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الموضوع: Generation of ATP from Glucose: Glycolysis

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    Generation of ATP from Glucose: Glycolysis

    بسم الله الرحمن الرحيم .
    Glucose
    is the universal fuel for human cells. Every cell type in the human is able
    to generate adenosine triphosphate (ATP) from glycolysis, the pathway in which
    glucose is oxidized and cleaved to form pyruvate. The importance of glycolysis in
    our fuel economy is related to the availability of glucose in the blood, as well as
    the ability of glycolysis to generate ATP in both the presence and absence of O
    2.
    Glucose is the major sugar in our diet and the sugar that circulates in the blood
    to ensure that all cells have a continuous fuel supply. The brain uses glucose
    almost exclusively as a fuel.

    Glycolysis
    begins with the phosphorylation of glucose to glucose 6-phosphate
    (
    glucose-6-P) by hexokinase (HK). In subsequent steps of the pathway, one glucose-
    6-P molecule is oxidized to two
    pyruvate molecules with generation of two
    molecules of
    NADH . A net generation of two molecules of ATP occurs
    through direct transfer of
    high-energy phosphate from intermediates of the pathway
    to ADP (
    substrate level phosphorylation).
    Glycolysis occurs in the
    cytosol and generates cytosolic NADH. Because
    NADH cannot cross the inner mitochondrial membrane, its reducing equivalents
    are transferred to the electron transport chain by either the
    malate-aspartate
    shuttle
    or the glycerol 3-phosphate shuttle . Pyruvate is then oxidized
    completely to CO
    2 by pyruvate dehydrogenase and the TCA cycle. Complete

    aerobic oxidation
    of glucose to CO2 can generate approximately 30 to 32 moles
    of ATP per mole of glucose
    .
    When cells have a limited supply of oxygen (e.g., kidney medulla), or few or
    no mitrochondria (e.g., the red cell), or greatly increased demands for ATP
    (e.g., skeletal muscle during high-intensity exercise), they rely on
    anaerobic
    glycolysis
    for generation of ATP. In anaerobic glycolysis, lactate dehydrogenase

    oxidizes the NADH generated from glycolysis by reducing pyruvate to
    lactate
    . Because O2 is not required to reoxidize the NADH, the
    pathway is referred to as anaerobic. The energy yield from anaerobic glycolysis
    (2 moles of ATP per mole of glucose) is much lower than the yield from aerobic
    oxidation. The lactate (lactic acid) is released into the blood. Under pathologic
    conditions that cause
    hypoxia, tissues may generate enough lactic acid to
    cause
    lactic acidemia.
    In each cell, glycolysis is regulated to ensure that
    ATP homeostasis is
    maintained, without using more glucose than necessary. In most cell types,

    hexokinase (HK)
    , the first enzyme of glycolysis, is inhibited by glucose
    6-phosphate . Thus, glucose is not taken up and phosphorylated
    by a cell unless glucose-6-P enters a ****bolic pathway, such as glycolysis or
    glycogen synthesis. The control of glucose-6-P entry into glycolysis occurs at
    phosphofructokinase-1(
    PFK-1), the rate-limiting enzyme of the pathway.
    PFK-1 is
    allosterically inhibited by ATP and allosterically activated by AMP.
    AMP increases in the cytosol as ATP is hydrolyzed by energy-requiring
    reactions.




    Overview of glycolysis and the TCA cycle.

    Anaerobic glycolysis (shown in
    blue). The conversion of glucose to lactate
    generates 2 ATP from substrate-level phosphorylation.
    Because there is no net generation of
    NADH, there is no need for O
    2, and, thus, the
    pathway is anaerobic.

    Glycolysis has functions in addition to ATP production. For example, in liver
    and adipose tissue, this pathway generates pyruvate as a precursor for
    fatty acid
    biosynthesis
    . Glycolysis also provides precursors for the synthesis of compounds
    such as amino acids and 5-carbon sugar phosphates.

    GLYCOLYSIS
    Glycolysis is one of the principle pathways for generating ATP in cells and is
    present in all cell types. The central role of glycolysis in fuel ****bolism is
    related to its ability to generate ATP with, and without, oxygen. The oxidation of
    glucose to pyruvate generates ATP from substrate-level phosphorylation (the
    transfer of phosphate from high-energy intermediates of the pathway to ADP) and
    NADH. Subsequently, the pyruvate may be oxidized to CO
    2 in the TCA cycle and
    ATP generated from electron transfer to oxygen in oxidative phosphorylation.
    However, if the pyruvate and NADH from glycolysis are converted to lactate
    (anaerobic glycolysis), ATP can be generated in the absence of oxygen, via
    substrate-level phosphorylation.
    Glucose is readily available from our diet, internal glycogen stores, and the
    blood. Carbohydrate provides 50% or more of the calories in most diets, and glucose
    is the major carbohydrate. Other dietary sugars, such as fructose and galactose,
    are oxidized by conversion to intermediates of glycolysis. Glucose is stored in cells
    as glycogen, which can provide an internal source of fuel for glycolysis in emergency
    situations (e.g., decreased supply of fuels and oxygen during ischemia, a low
    blood flow). Insulin and other hormones maintain blood glucose at a constant level
    (glucose homeostasis), thereby ensuring that glucose is always available to cells that
    depend on glycolysis for generation of ATP.
    In addition to serving as an anaerobic and aerobic source of ATP, glycolysis is an
    anabolic pathway that provides biosynthetic precursors. For example, in liver and
    adipose tissue, this pathway generates pyruvate as a precursor for fatty acid biosynthesis.
    Glycolysis also provides precursors for the synthesis of compounds such as
    amino acids and ribose-5-phosphate, the precursor of nucleotides.

    The Reactions of Glycolysis
    The glycolytic pathway, which cleaves 1 mole of glucose to 2 moles of the 3-carbon
    compound pyruvate, consists of a preparative phase and an ATP-generating
    phase. In the initial preparative phase of glycolysis, glucose is phosphorylated
    twice by ATP and cleaved into two triose phosphates . The ATP expenditure
    in the beginning of the preparative phase is sometimes called “priming the
    pump,” because this initial utilization of 2 moles of ATP/ mole of glucose results
    in the production of 4 moles of ATP/mole of glucose in the ATP-generating
    phase.
    In the ATP-generating phase, glyceraldehyde 3-phosphate (a triose phosphate) is
    oxidized by NAD
    and phosphorylated using inorganic phosphate. The highenergy
    phosphate bond generated in this step is transferred to ADP to form ATP. The
    remaining phosphate is also rearranged to form another high-energy phosphate
    bond that is transferred to ADP. Because there were 2 moles of triose phosphate
    formed, the yield from the ATP-generating phase is 4 ATP and 2 NADH. The result
    is a net yield of 2 moles of ATP, 2 moles of NADH, and 2 moles of pyruvate per
    mole of glucose.


    Phases of the glycolytic pathway.
    1. CONVERSION OF GLUCOSE TO GLUCOSE 6-PHOSPHATE

    Glucose ****bolism begins with transfer of a phosphate from ATP to glucose to
    form glucose-6-P . Phosphorylation of glucose commits it to ****bolism
    within the cell because glucose-6-P cannot be transported back across the plasma
    membrane. The phosphorylation reaction is irreversible under physiologic conditions
    because the reaction has a high negative
    G0. Phosphorylation does not,
    however, commit glucose to glycolysis.
    Glucose-6-P is a branchpoint in carbohydrate ****bolism. It is a precursor for
    almost every pathway that uses glucose, including glycolysis, the pentose phosphate
    pathway, and glycogen synthesis. From the opposite point of view, it also can be
    generated from other pathways of carbohydrate ****bolism, such as glycogenolysis
    (breakdown of glycogen), the pentose phosphate pathway, and gluconeogenesis
    (the synthesis of glucose from non-carbohydrate sources).
    Hexokinases, the enzymes that catalyze the phosphorylation of glucose, are a
    family of tissue-specific isoenzymes that differ in their kinetic properties. The
    isoenzyme found in liver and
    cells of the pancreas has a much higher Km than
    other hexokinases and is called glucokinase. In many cells, some of the hexokinase
    is bound to porins in the outer mitochondrial membrane (voltage-dependent anion
    channels), which gives these enzymes first access to newly synthesized
    ATP as it exits the mitochondria.


    Phases of the glycolytic pathway.


    2. CONVERSION OF GLUCOSE-6-P TO THE TRIOSE PHOSPHATES

    In the remainder of the preparative phase of glycolysis, glucose-6-P is isomerized
    to fructose 6-phosphate (fructose-6-P), again phosphorylated, and subsequently
    cleaved into two 3-carbon fragments . The isomerization, which positions
    a keto group next to carbon 3, is essential for the subsequent cleavage of the bond
    between carbons 3 and 4.
    The next step of glycolysis, phosphorylation of fructose-6-P to fructose 1,6-
    bisphosphate (fructose-1,6-bisP) by phosphofructokinase-1 (PFK-1), is generally
    considered the first committed step of the pathway. This phosphorylation requires
    ATP and is thermodynamically and kinetically irreversible. Therefore, PFK-1 irrevocably
    commits glucose to the glycolytic pathway. PFK-1 is a regulated enzyme in
    cells, and its regulation controls the entry of glucose into glycolysis. Like hexokinase,
    it exists as tissue-specific isoenzymes whose regulatory properties match variations
    in the role of glycolysis in different tissues.
    Fructose-1,6-bisP is cleaved into two phosphorylated 3-carbon compounds
    (triose phosphates) by aldolase . Dihydroxyacetone phosphate
    (DHAP) is isomerized to glyceraldehyde 3-phosphate (glyceraldehyde-3-P), which
    is a triose phosphate. Thus, for every mole of glucose entering glycolysis, 2 moles
    of glyceraldehyde-3-P continue through the pathway.
    Glucose 6-phosphate ****bolism.
    3. OXIDATION AND SUBSTRATE LEVEL PHOSPHORYLATION
    In the next part of the glycolytic pathway, glyceraldehyde-3-P is oxidized and phosphorylated
    so that subsequent intermediates of glycolysis can donate phosphate to
    ADP to generate ATP. The first reaction in this sequence, catalyzed by glyceraldehyde-
    3-P dehydrogenase, is really the key to the pathway . This
    enzyme oxidizes the aldehyde group of glyceraldehyde-3-P to an enzyme-bound
    carboxyl group and transfers the electrons to NAD
    to form NADH. The oxidation
    step is dependent on a cysteine residue at the active site of the enzyme, which forms
    a high-energy thioester bond during the course of the reaction. The high-energy
    intermediate immediately accepts an inorganic phosphate to form the high-energy
    acyl phosphate bond in 1,3-bisphosphoglycerate, releasing the product from the
    cysteine residue on the enzyme. This high-energy phosphate bond is the start of substrate-
    level phosphorylation (the formation of a high-energy phosphate bond where
    none previously existed, without the utilization of oxygen).
    In the next reaction, the phosphate in this bond is transferred to ADP to form ATP
    by 3-phosphoglycerate kinase. The energy of the acyl phosphate bond is high
    enough (13 kcal/mole) so that transfer to ADP is an energetically favorable
    process. 3-phosphoglycerate is also a product of this reaction.
    To transfer the remaining low-energy phosphoester on 3-phosphoglycerate to
    ADP, it must be converted into a high-energy bond. This conversion is accomplished
    by moving the phosphate to the second carbon (forming 2-phosphoglycerate)
    and then removing water to form phosphoenolpyruvate (PEP). The enolphosphate
    bond is a high-energy bond (its hydrolysis releases approximately 14
    kcal/mole of energy), so the transfer of phosphate to ADP by pyruvate kinase is
    energetically favorable . This final reaction converts PEP to pyruvate.


    4. SUMMARY OF THE GLYCOLYTIC PATHWAY

    The overall net reaction in the glycolytic pathway is:
    Glucose+2NAD
    + 2Pi +2ADP --->2Pyruvate+2NADH+4H2ATP+2H2O
    The pathway occurs with an overall negative
    G0 of approximately 22 kcal.
    Therefore, it cannot be reversed without the expenditure of energy.

    و السلام عليكم :sm182:

    المصدر : كتاب Basic Medical Biochemistry - A Clinical Approach

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    الخفاجي (12-04-2010)

  3. #2
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    :sm199::sm199: ARABS LAB:sm199: :sm199:


    ماشاء الله موضووووع كامل بدور على شي ناقص ممكن اضيفه ماحصلت

    عجبني بالموضوووع انك معرف العملية من الى

    وايضا عن كيفية تنظيم الجلايكوليسس

    ماشاء الله شامل جدا

    وعشرة من عشرة ياجميل :sm188:


    لاتنسوني من دعـواتكم الطيبة





  4. #3
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    شرح وافي وكافي

    ماشالله

    يعطيك العافية

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    الله يعطيك العافية على الموضوع

    قرأت جزئيات منه وأكيد موضوع مميز

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    السمرة

    الله يحييك أحرجتيني

    الكمال لوجه الله عز وجل ... شكراً للمجاملة

    وايت فالكون ...

    يعافيك ربي

    راعي مايكروبات ..

    ربي يسلمك و إن شاء الله قريته كامل و أعجبك

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    iam so glad this is an important
    and basic information

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    ما شا الله الموضوع رائع وجدا مفيد ..
    يعطيك العافية ..

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    الله يعطيك العافيه ...
    الموضوع كامل ومفيد...

  10. #9
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    Smile شكرا

    شكرا على المعلومات
    ويعطيك ألف عافية
    (ذكرتنا بأيام الجامعة)

    :sm178::sm178:

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