Biochem Gluconeogenesis

Gluconeogenesis

• -Gluconeogenesis (GNG) is a metabolic pathway that
• generates GLUCOSE from non-carbohydrate carbon
• substrates such as pyruvate, lactate, glycerol, and
• glucogenic amino acids
• When Blood Glucose level is reduced Gluconeogenesis takes place in liver
• 

Glycolysis vs Gluconeogenesis

Glycolysis vs Gluconeogenesis

• regulating steps are
• glycolysis: hexokinase from glucose to g6p
• phosphofructo kinase from F6P to F 1,6 BP
• Pyruvate kinase from PEP to pyruvate
• gluconeogensis
• basically in the same steps but by different enzymes
• G6P'ase, F-1,6-BP'ase and but only differnt thing is the PEP----->oxaloacetate-------->pyruvate
• PEP carboxylase pyruvate carboxylase
• 

Pyruvate: the starting point Of Gluconeogenesis

• Pyruvate
• (synthesized in the cytoplasm by
• glycolysis enters mitochondria
• 

Step 1.a. Gluconeogenesis: pyruvate to oxaloacetate

• Enzyme: Pyruvate decarboxylase.
• Energy: One ATP molecule used.
• Biotin is a covalently attached
• prosthetic group, which serves as
• a carrier of activated CO2
• .
• 

Pyruvate carboxylase and Biotin

• Biotin is attached to
• pyruvate carboxylase by a
• long, flexible chain at the
• latter’s C-terminus.
• (attach @lysine?)
• 

Step 1.b. Oxaloacetate to Malate to Oxaloacetate

• Pyruvate carboxylase: mitochondrial.
• Other gluconeogenesis enzymes: cytoplasmic
• 1. Oxaloacetate is reduced by an NADH linked
• malate dehydrogenase to malate
• inside the mitochondrion.
• 2. Malate is transported to cytosol. (out of mitochondria)
• 3. Malate is reoxidized to oxaloacetate by an
• NAD+-linked malate dehydrogenase in the
• cytoplasm
• 

Step 1.c: Oxaloacetate to Phosphoenolpyruvate

• 1. Oxaloacetate is decarboxylated and phosphorylated to yield phosphoenolpyruvate (PEP) , at the expense of the high phosphoryl-transfer potential of GTP
• 2. Enzyme: phosphoenolpyruvate carboxykinase (PEPCK
• 

From phosphoenolpyruvate to Fructose 1-6 bisphosphate

• All reactions are reversible
• under intracellular conditions.
• Therefore when conditions
• favor gluconeogenesis, the
• reverse reactions will take
• place until the next
• irreversible step is reached

Conversion of Fructose 1,6-bisphosphate into Fructose 6-phosphate and orthophosphate

• *An irreversible step
• 

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• Glucose 6-phosphate to Glucose
• 

Generation of free glucose is an important control point

• 1. Free glucose is generated in liver (and less in kidney).
• 2. Glucose 6-phosphate is transported to the lumen of
• the endoplasmic reticulum.
• 3. Glucose 6-phosphatase converts Glucose 6-
• phosphate to free glucose.
• 4. Two glucose transporters carry glucose to cytoplasm
• 

Six high-transfer-potential phosphoryl groups are spent in synthesizing glucose from pyruvate

• 2 Pyruvate + 4 ATP + 2 GTP + 2 NADH + 6 H2O =========>>>>>>
• Glucose + 4 ADP + 2 GDP + 6 Pi + 2 NAD+ + 2H+

Glycolysis and gluconeogenesis are coordinated

• The amounts and activities of the distinctive enzymes of
• each pathway are controlled to keep one pathway active and
• one inactive at the same time.
• 

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• 
• Pie de imagen: high energy, high resources for energy turns convert those things back to glucose.

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Liver and Gluconeogenesis

• From Glucose-> G6P ->F6P
• To go to glycolysis, using PFK you go to F-1,6-BP
• for gluconeogenesis PFK2, F-2,6 BP'ase
• Bifunctional enzyme PFK2 - FBPase2 plays a major role in
• Deciding Glycolysis vs Gluconeogenesis.
• 

Lactate formed by contracting muscle is used by other organs

• Pyruvate formation --> Reduced to Lactate -->Diffuse into Blood and
• then to other organs
• from leg muscle, lactate enter cardiac muscle cells.
• Lactate is converted to pyruvate and
• metabolized by
• TCA cycle to generate ATP.
• More circulating glucose available for active muscle cells

Lactate formed by contracting muscle is used by other organs:

• Fate 2: In the liver
• Cori cycle: Contracting skeletal muscle supplies lactate to
• the liver, which uses it to synthesize and release glucose.
• Thus, the liver restores the level of glucose necessary for
• active muscle cells, which derive ATP from the glycolysis.
• 

Gluconeogenesis of Alanine formed by contracting muscle

• Alanine is generated in the muscle
• when the carbon skeletons of
• some amino acids are used as
• fuels. The nitrogens from these
• amino acids are transferred to
• pyruvate to form alanine.
• The reverse reaction takes
• place in the liver:
• Alanine generates Pyruvate that
• enters Gluconeogenesis

Interplay between Glycolysis and gluconeogenesis

• During a sprint:
• In leg muscle:
• Glucose metabolized anaerobically
• to lactate or (aerobically to CO2
• and H2O)
• In cardiac muscle:
• Lactate can be converted into
• pyruvate and used as a fuel, along
• with glucose, to power the
• heartbeats to keep the sprinter’s
• blood flowing.
• In the liver: Gluconeogenesis, will
• take place rapidly to ensure that
• enough glucose is present in the
• blood for skeletal and cardiac
• muscle, and other tissues.
• Glycogen, glycerol, and amino
• acids are other sources of energy

Gluconeogenesis and Liver

Summary:

• Gluconeogenesis
• 1. Gluconeogenesis generates glucose from noncarbohydrate
• carbon substrates such as pyruvate,
• lactate, glycerol, and glucogenic amino acids.
• 2. Gluconeogenesis helps maintain blood glucose levels.
• 3. Gluconeogenesis bypasses the three virtually
• irreversible reactions of glycolysis.
• 4. Glycolysis and gluconeogenesis are coordinated in
• liver, muscle and other organs to maintain blood
• glucose level.