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Overview of Hexose monophosphate shunt pathway

Hexose Monophosphate Shunt (HMP) Pathway is also known as the pentose phosphate pathway (PPP) or phosphogluconate pathway or the pentose shunt. An alternative pathway for glucose oxidation.

However, in the HMP, no ATP is directly consumed or produced; instead, the HMP pathway is most important for the production of reducing power in the form of NADPH.

Hexose Monophosphate Shunt Pathway

Location: It is present in all cells in the body but mainly occurs in the liver, lactating mammary glands, adipose tissue, adrenal cortex, and red blood cells (RBCs), etc.

Occurs in cell cytoplasm: 

The Hexose Monophosphate Shunt (HMS) Pathway provides a means by which glucose can be oxidized to give rise to NADPH and is the source of much of the NADPH that is needed for the biosynthesis of numerous biomolecules, most notably fats.

The Hexose Monophosphate Shunt Pathway (HMP) can also be used for the catabolism of pentose (5-carbon) sugars from the different diet, the synthesis of pentose sugars for nucleotide biosynthesis, and the catabolism & synthesis of less common four- and seven-carbon sugars compounds.

Biological Importance of Hexose Monophosphate Shunt Pathway (HMP):

  • NADPH produced in the HMP shunt is utilized for the biosynthesis of several important factors in various organs.
    • In the liver, NADPH is utilized for fatty acid synthesis, cholesterol synthesis, bile acid synthesis, glutamate synthesis, and cytochrome P450-hydroxylase system in the body.
    • In the adrenal cortex and gonads, NADPH is utilized for cholesterol and hormone synthesis.
    • In the adipose tissue, NADPH is utilized for fatty acid synthesis.
    • NADPH is utilized for the formation of deoxyribonucleotides and pyrimidine nucleotides in the body.
Hexose Monophosphate Shunt Pathway
  • In RBC, NADPH produced is utilized for the formation of reduced glutathione from oxidized glutathione. glutathione reductase catalyzes this reaction.
  • Reduced glutathione is required for the removal of hydrogen peroxide (H2O2) by glutathione peroxidase for the conversion of methemoglobin to normal hemoglobin and improvement of –SH groups of erythrocyte proteins.
  • So, lessen glutathione is essential for the integrity of normal red cell structure.
  • Generally, cells with lessen glutathione levels are more prone to hemolysis.
  1. Pentoses produced in this pathway are utilized for nucleic acid synthesis & nucleotide coenzymes like NAD+, FAD, and FMN synthesis.
  2. A non-oxidative phase of this pathway turns pentoses of endogenous or dietary nucleic acids into intermediates of glycolysis where they are, further oxidized to generate energy.
  3. Interconversion of three, four, five, six, and seven carbon sugar compounds in the non-oxidative phase metabolically connects these sugars to the glycolysis pathway.

Tissues in which Pentose Phosphate Pathway is Active:

  • High Activity occurs in the Liver, adipose tissue, adrenal cortex, thyroid, erythrocytes, testis, and lactating mammary gland.
    • These tissues use NADPH in the reductive pathway, for example, fatty acids, steroids, amino acids.
  • Low Activity occurs in the skeletal muscle, non-lactating mammary gland.

Reactions (Steps) of Hexose Monophosphate Shunt Pathway (HMP):

This pathway occurs in the following two phases:

  1. Oxidative (irreversible) phase:
    • Glucose-6-phosphate is converted into ribulose-5-phosphate (pentose) with a production of NADPH, H+ ions, & carbon-dioxide (CO2).
  2. Non-oxidative (reversible) phase:
    • Three molecules of ribulose-5-phosphate are converted into one molecule of fructose-6-phosphate & one molecule of other glyceraldehyde-3-phosphate.
Hexose Monophosphate Shunt Pathway is also known as pentose phosphate pathway or phosphogluconate pathway or the pentose shunt. An alternative pathway for the oxidation of glucose

Oxidative Phase of the Pentose Phosphate Pathway:

  • NADPH Production:
    • In the oxidative 1st phase of the HMP pathway, glucose 6-phosphate is oxidatively decarboxylated to a pentose sugar, ribulose 5-phosphate.
    • The 1st enzyme of this HMP pathway, glucose 6-phosphate dehydrogenase, oxidizes the aldehyde at C1 & reduces NADP molecule to NADPH molecule.
    • Thus, 2 moles of NADPH per mole of glucose 6-phosphate are formed from this part of the pathway.
    • Glucose-6-P is a branch site in carbohydrate metabolism.
    • It is a precursor for almost every pathway that utilized glucose, including the glycolysis cycle, the pentose phosphate pathway, and glycogen synthesis.
    • From the opposite perspective, it also can be generated from other pathways of carbohydrate metabolism in the body, such as glycogenolysis (the breakdown of glycogen compound), the pentose phosphate pathway, and gluconeogenesis (the synthesis of glucose from non-carbohydrate compounds).
  • Ribose 5-phosphate from the oxidative branch of this pathway

To generate or produced ribose 5-phosphate from the oxidative pathway, the ribulose 5-phosphate formed from the action of the 2 oxidative steps which is isomerized to produce ribose 5-phosphate (a ketose-to-aldose transformation, that similar to fructose 6-phosphate being isomerized to glucose 6-phosphate).

The ribose 5-phosphate can then penetrate the pathway for nucleotide synthesis, if required, or can be converted to glycolytic intermediates compounds, as explained below for the non-oxidative phase of the HMP.

The Non-oxidative Phase HMP:

The non-oxidative reactions of this pathway are reversible reactions that permits intermediates of the glycolysis pathway (specifically glyceraldehyde-3-P and fructose-6-P) to be converted to 5-carbon sugars (such as ribose-5-P), and vice versa in this pathway. The needs of the cell will dictate in which direction this pathway proceeds.

Regulation of HMP shunt:

  • G-6-Phosphate Dehydrogenase is the rate-limiting enzyme of HMP-shunt.
  • It is stimulated by insulin molecules & NADP+.
  • It is inhibited by NADPH, H+, and Acetyl CoA molecule.

Control of the pentose phosphate pathway (PPP):

The major control of the pathway is exerted at the 1st step, which is the glucose-6-phosphate dehydrogenase reaction. Features are

  1. This is an essentially irreversible reaction.
  2. The major controlling factor is the ratio of NADPH to NADP+.
  3. As the cell utilizes NADPH the concentration of NADP+ increases. This activates this pathway, increasing NADPH generation (formation) to compensate.
  4. Therefore, the pentose phosphate pathway is operated by a low NADPH: NADP+.
    • The control of the non-oxidative phase is by the essential for products, namely ribose-5-phosphate and NADPH.
    • The individual needs of the cell for either of these decide whether the production of ribose-5-phosphate or fructose-6-phosphate and glyceraldehyde-3-phosphate predominates. For example,
      1. If the NADPH requirements are considerable than the ribose-5-phosphate requirement, for example in the cells that take part in a lot of reductive synthetic reactions, all the ribose-5-phosphate formed is converted to fructose-6-phosphate and glyceraldehyde-3-phosphate. These are converted back to glucose-6-phosphate to enter again the PPP and therefore generate more NADPH.
      2. When numerous pentoses are needed glucose-6-phosphate is converted to fructose-6-phosphate and glyceraldehyde-3-phosphate by glycolysis. Pentoses are formed from these molecules through the non-oxidative phase of the pathway and there is no NADPH production.
Hexose Monophosphate Shunt Pathway

Differences between HMP shunt and glycolysis:

Glycolysis HMP pathway  
In all cells In certain cells Location
Phosphorylation occurs 1st then oxidation Occurs in the 1st reaction Oxidation of glucose
NAD+ NADP+ Coenzyme
2 or 8 ATP No energy production Energy
Not produced Produced CO2
Not produced Produced Pentoses

HMP Shunt & Glutathione Peroxidase Protect Erythrocytes against Hemolysis:

  • In RBCs, the HMP Shunt pathway provides NADPH for the reduction of oxidized glutathione.
  • Reduced glutathione removes H2O2.
  • Accumulation of hydrogen peroxide (H2O2) may decrease the life span of RBCs by causing oxidative damage to the cell membrane, leading to hemolysis.

Medical Importance of Pentose Phosphate Pathway:

HMP shunt pathway is defective in few diseases.

  1. Glucose-6-phosphate dehydrogenase deficiency: In some people, 10-fold lessen active glucose-6-phosphate dehydrogenase is produced in RBC due to sex-linked defective genes.
    • The less active glucose-6-phosphate dehydrogenase becomes inactive in the presence of certain drugs. So, the affected individuals are normal until they are exposed to those drugs.
    • Glucose-6-phosphate dehydrogenase deficiency occurs when drugs like aspirin, primaquine anti-malarial drug, and sulfonamide are administered to these individuals.
    • Since NADPH secretion is blocked in these individuals because of the deficiency of glucose-6-phosphate dehydrogenase the susceptibility of RBC to hemolysis is increased.
    • Therefore, the affected individuals chance to develop hemolytic anemia on exposure to these drugs.
    • Consumption of fava beans also causes glucose-6-phosphate dehydrogenase deficiency in susceptible individuals.
    • Favism is the name given to this type of glucose-6-phosphate dehydrogenase deficiency.
  2. Transketolase deficiency can occur in thiamine deficiency cases.
  3. Wernicke-korsakoff encephalopathy:
    • It is due to defective genes.
    • Transketolase of affected individuals has a lower affinity for TPP.
    • The characteristic symptoms are the following abnormal walking and standing, memory loss, and paralysis of eye movements.
    • The disease demostrates only when there is thiamine deficiency.
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