Gluconeogenesis biochemistry, Lecture notes of Medical Biochemistry

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Gluconeogenesis

SAIU, MBChB

Gluconeogenesis

• (^) A metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates
• (^) It is one of the two main mechanisms the body uses to keep blood glucose levels from dropping too low
• (^) In animals, gluconeogenesis takes place mainly in the liver
• (^) This process occurs during periods of fasting, starvation, or intense exercise

Irreversible glycolytic steps bypassed

1. Hexokinase
2. Phosphofructokinase-
3. Pyruvate kinase (PyrK) by Glucose-6-phosphatase by Fructose 1,6-bisphosphatase by Pyruvate Carboxylase and Phosphoenolpyruvate carboxykinase Glycolysis (^) Gluconeogenesis

Fructose-1,6-bisphosphatase catalyzes: fructose-1,6-bisP + H 2 O  fructose-6-P + P i Bypass 2:

Bypass 3: Pyruvate carboxylase and PEP carboxykinase catalyze: Pyruvate + ATP+ GTP  PEP + ADP + GDP + Pi + CO 2

PEP carboxykinase located in both cytosol and mitochondria. So there are two ways to transfer pyruvate to PEP. Lactate feeds into gluconeogenesis through pyruvate.

Intermediates in citric acid cycle can be used for gluconeogenesis through oxaloacetate PEP

Pyruvate can go “up” or “down” depending upon energy needs

• (^) Pyruvate is first transported from the cytosol into mitochondria or is generated from alanine within mitochondria by transamination, in which the - amino group is removed from alanine (leaving pyruvate) and added to an α-keto carboxylic acid
• (^) Then pyruvate carboxylase, a mitochondrial enzyme that requires the coenzyme biotin, converts the pyruvate to oxaloacetate

• (^) The important precursors of glucose in animals are three-carbon compounds such as lactate, pyruvate, and glycerol, as well as certain amino acids
• (^) In mammals: it occurs mainly in the liver, and a lesser extent in renal cortex
• (^) The glucose produced passes into the blood to supply other tissues
• (^) Lactate produced by anaerobic glycolysis in skeletal muscle returns to the liver and is converted to glucose, which moves back to muscle and is converted to glycogen—>Cori cycle

• (^) Lactate and glucose shuttle between active muscle/RBC and liver
• (^) Liver gluconeogenesis supplies the blood glucose for use by muscle, RBC’s and brain (120 g/day)
• (^) Note: the brain fully oxidizes glucose, so it does not funnel back lactate

• (^) The liver can also use the amino acid Alanine similarly to form lactate
• (^) Following transamination to pyruvate, gluconeogenesis allows the liver to convert it to glucose for secretion into the blood

• (^) ALT/ALAT (serum glutamate-pyruvate transaminase ( SGPT ) or serum glutamic-pyruvic transaminase (SGPT) catalyzes the transfer of an amino group from L-alanine to α-ketoglutarate
• (^) ALT & all transaminases require the coenzyme pyridoxal phosphate L-glutamate + pyruvate ⇌ α-ketoglutarate + L-alanine α-ketoglutarate + L-alanine Clinical significance of ALT (read & note)