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Biochemistry Week8, Overview, Importance, Gluconeogenic Steps In…

- - - - No ATP is used in the nonoxidative phase
      - Complete conversion of ribose-5-phosphate to glucose-6- phosphate requires 6 R5P to make 5 G6P(65 or 56)
  - - - H2O2藉由GSH還原成H2O，
        GSSG再藉由NADPH還原成GSH，
        而NADPH的供應由G-6-P(PPP)而來。
        
        However, if G-6-P is deficient…
        
        沒有足夠的G-6-P生成足夠的NADPH，
        即無法還原足夠的GSSG成GSH，
        導致體內氧化物無法被清除
- - - - different enzymes in the different pathways
      - differentially regulated to prevent a futile cycle
      - no ATP generated during gluconeogenesis
    - - Step 2
        
        Oxaloacetate
        
        Phosphoenolpyruvate carboxykinase /GTP
        
        PEP+GDP+CO2
        
        將上個步驟的CO2脫去，再接上磷酸根。
        This step occurs in mitochondria or cytosol depending on the organism.
        And during this conversion, the same carbon is added
        and immediately removed from the structure.
      - The third to last step
        (糖解的第3步驟逆反應)
        
        F-1,6-B
        
        fructose bisphosphatase-1 /H2O
        
        F-6-P
        
        coordinately/oppositely regulated with PFK.
        Cleaves phosphate with water.
        DOES NOT generate ATP.
      - Step1
        
        Pyruvate (3C)
        
        Pyruvate carboxylase /biotin
        /ATP(故此步驟需在mitochondria內反應)
        
        Oxaloacetate (4C)+ADP+pi
        
        Biotin Is 羧酸轉移酶的cofactor,會攜帶bicarbonate上的羧基至Pryuvate
      - The first to last step
        (糖解的第1步驟逆反應)
        
        G-6-P
        
        glucose 6-phosphatase /H2O
        
        Glucose
        
        segregated in the endoplasmic reticulum內質網
        Cleaves phosphate with water.
        DOES NOT generate ATP.
  - - - during starvation,vigorous exercise
      - can generate glucose from amino acids, but not fatty acids
  - - - sugars
        
        pyruvate, lactate, or oxaloacetate
      - proteins
        
        amino acids that can be converted to citric
        acid cycle intermediates (or glucogenic amino acids)
    - - Fatty acids
        
        product of fatty acid degradation is acetyl-CoA
        
        cannot have a net converstion of acetyl-CoA to Oxaloacetate
      - However,Plants, yeast, and many bacteria can do this,
        thus producing glucose from fatty acids.
- - - - Phosphohexose Isomerization
        醛醣變成酮醣
        
        Rationale
        
        makes next steps easier
        (less energy required):
        
        C1 of fructose is easier to phosphorylate by PFK
        上個步驟的C1因在結構內故不易反應。
        
        allows for symmetrical 對稱性cleavage by aldolase
        
        Key points
        
        The isomerization is catalyzed by the active-site glutamate via general acid/base catalysis.
        
        Slightly thermodynamically 不易發生的unfavorable/reversible
        
        An aldose (glucose) can isomerize into a ketose (fructose) via an enediol intermediate.
      - 2nd Priming Phosphorylation
        
        Rationale
        
        further activation of glucose
        
        allows for 1 phosphate/
        3-carbon sugar after step 4
        
        Key points
        
        This process uses the energy of ATP
        
        Highly thermodynamically favorable/irreversible
        
        Second committed step of glycolysis-
        fructose 1,6-bisphosphate is committed
        to become pyruvate and yield energy
        
        Phosphofructokinase-1 (PFK-1) is highly regulated.
        
        ATP-bound Mg++ facilitates this process by shielding the negative charges on
        ATP中和ATP的負電，加速反應
      - Phosphorylation of Glucose
        
        Rationale
        
        traps glucose inside the cell 磷酸化後出不了細胞
        
        lowers intracellular (unphosphorylated) glucose concentration to allow further uptake
        
        Key points
        
        uses the energy of ATP.
        
        Multiple isoforms of hexokinase exist in organisms (e.g.,hexokinase I, II, III, and IV (glucokinase))
        
        Nucleophilic oxygen at C6 of glucose
        attacks the last (gamma)phosphate of ATP
        
        ATP-bound Mg++ facilitates this process by shielding the negative charges on
        ATP中和ATP的負電，加速反應
        
        Highly thermodynamically favorable/irreversible
      - Aldol Cleavage of F-1,6-bP
        
        Rationale
        
        6C sugar is cleaved into two 3C sugars.
        
        High-energy phosphate sugars are 3C sugars
        
        Key points
        
        The reverse process is the familiar aldol condensation (和糖質新生有關)
        
        Multiple mechanisms to result in same product (i.e., convergent evolution)
        
        Thermodynamically unfavorable/reversible
        
        product (GAP) concentration kept low to pull reaction forward 厄沙特勒原理
    - - 1st Production of ATP
        
        Rationale
        
        substrate-level phosphorylation to make ATP
        
        Key points
        
        Kinases (與ATP合成或分解有關的酵素)are enzymes that transfer phosphate groups between ATP and various substrates.
        
        Highly thermodynamically favorable/reversible
        
        1,3-bisphosphoglycerate is a high-energy compound, can donate the phosphate group to ADP to make ATP
      - Migration of the Phosphate
        
        Rationale
        
        be able to form high-energy phosphate compound
        
        Key points
        
        One of the active-site histidines is posttranslationally modified to phosphohistidine.
        
        Mutases catalyze the (apparent) migration of functional groups.
        
        Thermodynamically unfavorable/reversible
        
        Phosphohistidine donates its phosphate to 3-phosphoglycerate at the 2-carbon oxygen before retrieving another phosphate from the 3-carbon oxygen.
      - Oxidation of GAP
        
        Rationale
        
        generation of a high-energy phosphate compound
        
        incorporates inorganic phosphate
        
        which allows for net production of ATP via glycolysis
        
        Key points
        
        Oxidation of aldehyde with NAD+ gives NADH.
        
        Thermodynamically unfavorable/reversible
        
        First energy-yielding step in glycolysis(NADH)
      - Dehydration of 2-PG to PEP
        
        Rationale
        
        generate a high-energy phosphate compound
        
        2-Phosphoglycerate is not a good enough phosphate
        donor to generate ATP.
        
        two negative charges in 2-PG are fairly close
        
        but loss of phosphate from 2-PG would give a secondary alcohol with no further stabilization
        
        Key points
        
        Slightly thermodynamically unfavorable/reversible
      - Triose Phosphate Interconversion 醛變酮
        
        Rationale
        
        allows glycolysis to proceed to payoff
        phase by a single chemical pathway
        
        Key points
        
        Aldolase creates two triose phosphates DHAP and GAP
        
        Only GAP is the substrate for the next enzyme.
        
        Completes preparatory phase of glycolysis
        
        Thermodynamically unfavorable/reversible
        
        DHAP must be converted to GAP
        by triose Phosphate isomerase
      - 2nd Production of ATP
        
        Rationale
        
        substrate-level phosphorylation to make ATP
        
        net production of 2 ATP/glucose
        
        Keypoints
        
        Loss of phosphate from PEP yields an enol that tautomerizes into ketone.
        
        Pyruvate kinase requires divalent metals (Mg++ or Mn++) for activity.
        
        Tautomerization
        
        effectively lowers the concentration of the reaction product
        
        drives the reaction toward ATP formation
        
        Highly thermodynamically favorable/irreversible
        
        Fates of Pyruvate
        
        Aerobic condition
        
        Citric acid cycle
        
        Produce CO2+H2O
        
        Hypoxic or anaerobic condition
        
        Characteristics
        
        Reduction of pyruvate to another product
        
        Regenerates NAD+ for further glycolysis under anaerobic conditions
        
        No net change in oxidation state of the sugars
        
        The process is used in the production of food from beer to yogurt to soy sauce.
        
        Generation of energy (ATP) without consuming oxygen or NAD+
        
        Classification
        
        Animals Undergo Lactic Acid Fermentation
        (Reduction of pyruvate to lactate, reversible)
        
        5 more items...
        
        Yeast Undergo Ethanol Fermentation
        (Two-step reduction of pyruvate to ethanol)
        
        5 more items...
- - - - Hexokinase
        
        G-6-P
        
        Pyrophoshorylase
        
        G-1-P
        
        NDP-sugar pyrophosphorylase
        
        NDP-sugar
        
        3 more items...
    - - Insulin-signaling pathway
        
        stimulates the activity of muscle hexokinase
        
        activates glycogen synthase
        
        increases glucose import into muscle
      - Increased hexokinase activity enables activation of glucose.
      - Glycogen synthase makes glycogen for energy storage.
  - - - Glycogen phosphorylase/
        Debranching enzyme (release glucose unit instead of G-1-P)
        
        Nonreducing end of glucose+phosphate
        =G-1-P
        
        Phosphoglucomutase
        
        G-6-P
        
        Glucose-6-phosphates( **in liver)
        
        Glucose (through glucose transporter & GLUT2 to capillary)
        
        1 more item...
    - - Glucogon/epinephrine signaling pathway
      - Glycogen phosphorylase cleaves glucose residues of glycogen, generating glucose-1-phosphate.
- - - - can be efficiently stored in the polymeric form
      - Many organisms and tissues can meet their energy
        needs on glucose only.
      - yields good amount of energy upon oxidation • −2840 kJ/mol glucose
        (有些器官能量是靠糖質新生而來)
    - - Glucose is a versatile biochemical precursor, Many organisms can use glucose to generate :
        
        membrane lipids
        
        nucleotides in DNA and RNA
        
        all the amino acids
        
        cofactors needed for the metabolism
  - - - generates energy via oxidation of glucose
      - short-term energy needs
    - - generates NADPH (PPP) for use in relieving oxidative stress and synthesizing fatty acids
      - generates pentose phosphates for
        use in DNA/RNA biosynthesis
    - - used for generation of alternate carbohydrates used in cell walls
        
        of bacteria, fungi, and plants
    - - can be stored in the polymeric form (starch, glycogen)
      - used for later energy needs