Gluconeogenesis

Dr. Sooad Al-DaihanDr. Sooad Al-DaihanBiochemistry department Biochemistry department

IntroductionIntroduction

Some tissues, such as the brain, and red blood cells require a continuous supply of glucose as a metabolic fuel.

During a prolonged fast, hepatic glycogen stores are depleted, and glucose is formed from precursors such as lactate, pyruvate, glycerol, and α-ketoacids by a special pathway, gluconeogenesis, that requires both mitochondrial and cytosolic enzymes.

Gluconeogenesis occurs mainly in liver.

It also occurs to a more limited extent in kidney & small intestine under some conditions. 

Synthesis of glucose from pyruvate utilizes many of the same enzymes as Glycolysis.

Almost reverse of glycolysis exceptexcept for 3 reactions ,which are essentially irreversible. Hexokinase (or Glucokinase) Phosphofructokinase Pyruvate Kinase.

These steps must be bypassed in Gluconeogenesis.

Four enzymes are needed to reverse the 3 irreversible steps of glycolysis:

Mitochondrial ‐ Pyruvate Carboxylase (liver, kidney but not in muscle)

Cytoplasmic ‐ Phosphoenolpyruvate (PEP) Carboxykinase

Cytoplasmic ‐Fructose‐1,6,‐Bisphosphatase

Cytoplasmic ‐Glucose 6‐Phosphatase

1-Bypass of Pyruvate Kinase:

In gluconeogenesis PK is bypassed by 2 enzyme catalyzed reactions:

1- Pyruvate Carboxylase :

Pyruvate is carboxylated to oxaloacetate in the mitochondria .

pyruvate + HCO3- + ATP oxaloacetate + ADP + Pi

2- PEP Carboxykinase :

Oxaloacetate is decarboxylated and phosphorylated to yield PEP in the cytosol .

oxaloacetate + GTP PEP + GDP + CO2

Transport of oxaloacetate to the cytosol

2- Bypass of Phosphofructokinase:

In gluconeogenesis PFK bypassed by Fructose 1,6 ‐ bisphosphatase reaction (Removes phosphate group)

fructose‐1,6‐bisP + H2O fructose‐6‐P + Pi

3- Bypass of Hexokinase (or Glucokinase)

In gluconeogenesis this reaction bypassed by glucose 6‐phosphatase reaction (Removes phosphate group) :

Glucose-6‐P + H2O Glucose+ Pi

Free glucose is formed by the action of glucose‐6‐ phosphatase in liver and kidney while it is absent in muscles and adipose tissues

Glucose can not be formed by these organs Glucose can not be formed by these organs

Total Energy Cost

Precursors for Gluconeogenesis

i- Cori Cycle

Lactate released by active skeletal muscle or red blood cells is carried to the liver where it is converted to glucose by gluconeogenic pathway (Cori cycle) and released for reuptake by skeletal muscle

ii- Glucose-Alanine Cycle

Protein broken down in skeletal muscle during exercise

Amino acids converted to alanine and released by skeletal muscle

Taken up by liver and converted to glucose and released for reuptake by skeletal muscle

iii- Glycerol

Glycerol released from adipocytes and skeletal muscle during lipolysis.

 Glycerol enters gluconeogenic pathway as dihydroxyacetone phosphate “active form of glycerol”.

 2 glycerol required to make one glucose in liver and kidney in fasting or low CHO diet .

Glycerol cannot be utilized in adipose tissue due to the lack of glycerol kinase in the adipose tissue.

iv- Propionate:

Propionyl‐CoA is converted to the TCA intermediate, succinylCoA.

This conversion is carried out by the ATP‐requiring enzyme, propionyl‐CoA carboxylase then methylmalonyl‐CoA epimerase and finally the vitamin B12 requiring enzyme, methylmalonyl‐CoA mutase

The utilization of propionate in gluconeogenesis only has quantitative significance in ruminants.

Regulation of Gluconeogenesis

Control of glycolysis and gluconeogenesis is reciprocal

Gluconeogenesis and Glycolysis are regulated by similar effector molecules but in the opposite direction

When one pathway is activated , the other is inhibited

Gluconeogenesis is subject to both:

- Hormonal control by Glucagon, Cortisol, Adrenaline and Insulin

- Allosteric regulation of gluconeogenic enzymes

Hormonal Regulation

Glucagon, Cortisol, Adrenaline

Are secreted during fasting, stress and sever muscular exercise

Induce gluconeogenic enzymes

Repress glycolytic enzymes

Insulin

Secreted after CHO meal

Induce glycolytic enzymes

Repress gluconeogenic enzymes

Allosteric regulation

Uronic Acid PathwayUronic Acid Pathway

Dr. Sooad Al-DaihanDr. Sooad Al-DaihanBiochemistry department Biochemistry department

OverviewOverview

It is an alternative oxidative pathway for glucose that doesn’t lead to ATP generation.

It includes oxidation of glucose to1. Glucuronic acid2. Ascorbic acid

It occurs mainly in the liver cytoplasm.

Metabolic reactionsMetabolic reactions

.1Glucose 6-phosphate is isomerized to glucose 1-phosphate

.2Glucose 1-phosphate reacts with uridine triphosphate (UTP) to form uridine diphosphate glucose (UDPGlc) in a reaction catalyzed by UDPGlc

pyrophosphorylase .3UDPGlc is oxidized at carbon 6 by NAD-dependent

UDPGlc dehydrogenase in a two-step reaction to yield UDP-glucuronate 1 2

3

UDP Glucuronic acid (active form) is needed in :

Conjugation to less polar compounds as bilirubin, steroids and some drugs making them

more water soluble (detoxicated). Synthesis of glycosaminoglycans

(mucopolysaccharide) as heparin, hyaluronic acid.In plants and some animals (not Human)

glucuronic acid serves as a precursor of L-ascorbic acid .

The uronic acid pathway also provides a mechanism by which dietary D-xylulose enter

the central pathway .