Gluconeogenesis

Introduction image

Gluconeogenesis is a reverse cycle of the glycolytic pathway, which produce glucose by the precursors like pyruvate, lactate, glycerol etc. and also refers as Neoglucogenesis. Its a ubiquitous or universal pathway that occurs in humans, animals, plants, fungi and other living organisms. Gluconeogenesis is the opposite process to glycolysis in only three irreversible steps, while the other seven steps are in common. It requires four reactions to bypass three irreversible reactions of the glycolytic cycle.

To understand the meaning of gluconeogenesis, break the term into gluco, neo and genesis. Now, it is quite easy to remember the meaning of gluconeogenesis, where gluco means glucose, neo means new, and genesis means synthesis. Don’t get confused with the terms like glycolysis, glycogenesis, glycogenolysis etc.

Content: Gluconeogenesis

  1. Definition
  2. Site of Occurrence
  3. Three Irreversible Steps
  4. Substrates
  5. Importance
  6. Regulation

Definition of Gluconeogenesis

GNG is an acronym for the term gluconeogenesis, which can define as a metabolic pathway of synthesizing new glucose molecules from the non-glucose substrates like lactate, TCA intermediates etc. Sometimes, it also refers as “Endogenous glucose pathway” as it needs an input of energy. It is an anabolic process, where the small precursor’s molecules combine to produce a high energy product like glucose. Gluconeogenesis is an important cycle, as glucose is a “Key metabolite” to carry out all catabolic processes and to sustain life.
Gluconeogenesis pathway

Site of Occurrence

The process of neoglucogenesis takes place inside the liver, cortex of kidney and enterocyte cells of the small intestine. Most of the steps in gluconeogenesis occur inside the cytosol than in mitochondria.

Three Irreversible Steps of Gluconeogenesis

Gluconeogenesis differs from glycolysis by three irreversible reactions, mediated by three different enzymes.

Step-1: Conversion of pyruvate into phosphoenolpyruvate

It is the first reaction that bypasses an irreversible reaction of glycolysis, mediated by pyruvate kinase. The transformation of pyruvate into phosphoenolpyruvate includes two series of steps like:
bypass step-1 of neoglucogenesis

Carboxylation of pyruvate into oxaloacetate

Pyruvate carboxylase mediates the transformation of pyruvate to oxaloacetate by adding one carbon-dioxide molecule. This enzyme was first discovered in the year 1960, by a scientist named Merton Utter. Pyruvate carboxylase is a mitochondrial enzyme, which helps pyruvate present in the cytosol to enter into the mitochondrial matrix through the help of MPC-1 and MPC-2 complexes. The carboxylation of pyruvate into oxaloacetate requires the use of high energy ATP molecule and the presence of Mg2+ and Mn2+ ions. As a result of pyruvate carboxylation, oxaloacetate and one ADP molecule produce.

Decarboxylation of oxaloacetate into Phosphoenolpyruvate

The transport of oxaloacetate from mitochondria to cytosol does not involve any carrier complex or transporters. It only occurs by the reduction of oxaloacetate into malate via mitochondrial malate dehydrogenase. Malate then moves beyond the inner mitochondrial membrane through the malate aspartate shuttle by the help of malate α-ketoglutarate transporter. In a cytosol, malate reoxidizes into oxaloacetate by an enzyme (cytosolic malate dehydrogenase).

Phosphoenolpyruvate carboxykinase changes oxaloacetate into phosphoenolpyruvate by the removal of carbon dioxide. It is an isoenzyme that is equally present in both mitochondria and cytosol. The decarboxylation of oxaloacetate into Phosphoenolpyruvate needs high energy ATP molecule and the presence of Mg2+ and Mn2+ ions. This reaction is reversible under normal cellular conditions.

Step-2: Dephosphorylation of fructose 1, 6- biphosphate into fructose 6-phosphate

It is a second reaction that bypasses an irreversible reaction of glycolysis, mediated by the enzyme phosphofructokinase.  In gluconeogenesis, fructose 1, 6-phosphatase enzyme mediates the dephosphorylation of fructose 1, 6- biphosphate into fructose 6-phosphate, and requires Mg2+ ions. This enzyme cause hydrolysis of C-1 phosphate in the fructose 1, 6- biphosphate molecule, without a release of ATP.
bypass step-2 of gluconeogenesis

Step-3: Dephosphorylation of glucose 6-phosphate into glucose

It is a third step, which bypasses an irreversible reaction of glycolysis, catalyzed by an enzyme hexokinase. In contrary, glucose 6-phosphatase promotes this reaction in a gluconeogenesis cycle and dephosphorylates glucose 6-phosphate into glucose. Glucose 6-phosphatase is a protein complex in the membrane of the endoplasmic reticulum. It consists of an active catalytic site and a transporter complex.
bypass step-3 of neoglucogenesis

The active catalytic site mediates the release of glucose in the lumen of the endoplasmic reticulum (not cytosol), by the transporter complex “glucose 6-phosphate translocase or T1”. Glucose 6-phosphatase is dependent on Mg2+ ions and catalyze the last step. The glucose molecule formed after dephosphorylation of glucose 6-phosphate is shuttled into the cytoplasm by the glucose transporters of the endoplasmic reticulum.

Substrates

All the intermediates of glycolysis and tricarboxylic acid cycle provide a substrate for the neoglucogenesis. Substrates like glycerol, lactate, glucogenic amino acid etc.

Glycerol

It is a product formed as a result of triglyceride hydrolysis in the adipose tissue and transferred to the liver via blood. Glycerol is an intermediate which can produce glucose solely in the cytosol. It enters the cycle by two sequential steps:
glycerol as a substrate of neoglucogenesis
Glycerol kinase is an enzyme found in both liver and kidney that undertakes the phosphorylation of glycerol into glycerol 3-phosphate, by the use of ATP. Then oxidation of glycerol phosphate into dihydroxyacetone phosphate occurs, by the reduction of NAD into NADH. Dihydroxyacetone is an intermediate of the glycolytic pathway.

Lactate

It is a product formed as a result of anaerobic glycolysis in skeletal muscles and erythrocytes. Lactate is transferred from muscle to the liver via blood. It reconverts into pyruvate inside a liver, and later undertake the production of glucose through gluconeogenesis.
lactate as a precursor of gluconeogenesis

Glucogenic amino acids

These are derived by the hydrolysis of tissue proteins. Glucogenic acids like α-ketoglutarate, Succinyl Co-A, fumarate, oxaloacetate and fumarate are the only precursors which can produce glucose. There are two entry points, namely pyruvate and oxaloacetate, through which the glucogenic amino acids can enter the cycle of neoglucogenesis.
glucogenic acid as a precursor of neoglucogenesis

Importance
  1. The gluconeogenesis cycle performs a crucial role in blood-glucose homeostasis, during starvation.
  2. Glucose produced in this cycle fulfils the energy demands of many cells and tissues like RBCs, neurons, skeletal muscle, medulla of the kidney, testes, embryonic tissue etc.
  3. Neoglucogenesis cycle clears metabolites accumulated in the blood, like lactate (produced from muscles and RBCs) and glycerol (produced from adipose tissue) etc.

Regulation

The regulation of gluconeogenesis includes the following factors:

Acetyl CoA

It is a kind of reciprocal regulation, which regulates the transformation of pyruvate to PEP. Acetyl Co-A cumulates in the liver as a result of excessive lipolysis of adipose tissue. When its concentration is more, it inhibits the activity of glycolytic enzyme “Phosphate dehydrogenase” and stimulates the activity of pyruvate carboxylase. Thus the high level of acetyl Co-A influences the gluconeogenesis cycle. It can regulate the pathway both positively and negatively.

  • Positive regulation: Acetyl Co-A promotes the enzymatic activity by the pyruvate carboxylase, which in turn produce more oxaloacetate and end product glucose.
  • Negative regulation: Acetyl Co-A inhibits the enzymatic activity of pyruvate dehydrogenase, which function is to convert pyruvate carboxylase to acetyl Co-A.

Glucagon

It is a kind of hormonal regulation that is secreted from the α-cells of pancreatic islets when the blood glucose level in a body starts decreasing. Glucagon regulates the conversion of fructose 1, 6-biphosphate to fructose 6-phosphate or favours the process of gluconeogenesis by the following two mechanisms:

  • Glucagon mediates cyclic AMP that can convert the pyruvate kinase to an inactive form, which results in a decrease in the conversion of PEP to pyruvate. Finally, it diverts the cycle for the synthesis of glucose.
  • Secondly, glucagon reduces the concentration of fructose 2, 6-phosphate that inhibits the enzymatic activity of phosphofructokinase and activates fructose 1, 6-biphosphate to promote glucose synthesis.

Glucogenic amino acids

It is a kind of substrate-level regulation, which regulates the conversion of glucose 6-phosphate into glucose. Substrates like glucogenic acid influence the process of neoglucogenesis at the time of decreased insulin level. When the concentration of insulin decreases, the muscle protein metabolizes into the amino acids for the purpose of gluconeogenesis.

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