.

    In this chapter, we first examine how ATP is generated in glycolysis and howATP can be generated in the absence of oxygen. We then see how sugars other thanglucose are converted into glycolytic intermediates. The chapter ends with adiscussion of the regulation of glycolysis.

    Usain Bolt sprints through a world record in the 200-meter finals at the Olimpics in Beijingin 2008. Glucose metabolism can generate the ATP to power muscle contraction. During asprint, when the ATP needs outpace oxygen delivery, as would be the case for Bolt, glucoseis metabolized to lactate. When oxygen delivery is adequate, glucose is metabolized moreefficiently to carbon dioxide and water. [Reix-Liews/For Photo/Corbis.]

    Glucose

    O

    OH

    CH2OH

    OH

    OH

    HO

  • 15.1 Glycolysis Is an Energy-Conversion PathwayWe now begin our consideration of the glycolytic pathway. This pathway iscommon to virtually all cells, both prokaryotic and eukaryotic. In eukaryotic cells,glycolysis takes place in the cytoplasm. Glucose is converted into two molecules ofpyruvate with the concomitant generation of two molecules of ATP.

    Glycolysis can be thought of as comprising three stages (Figure 15.1). Stage 1,which is the conversion of glucose into fructose 1,6-bisphosphate, consists of threesteps: a phosphorylation, an isomerization, and a second phosphorylation reac-tion. The strategy of these initial steps in glycolysis is to trap the glucose in the cell andform a compound that can be readily cleaved into phosphorylated three-carbon units.Stage 2 is the cleavage of the fructose 1,6-bisphosphate into two three-carbonfragments. These resulting three-carbon units are readily interconvertible. Instage 3,ATP is harvested when the three-carbon fragments are oxidized to pyruvate.

    Hexokinase Traps Glucose in the Cell and Begins GlycolysisGlucose enters cells through specific transport proteins (p. 244) and has oneprincipal fate inside the cell: it is phosphorylated by ATP to form glucose6-phosphate. This step is notable for two reasons: (1) glucose 6-phosphate can-not pass through the membrane to the extracellular side, because it is not asubstrate for the glucose transporters, and (2) the addition of the phosphorylgroup acts to destabilize glucose, thus facilitating its further metabolism. Thetransfer of the phosphoryl group from ATP to the hydroxyl group on carbon 6of glucose is catalyzed by hexokinase.

    22715.1 Glycolytic Pathway

    + ATP + ADP H++Hexokinase

    Glucose Glucose 6-phosphate(G-6P)

    O

    OH

    CH2OH

    OH

    OH

    HO

    O

    OH

    CH2OPO32

    OH

    OHHO

    Phosphoryl transfer is a fundamental reaction in biochemistry. Kinases areenzymes that catalyze the transfer of a phosphoryl group from ATP to an acceptor.Hexokinase, then, catalyzes the transfer of a phosphoryl group from ATP to a vari-ety of six-carbon sugars (hexoses), such as glucose and mannose. Hexokinase, as wellas all other kinases, requires Mg2 (or another divalent metal ion such as Mn2) foractivity. The divalent metal ion forms a complex with ATP.

    X-ray crystallographic studies of yeast hexokinase revealed that the bindingof glucose induces a large conformational change in the enzyme. Hexokinaseconsists of two lobes, which move toward each other when glucose is bound(Figure 15.2). The cleft between the lobes closes, and the bound glucosebecomes surrounded by protein, except for the carbon atom that will accept thephosphoryl group from ATP. The closing of the cleft in hexokinase is a strikingexample of the role of induced fit in enzyme action (p. 70).

    Why are the structural changes in hexokinase of biochemical consequence?The environment around glucose becomes more nonpolar as water is extrudedand the hydrophobic R groups of the protein surround the glucose molecule,which favors the donation of the terminal phosphoryl group of ATP. The removalof water from the active site enhances the specificity of the enzyme. If hexokinasewere rigid, a molecule of H2O occupying, by chance, the binding site for the

    CH2OH of glucose could attack the phosphoryl group of ATP, forming ADPand Pi. In other words, a rigid kinase would likely also be an ATPase. Substrate-induced cleft closing is a general feature of kinases.

  • 22815 Glycolysis

    Glucose

    Glucose 6-phosphate

    Fructose 6-phosphate

    Fructose 1,6-bisphosphate

    Dihydroxyacetonephosphate

    Glyceraldehyde3-phosphate

    1,3-Bisphosphoglycerate

    3-Phosphoglycerate

    2-Phosphoglycerate

    Phosphoenolpyruvate

    Pyruvate

    2 X

    Aldolase

    Stage 1

    Stage 2

    Stage 3

    O

    OH

    CH2OH

    OH

    OH

    HO

    O

    OH

    CH2OPO32

    OH

    OHHO

    OCH2OH

    HO

    HO

    2O3POH C2

    OH

    32

    OCH2OPO

    HO

    OH

    2O3POH C2

    OH

    C

    C

    CH2OPO32

    OHH

    OO

    C

    C OPO32H

    OO

    CH2OH

    OPO32

    H H

    O

    O

    CH3

    OO

    O

    CO

    CH2OPO32

    CH2OH

    C

    C

    CH2OPO32

    OHH

    O PO32 O

    C

    C

    CH2OPO32

    OHH

    OH

    ATP

    ADPHexokinase

    Phosphofructokinase

    ATP

    ADP

    Pyruvate kinase

    ADP

    ATP

    Phosphoglucoseisomerase

    Triose phosphateisomerase

    Pi, NAD+

    NADH

    Glyceraldehyde3-phosphate

    dehydrogenase

    Phosphoglyceratekinase

    ADP

    ATP

    Phosphoglyceratemutase

    H2OEnolase

    C

    CC

    C

    C

    Figure 15.1 Stages of glycolysis. The glycolytic pathway can be divided into three stages:(1) glucose is trapped and destabilized; (2) two interconvertible three-carbon molecules aregenerated by the cleavage of six-carbon fructose; and (3) ATP is generated.

  • Fructose 1,6-bisphosphate Is Generated from Glucose 6-phosphateThe next step in glycolysis is the isomerization of glucose 6

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