HMP Shunt pathway- Definition, Phases, Significance

Table of Contents

Introduction:

The hexose monophosphate pathway, also known as the pentose phosphate pathway or the phosphogluconate pathway, is an anabolic pathway that occurs in the cytosol of eukaryotic cells and bacteria.
The hexose monophosphate pathway (HMP) and the pentose phosphate pathway (PPP) are two metabolic pathways that are involved in the production and utilization of glucose.
The HMP, also known as the hexose monophosphate shunt or the Warburg-Dickens pathway, is a metabolic pathway that produces NADPH, a reducing agent that is used in various reactions, such as the synthesis of fatty acids and cholesterol, and the detoxification of drugs and toxins.
It is a secondary pathway for the metabolism of glucose and is responsible for the production of NADPH, a cofactor that is essential for many biosynthetic reactions, including the synthesis of fatty acids and cholesterol, the detoxification of drugs and toxins, and the protection of cells against oxidative stress.

Occurrence:

The hexose monophosphate pathway occurs in the cytosol of eukaryotic cells and bacteria. In eukaryotic cells, the pathway is found in most cell types, including liver cells, muscle cells, and red blood cells. In bacteria, the pathway occurs in a wide range of species, including Escherichia coli, Bacillus subtilis, and Streptomyces coelicolor.
In eukaryotic cells, the hexose monophosphate pathway is a secondary pathway for glucose metabolism, meaning that it is not the primary pathway for the breakdown of glucose to generate energy. Instead, the primary pathway for glucose metabolism in eukaryotes is glycolysis, which occurs in the cytosol and results in the production of ATP.
In bacteria, the hexose monophosphate pathway can be the primary pathway for glucose metabolism, depending on the species and the growth conditions. In some bacteria, the pathway may be activated under specific conditions, such as when the cell is exposed to certain environmental stresses or when it needs to produce NADPH for specific metabolic processes.

Features:

Conversion of glucose-6-phosphate to 6-phosphogluconate: The hexose monophosphate pathway starts with the conversion of glucose-6-phosphate to 6-phosphogluconate, which is catalyzed by the enzyme glucose-6-phosphate dehydrogenase.
Production of NADPH: The hexose monophosphate pathway involves the reduction of ribulose 5-phosphate to ribose 5-phosphate, which is an important intermediate in the synthesis of nucleotides and other biomolecules. The reduction of ribulose 5-phosphate to ribose 5-phosphate is catalyzed by the enzyme transketolase, which requires the cofactor NADPH.
Regulation of the pathway: The hexose monophosphate pathway is regulated by a number of enzymes and regulatory factors, including glucose-6-phosphate dehydrogenase, transketolase, and 6-phosphogluconate dehydrogenase. The activity of these enzymes is regulated by various mechanisms, including allosteric regulation and covalent modification

Phases of the HMP Shunt:

The HMP pathway can be divided into two phases: the oxidative phase and the non-oxidative phase.

The oxidative phase

In the oxidative phase, glucose-6-phosphate is converted to 6-phosphogluconolactone by the enzyme glucose-6-phosphate dehydrogenase, which consumes NADPH. 6-phosphogluconolactone is then converted to 6-phosphogluconate by the enzyme 6-phosphogluconate dehydrase, which also consumes NADPH. The primary role of the oxidative phase is the production of NADPH, which is used in a variety of reductive reactions in the cell.

Fig: Oxidative phase of Hexose Monophosphate (HMP) pathway

The non-oxidative phase

In the non-oxidative phase, 6-phosphogluconate is converted to ribulose 5-phosphate by the enzyme transketolase, which consumes a molecule of thiamine pyrophosphate (TPP). Ribulose 5-phosphate is then converted to xylulose 5-phosphate by the enzyme transaldolase, which also consumes a molecule of TPP. Xylulose 5-phosphate is then converted to ribose 5-phosphate by the enzyme xylulose 5-phosphate epimerase. The primary role of the non-oxidative phase is the production of ribose 5-phosphate, which is used in the synthesis of nucleic acids.

The HMP pathway can operate in either direction, depending on the needs of the cell. When the cell needs NADPH for reductive reactions, the pathway operates in the oxidative direction. When the cell needs ribose 5-phosphate for nucleic acid synthesis, the pathway operates in the non-oxidative direction.

Fig: Non-oxidative phase of Hexose Monophosphate (HMP) pathway

Significance:

The hexose monophosphate pathway plays a crucial role in maintaining the redox balance.
This pathway is activated in conditions of stress, such as oxidative stress or nutrient deprivation, when the cell needs to produce NADPH to protect itself against damage or to support biosynthetic reactions.
In addition to its role in the production of NADPH, the hexose monophosphate shunt also plays a role in the synthesis of ribose-5-phosphate, which is an important intermediate in the synthesis of DNA and RNA and many nucleotides like NADH, ATP, FADH₂, CoA etc. The pathway also generates intermediates that can be used for the synthesis of other biomolecules, including amino acids, cholesterol synthesis, steroid, lipid, fatty acid, and pigments.

Clinical Significance:

Dysregulation of the hexose monophosphate pathway has been linked to a variety of diseases, including diabetes, cancer, and autoimmune disorders. Here are some examples of the clinical significance of the hexose monophosphate shunt:

Diabetes: Dysregulation of the hexose monophosphate shunt has been linked to the development of diabetes. In particular, defects in the activity of the enzyme glucose-6-phosphate dehydrogenase, which is involved in the early steps of the pathway, have been associated with an increased risk of diabetes.
Cancer: The hexose monophosphate shunt has been implicated in the development of cancer. Some studies have suggested that the pathway may be activated in cancer cells to support the synthesis of nucleotides and other biomolecules needed for cell proliferation and survival.
Autoimmune disorders: Dysregulation of the hexose monophosphate shunt has been linked to the development of autoimmune disorders, such as systemic lupus erythematosus (SLE). In SLE, the activity of the enzyme transketolase, which is involved in the hexose monophosphate shunt, is increased, leading to the accumulation of certain intermediates in the pathway.
Oxidative stress: The hexose monophosphate shunt is activated in conditions of oxidative stress, when the cell needs to produce NADPH to protect itself against damage. Defects in the pathway may lead to an increased susceptibility to oxidative stress, which has been linked to a variety of diseases, including neurodegenerative disorders and cardiovascular disease.
Overall, understanding the mechanisms of regulation and function of the hexose monophosphate shunt may help in the development of therapeutic strategies for a range of diseases.

References:

David, L., Nelson, D.L., Cox, M.M., Stiedemann, L., McGlynn Jr, M.E. and Fay, M.R., 2000. Lehninger principles of biochemistry.
Satyanarayana, U., 2021. Biochemistry, 6e-E-book. Elsevier Health Sciences.
Guitton J, Servanin S, Francina A. Hexose monophosphate shunt activities in human erythrocytes during oxidative damage induced by hydrogen peroxide. Arch Toxicol. 2003 Jul;77(7):410-7
Aziz H, Mohiuddin SS. Biochemistry, Hexose Monophosphate Pathway. 2022 May 8. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan. Akram M, Ali Shah SM, Munir N, Daniyal M, Tahir IM, Mahmood Z, Irshad M, Akhlaq M, Sultana S, Zainab R. Hexose monophosphate shunt, the role of its metabolites and associated disorders: A review. J Cell Physiol. 2019 Jan 29.