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Gluconeogenesis 2

Gluconeogenesis is the formation of glucose from non-carbohydrate substrates during periods of fasting. It occurs mainly in the liver and kidneys, utilizing different enzymes than glycolysis to essentially reverse the reactions. Key substrates that can enter gluconeogenesis include alanine, lactate, glycerol, and metabolites from fatty acid breakdown. The regulation of gluconeogenesis centers around three irreversible steps in glycolysis that require alternate enzymes, with the conversion of fructose-1,6-bisphosphate to fructose-6-phosphate being the rate-limiting step controlled by numerous effectors.

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62 views2 pages

Gluconeogenesis 2

Gluconeogenesis is the formation of glucose from non-carbohydrate substrates during periods of fasting. It occurs mainly in the liver and kidneys, utilizing different enzymes than glycolysis to essentially reverse the reactions. Key substrates that can enter gluconeogenesis include alanine, lactate, glycerol, and metabolites from fatty acid breakdown. The regulation of gluconeogenesis centers around three irreversible steps in glycolysis that require alternate enzymes, with the conversion of fructose-1,6-bisphosphate to fructose-6-phosphate being the rate-limiting step controlled by numerous effectors.

Uploaded by

Nikhitha Nunna
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GLUCONEOGENESIS

 Gluconeogenesis is the formation of new glucose from various metabolic substrates, and
occurs in the fasting state. Gluconeogenesis occurs predominantly in the liver, but
enzymes are also found in the kidney and intestinal epithelium.
 Muscle cells cannot raise blood glucose via gluconeogenesis because they lack glucose-
6-phosphatase. Because phosphorylated glucose is unable to exit the cell, glucose
remains trapped in the myocytes.
 The 3 regulated steps of glycolysis are essentially irreversible, so different enzymes are
required to regenerate glucose. Recall that the 3 irreversible steps of glycolysis are:

1) Glucose → G6P (Glucokinase/Hexokinase)

2) F6P → F1,6BP (Phosphofructokinase-1)

3) PEP → pyruvate (Pyruvate kinase)

 Gluconeogenesis utilizes different enzymes to perform these steps in the opposite


direction.
 There are four non-pyruvate carbon substrates that can enter gluconeogenesis through
various metabolic conversions. Alanine (from protein breakdown and the Cahill
cycle) and lactate (the most significant substrate) are converted directly to pyruvate to
enter gluconeogenesis.
 All triacylglycerides (TAGs) can be metabolized to form glycerol, which can enter
gluconeogenesis through several reactions resulting in the formation of DHAP. This entry
point is the furthest upstream among the non-pyruvate substrates.
 Metabolites from fatty acid metabolism can enter gluconeogenesis as propionyl-CoA.
They are converted in the following way:
o Propionyl-CoA → Methylmalonyl-CoA → Succinyl-CoA
o Succinyl-CoA →→→ Oxaloacetate, via the TCA cycle

Note: that only odd-chain fatty acids can produce metabolites that undergo this pathway;
even-chain fatty acids do not produce propionyl-CoA.

 1st reaction of gluconeogenesis: Pyruvate → Oxaloacetate


o Pyruvate carboxylase catalyzes this reaction, which occurs in the mitochondria.
 Biotin is a cofactor of the pyruvate → oxaloacetate reaction catalyzed by pyruvate
carboxylase.
 Pyruvate carboxylase requires acetyl-CoA as an allosteric activator. This is intuitive,
as acetyl-CoA is the next downstream metabolite for pyruvate in glycolysis; excess
acetyl-CoA is indicative of a need for a shift from glycolysis to gluconeogenesis.
 2nd reaction of gluconeogenesis: Oxaloacetate → Phosphoenolpyruvate (PEP)
o PEP carboxykinase catalyzes this reaction, which occurs in the cytosol.
 1 GTP is consumed in the conversion of oxaloacetate to PEP (2 GTPs per glucose).
 Oxaloacetate is transported to the cytosol using the malate shuttle.
 A series of reactions that are simply reversed versions of glycolysis convert PEP to
fructose-1,6-bisphosphate. The 3rd reaction unique to gluconeogenesis is: Fructose-1,6-
bisphosphate → Fructose-6-phosphate.
o Fructose-1,6-bisphosphatase catalyzes this reaction, which occurs in the cytosol.
 The conversion of fructose-1,6-bisphosphate to fructose-6-phosphate, catalyzed by
fructose-1,6-bisphosphatase, is the rate-limiting step of gluconeogenesis.
 Recall that the equivalent glycolysis step (i.e. fructose-6-phosphate to fructose-1,6-
bisphosphate) is the rate-limiting step of glycolysis.
 As the rate-limiting step of gluconeogenesis, fructose-1,6-bisphosphatase has many
allosteric activators and inhibitors. Citrate, ATP, and acetyl-CoA allosterically activate
fructose-1,6-bisphosphatase, as they are indicative of a heavily glycolytic environment.
 Fructose-2,6-bisphosphate and AMP inhibit fructose-1,6-bisphosphatase.
 Fructose-6-phosphate is isomerized to glucose-6-phosphate by the same enzyme in
glycolysis. The final reaction unique to gluconeogenesis is glucose-6-phosphate →
glucose.
 Glucose-6-phosphatase catalyzes this reaction, which occurs in the smooth endoplasmic
reticulum. The sequestration of this enzyme assures it does not compete with
glucokinase/hexokinase during glycolysis.
 Substrates for Gluconeogenesis
o Glucogenic Amino Acid (Alanine0 is the major contributor)
o Lactate
o Glycerol
o Propionyl CoA
 Sites of Gluconeogenesis
o Liver (60-90%) Kidney (10-40%).
o Organelle-Cytoplasm and Mitochondri.
 There is a role for Smooth endoplasmic reticulum also
o Propionyl-CoA carboxylase require Biotin and ATP
o Methyl-Malonyl-CoA Mutase require vitamin B1
 Enzymes Common to Glycolysis and Gluconeogenesis
o All the enzymes other than the irreversible enzymes in theglycolysis.
o One mot of lactate converted to glucose, 6 ATPs are utilised
 2 ATPs for Pyruvate Carboxylase
 2 ATPs for PEPCK
 2 ATPs for 1,3 BPG Kinase

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