Lecture 21: Anabolic Reactions

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61 Terms

1

Gluconeogenesis

  • Synthesis of glucose from non-carbohydrate precursors e.g. lactate and alanine via pyruvate conversion

    • Reaction doesn’t occur in all cells → liver and kidney

  • Maintains glucose levels in the blood → provides energy to brain and muscle

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How do glycolysis and gluconeogenesis handle reversible and irreversible steps?

  • Most reactions are reversible.

    • use the same enzymes for these steps.

  • 3 Irreversible Steps:

    • Gluconeogenesis uses different enzymes to bypass these steps e.g. Phosphatase in the last step counteracts the kinase used in the first step of glycolysis.

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How does gluconeogenesis convert pyruvate back into phosphoenolpyruvate (PEP)?

  • Two-Step Process: Requires two enzymes for a more complex conversion than the reverse reaction in glycolysis.

  • Enzymes:

    1. Pyruvate Carboxylase: Converts pyruvate to oxaloacetate.

    2. PEP Carboxykinase: Converts oxaloacetate to PEP.

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Non-Carbohydrate Pre-Cursors Used In Gluconeogenesis

  • Lactate ⇄ pyruvate

  • Some amino acids (e.g. alanine) ⇄ pyruvate

    • Removal of NH3 group

  • Some amino acids (e.g. aspartate) ⇄ oxaloacetate

  • Glycerol (fats) ⇄ dihydroxyacetone phosphate

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Overall Equation for Gluconeogenesis

2 Pyruvate + 2 NADH + 4 ATP + 2 GTP + 6 H2O + 2 H+ → Glucose + 2 NAD+ + 4 ADP + 2 GDP + 6 Pi

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Net energy investment/gain of gluconeogenesis

  • Formation of glucose from pyruvate

  • Net Cost: 6 ATP/GTP per glucose molecule.

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Pyruvate Decarboxylase (PC)

  • An important enzyme that catalyses the metabolically irreversible reaction, that occurs in the mitochondrial matrix

    • addition of CO2 to pyruvate to form oxaloacetate

      Pyruvate + CO2 + ATP → oxaloacetate + ADP + P

  • Requires prosthetic group biotin

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Regulation of PC

  • Allosterically activated by acetyl CoA

  • An accumulate of acetyl-CoA signals an abundance of energy and so directs pyruvate to oxaloacetate for gluconeogenesis

    • Liver cells receive a signal

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Structure of Pyruvate Decarboxylase

  • Tetramer of 4 subunits

  • 2 x biotin carboxylase domains

  • Site where pyruvate is carboxylate using CO2 to then form oxaloacetate

  • Binding of a molecule to its domains induces a conformational change, activating the enzyme

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Biotin

  • Co-factor

  • Described as a prosthetic group when covalently attached to PC via Lys side chain

  • Carrier of Activated CO2 - captures CO2 from the atmosphere to form oxaloacetate

    • Carboxylbiotin

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How Is Glucose Stored in Plants and Animals

  • Starch

  • Glycogen - accumulates in the liver

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Glycogen

  • Polymers of glucose α(1,4), with α(1,6) branching linkage

  • Stored as cytosolic granules in the liver and muscles

  • Provides a low, but quick source of glucose for a sudden demand of energy

    • Can provide energy in the absence of oxygen - anaerboic activity

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1-4 Linkage

  • Ensure a linear structre/ polymer

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1-6 Linkage

  • Introduces branching into the glucose polymer

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Glycogenolysis

  • Degradation of glycogen to glucose-1,6-phosphate

    • Polymer is depolymerised to release glucose in the blood

  • Polymer then converted to Glucose-6-Phosphate by phosphoglucomutase

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Uses of Glucose-6-Phosphate

  • Glycolysis → ATP energy

  • Phosphate removed and then released into the liver/ blood stream

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How Does The Liver Raise Blood Glucose Levles

  • Glycogen → G1P → G6P → Glucose (glucose 6-phosphatase)

    • glycogen slowly degraded to maintain levels between sleeping and meals

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Structure of Glycogen

  • Branched polysaccharide chains

    • increase the amount of available ends – allow rapid hydrolysis from these ends to allow the faster release of glucose units for energy

  • Has 1-4 and 1-6 glycosidic linkages

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Glycogenin

  • A protein at the centre of glycogen

    • Acts as a primer for glycogen synthesis

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Glycogen Phosphorylase

  • Enzyme that catalyses the sequential removal of glucose residues at the then of of glycogen branches chains

  • Glycogen (n residues) + Pi ⇄ glucose-1-phosphate + Glucogen (n – 1 residues) from glycogen chain

    • removes 1 molecule of glucose from the end of the chain

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Phosphoglucosemutase

  • Enzyme that easily converts G1P to G6P

    • Mutase enzyme that changes the position of phosphate

  • Phosphorylated serine present in the enzyme to which glucose binds and the phosphate group is then transferred

  • This glucose is then phosphorylated to form a bisphosphate and can then change to form G-6-P

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Significance of glycogen phosphorylase stopping at 4 residues from a branch point

  • Enzyme stops at 4 residues from a branch point, leading to the truncation of glycogen chains, resulting in what is known as limit dextrin.

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What 2 Enzymes Remodel The Resulting ‘Limit Dextrin’ In Glycogen Degredation

  • Transferase

  • a-1,6-glucosidase

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Transferase

  • Used in limit dextrin remodelling

  • Shifts 3 glucose from one outer branch to anohter

    • Further linearises the glycogen chain

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α-1,6-Glucosidase

  • Used in limit dextrin remodelling

  • Glycogen debranching enzyme that removes the branched glucose and leaves an elongated unbranched chain

    • Can be further degraded by glycogen phosphorylase

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Steps Involved In Glycogen Sythesis

  • Glucose Conversion

    • requires energy

  • Isomerisation

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Glucose Conversion

  • Glucose + ATP → Glucose-6-phosphate (G6P) + ADP

  • Enzyme: Glucokinase (in the liver) or Hexokinase (in other tissues)

    • 1st step in glycogen synthesis

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Isomerisation

  • G6P → Glucose-1-phosphate (G1P)

  • Enzyme: Phosphoglucomutase (reversible)

    • Step in glycogen synthesis

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How is Glucose-1-phosphate activated and added to the glycogen chain?

  • Activation:

    • Glucose-1-phosphate + UTP → UDP-glucose + PPi

    • UDP-glucose is the activated form of glucose

  • Incorporation: using glycogen synthase which adds UDP-glucose to the growing glycogen chain, releasing UDP.

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UDP-Glucose Formation

  • The activated form of glucose for glycogen synthesis

  • Catalysed by UDP-glucose pyro phosphorylase

  • Liberates the outer two phosphate groups from UTP as PPi (pyrophosphate)

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UDP Glucose

  • An actived sugar formed by combining glucose-1-phosphate with UTP.

    • makes glucose suitable for addition to the growing glycogen chain

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UTP

  • Energetically similar to ATP (UTP + ADP ⇌ UDP + ATP)

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How much energy (ATP equivalents) are required to incorporate one glucose molecule into glycogen?

  • 2 ATP Equivalents:

    • 1 ATP: Glucokinase/Hexokinase reaction (glucose phosphorylation).

    • 1 UTP (equivalent to ATP): Formation of UDP-glucose.

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Addition of Glucose To Glycogen Chain

  • Free energy required to continue this continuation required UDP free energy

  • 1-4 glycosidic bonds form to form the linearised version of glycogen

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Glycogen Synthesis: Nulceation

  • The need for a starting point or "core" to initiate a process.

  • Glycogenin acts as a primer, attaching the first few (10-20) glucose molecules to itself.

    • This creates a core that glycogen synthase can then extend using 1-4 glucosidic bonds 

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Linear Growth

  • Allows the continuation of Glycogen Synthesis

    • Chain formed from 1-4 glycosidic bond

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Glycogen Synthesis: Branch Formation

  • A 1,4 glycosidic bond is broken and a block of ~7 glucose is transferred to a more interior site forming a 1,6 linkage

    • glycogen synthase can then enhance this branching

  • α1,6-glycosidic linkage assists reaction

  • Increases glycogen solubility, and rates of glycogen synthesis and degradation

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Glucokinase

  • a liver enzyme that catalyses the phosphorylation of glucose to glucose-6- phosphate

    • Diverts glucose when present at high levels to the synthesis of glycogen in the liver

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Inhibition of Hexokinase

  • Occurs in response to high levels of G6P

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Key characteristics of glucokinase.

  • Location: Primarily found in the liver.

  • Affinity: Lower affinity for glucose (higher Km) compared to hexokinase.

  • Function:

    • Active mainly when blood glucose levels are high.

    • Promotes glycogen synthesis (glucose storage).

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Key characteristics of hexokinase

  • Location: Found in most tissues, including brain and muscle.

  • Affinity: High affinity for glucose (lower Km).

  • Function:

    • Captures glucose for immediate energy needs.

    • Inhibited by its product, glucose-6-phosphate (G6P), providing feedback regulation.

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Glucose Transport

  • Glucose enters mammalian cells down a concentration gradient (thermodynamically downhill)

  • Passive transport, but can’t cross the membrane as glucose is polar – requires transporters

    • no ATP required – moves down a concentration gradient

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GLUT

  • a family of passive hexose transporters (up to 12 coding genes present in humans) that facilitate glucose transport – no ATP used

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GLUT1 and GLU3

  • Present in nearly all mammalian cells, constantly transport glucose into cell under normal conditions, at essentially constant rate

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GLUT2

  • Present in liver and pancreatic β cells, transports glucose when concentration in blood is high → pancreas detects level → insulin production

    • Pancreatic B-cells have mechanisms to detect levels of glucose in the blood

    • When high – insulin production is triggered

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GLUT4

  • Insulin dependent transporter present in muscle and fat cells,

    • the numbers increase rapidly in the presence of insulin

  • Excess glucose present after meals is stored as glycogen using insulin – accelerates the interconversion

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Structure of GLUT1

  • Single polypeptide chain, ~500 amino acids

  • 12 membrane-spanning α-helices.

  • Six of these form a polar channel in the membrane through which glucose travels.

  • Both N- and C-termini are on the cytoplasmic side of membrane.

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How does insulin trigger increased glucose uptake into cells?

  • Insulin (hormone) is secreted by the pancreas when blood glucose levels are high.

  • Insulin binds to the insulin receptor (a tyrosine kinase) on target cells.

  • This activates a signalling pathway inside the cell, increasing the number of GLUT4 receptors in the membrane

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How Does Insluin Promote GLUT4 Translocation

  • Insulin binds to its receptor, activating a signalling cascade within the cell.

  • The signal triggers vesicles containing GLUT4 to move towards the cell membrane and fuse with it.

  • This increases the number of GLUT4 transporters on the cell surface.

  • More GLUT4 enables greater glucose uptake from the blood.

  • Inside the cell, glucose is phosphorylated and can be used for energy or stored as glycogen in liver and muscles

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Insulin

  • Peptide hormone - Produced by β-cells of the pancreas

  • Two polypeptide chains (a and B) linked by disulphide bonds.

    • The α chain has an intramolecular disulphide bond

  • Synthesized as a single-chain precursor, proinsulin, processed by proteases

  • Increases the rate of glucose transport into muscle, adipose tissue

    • Stimulates glycogen synthesis in the liver

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Regulation of glycolysis and gluconeogenesis.

  • Coordinated: When one pathway is active, the other is generally less active.

  • Control by Substrate Availability:

    • Glycolysis: Driven by (high) glucose levels.

    • Gluconeogenesis: Driven by the availability of precursors like lactate (and low glucose levels).

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Fructose 2,6- Bisphosphate (F2,6BP)

  • Synthesis by the phosphorylation of F-6-P by liver PFK2

  • Degraded by Fructose bisphosphatase back to F6P

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Effect of F2,6BP On Glycolysis

  • A STRONG activator of phosphofructokinase – when F26BP is present in high levels, reaction is activated due to the upregulation of PFK

    • increased rate of reaction

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Effect of F2,6BP On Gluconeogenesis

  • Inhibits F1-6-BP a key enzyme the the metabolic pathway, decreasing rate of reaction

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Structure of PFK2/FBPase-2

  • 1 polypeptide with 2 domains

    • Kinase domain and phosphate domains→ allows the removal/ addition of phospahte

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Reglation of PFK-2/FBPase-2 fUNCTION

  • Controlled by the covalent modification of a single Ser residue

    • When phosphorylated - phosphatase activity is prominent; kinase activity is low

    • When unphosphorylated - kinase activity is dominant

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Glucagon

  • Produced by α-cells of the pancreas in response to low blood glucose

    • Stimulates glycogen degradation

  • Maintains blood glucose levels to ensure the brain and muscle function

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How does glucagon signalling affect the activity of PFK-2/FBPase-2?

  • Glucagon binds to its receptor on liver cells.

  • This activates Protein Kinase A (PKA).

  • PKA phosphorylates the Ser residue at position 29 in PFK-2/FBPase-2.

  • This favors FBPase-2 activity (phosphatase), decreasing F2,6BP levels.

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Effect of Low Blood Glucose on Glucagon

  • Glucagon levels rise, and insulin levels fall leading to phosphorylation of PFK-2/FBPase-2.

  • F2,6BP Decrease This favours the phosphatase activity of the enzyme, decreasing F2,6BP levels.

  • Glycolysis is inhibited due to the lack of its activator, F2,6BP.

    • Gluconeogenesis is stimulated, causing the liver to produce glucose

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Effect of High Blood Glucose on Glucagon

  • Glucagon levels fall and insulin levels rise leading to a dephosphorylation of PFK-2/FBPase-2.

  • F2,6BP Increase: This favours the kinase activity of the enzyme, increasing F2,6BP levels.

  • Glycolysis is stimulated by high F2,6BP, allowing the body to use excess glucose.

    • Gluconeogenesis is suppressed.

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Epinephrine (Adrenaline)

  • Produced. by the adrenal glands in response to sudden energy requirements

    • Stimulates the breakdown of glycogen to glucose and its subsequent release in the blood

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