The Hexose Monophosphate Shunt is also known as “Pentose Phosphate Pathway” (PPP). This is an alternative Glucose oxidation pathway. The hexose monophosphate pathway is used for the production of NADPH from NADP. The NADPH is required for biosynthetic reactions such as fatty acid synthesis, cholesterol synthesis, drug reduction, and as a cofactor for some non-synthetic enzymatic reactions. Hexose Monophosphate shunt is the alternative Glucose oxidative pathway.
In addition, it is used for the production of ribose for nucleotide and nucleic acid synthesis. The hexose monophosphate shunt also allows the entry of some carbohydrates into the glycolytic pathway (especially ribose, but also some others), and therefore acts as a connection route between different pathways.
- Glycolysis – Glucose Catabolic Pathway
- Citric acid cycle: Central metabolic cycle and its Significance
Steroidogenic tissues, red blood cells, and the liver are the major sites of the hexose monophosphate pathway. Muscle has small amounts of some of the Hexose Monophosphate Shunt enzymes, because it has little need for synthetic reactions, and therefore, little need for NADPH.
The muscle, however, like all tissues, needs to be able to synthesize Ribose in order to make nucleotides and nucleic acids.
The pentose phosphate pathway (also called “Phosphogluconate pathway” or “Hexose monophosphate Shunt”) occurs in the cytoplasm. It is a source of NADPH and ribose-5-Phosphate for nucleic acid biosynthesis. It has an oxidative phase (NADPH generation) and a non-oxidative (non-oxidative sugar interconversion).
Phases of Hexose Monophosphate Shunt
The pentose phosphate pathway occurs in the cytosol and can be divided into two phases:
- Oxidative phase: it generates NADPH.
- Non-oxidative phase: synthesize pentose-phosphate and other phosphate monosaccharides.
The oxidative portion of HMP shunt consists of 3 reactions that lead to the formation of Ribulose-5-Phosphate, Carbon dioxide and 2 molecules of NADPH, for each molecule of Glucose-6-Phosphate oxidized.
During the oxidative phase, from glucose-6-phosphate obtained by phosphorylation of the free glucose, NADPH finally obtained is formed pentose, ribulose 5-phosphate, why this metabolic process is called “the Pentose Monophosphate Pathway”.
Step 1: Dehydrogenation of Glucose – 6- Phosphate:
Glucose-6-Phosphate is converted into “6-Phospho Gluconate” in the presence of the enzyme, Glc-6-Phosphate dehydrogenase. In this reaction NADP+ act as a coenzyme. NADPH is a potent competitive inhibitor for the enzyme (Under some conditions).
- The first reaction is the oxidation of glucose 6-phosphate, carried out by the enzyme glucose-6-phosphate dehydrogenase. In this first step, the C1 group is dehydrogenated to give a group carboxyl, which, next to C5 forms a lactone, i.e. an ester intramolecular.
- It is here that two free hydrogen ions (proton) and two electrons are transferred to NADP+ which acts as electron acceptor being reduced to form the first molecule of NADPH; the remaining proton is released in the middle.
Step 2: Formation of Ribulose-5-Phosphate:
6-Phospho Gluconate is converted into Ribulose-5-Phosphate by eliminating CO2 from Carbon one of Glucose, in the presence of the enzyme 6-Phosphogluconate dehydrogenase.
- Then, it produces Lactone by hydrolysis and by the action of the lactonase, whereby the free acid is obtained 6-phosphogluconate.
- Then, the latter becomes ribulose-5-phosphate by the action of 6-phosphogluconate dehydrogenase.
- Here NADPH second molecule is obtained, in addition to the release of a molecule of CO 2 because of the oxidative decarboxylation.
- Finally, the enzyme pentose-5-phosphate isomerase, by an intermediary enediol, isomerizes the ribulose 5-phosphate and converts ribose-5-phosphate to the transformation of the group ketose in aldose.
- This latter reaction prepares a central component nucleotide synthesis for the biosynthesis of RNA, DNA and nucleotide cofactors. At the same time, it carries out the transition to the non-oxidative metabolic phase of the pentose phosphate pathway.
It ends thus obtaining two NADPH molecules which, besides their use in reductive biosynthesis, is also responsible for maintaining a reducing environment within the cell. This can be seen if there is a deficit of glucose-6-phosphate dehydrogenase, produced by a defect in a gene located on the X chromosome, which may affect more proportion to men.
The general reaction to this first phase is:
Glucose-6-phosphate + 2 NADP + + H 2 O
→ ribulose-5-phosphate + 2 NADPH + 2 H + + CO 2
The non-oxidative reaction of pentose phosphate pathway catalyzes the inter-conversion of 3, 4, 5 and 7- carbon sugars. The non-oxidative phase of the pentose phosphate pathway is initiated when the cell needs more NADPH than ribose-5-phosphate. In this second process are a complex sequence of reactions that let you change the C3, C4, C5, C6 and C7 pentose sugars to form finally glyceraldehyde-3-phosphate and fructose 6-phosphate, which can go directly to glycolysis.
Step 1: Epimerization of ribulose-5-P into Xylulose-5-P:
Ribulose-5-Phosphate is converted into Xylulose-5-Phosphate; in the presence of the enzyme “Phosphopento epimerase” this reaction is one of the examples to Epimerization. This phase includes a series of reversible reactions, the direction of which depends on the availability of substrate. Also, the isomerization of ribulose-5-phosphate to ribose-5-phosphate is also reversible.
Step 2: Isomerization of Ribulose-5-Phosphate to Ribose-5-Phosphate:
Ribulose-5-Phosphate is isomerized into Ribose-5-Phosphate by the enzyme “Phosphopentose isomerase”. This enables us to eliminate excess ribose-5-phosphate to finish transforming it into intermediates of glycolysis.
Step 3: Epimerization of Ribulose – 5- Phosphate to Xylulose-5-Phosphate :
The final product of oxidative reactions Ribulose-5-Phosphate is epimerized into Xylulose-5-Phosphate. This reaction proceeds by the utilization of the second glucose molecule. This reaction is catalyzed by “Phosphopentose Epimerase”.
The reaction is carried out epimerization, regulated by the pentose-5-phosphate epimerase enzyme, which converts the ribulose-5-phosphate, a product of the oxidative phase, xylulose-5-phosphate, thereby generating the necessary substrate for controlled by the following reaction transketolase, which acts together with coenzyme Thiamine Pyrophosphate (TPP).
Step 4: Transketolation:
When the Ribose-5-Phosphate reacts with Xylulose-5-Phosphate. It gives Sedoheptulose-7-Phosphate and Glyceraldehyde-3-Phosphate by the enzyme Transketolase. Here TPP (Thiamine Pyrophosphate) acts as a Co-enzyme. In this reaction first and second carbons of Xylulose-5-Phosphate. Simply this is a 2 carbon shifting mechanism.
This will convert Xylulose 5-phosphate into Ribose-5-phosphate and, by transferring unit C2 of the aldose to ketose, will produce glyceraldehyde-3-phosphate and sedoheptulose-7-phosphate.
Step 5: Transaldolation:
When Sedoheptulose-7-Phosphate reacts with Glyceraldehyde-3-Phosphate; it gives 4 carbon compound – Erythrose-4-Phosphate and 6 carbon compound Fructose-6-Phosphate. This reaction is catalyzed by the enzyme Transaldolase, In this reaction, the first 3 carbons of Sedoheptulose-7-Phosphate is shifted to the aldehyde group of the Glyceraldehyde-3-Phosphate. Simply this is a 3 carbon shifting mechanism.
Finally, the transaldolase, with the help of a rest Lysine in the active site, transfers a unit C3 sedoheptulose-7-phosphate to glyceraldehyde-3-phosphate, which will form the tetrose Erythrose-4-phosphate, in addition of one of the first end products: fructose 6-phosphate, which is directed towards glycolysis.
Step 6: Transketolation:
When the Erythrose-4-Phosphate reacts with Fructose-6-Phosphate gives Xylulose-5-Phosphate and Glyceraldehyde-3-Phosphate. This reaction is catalyzed by “Transketolase”. This is TPP dependent enzyme.
Then, again Transketolase enzyme transferring a C2 unit, from Xylulose-5-phosphate to Erythrose-4-phosphate, thus form another molecule of Fructose 6-phosphate and Glyceraldehyde-3-phosphate, both are intermediates of glycolysis. Thus, the phase of this non-oxidative metabolic pathway is closed.
This stage of the route will connect the metabolic processes that generate NADPH with originating NADH/ATP. Furthermore, glyceraldehyde-3-phosphate and fructose 6-phosphate may be involved instead of the glycolysis, in gluconeogenesis to form a new glucose synthesis.
The significance of HMP Shunt
Producing NADPH + H+
- Hexose Monophosphate Shunt producing Biochemical reductant NADPH + H+. This reductant participating in the reductive anabolic pathway. Especially in Fatty acid Biosynthesis
- NADPH involves in Glutathione Reductase catalysis. This enzyme neutralizes the superoxide and hydroxyl radicals from hydroxyl peroxide molecules.
- The NADPH is one of the important coenzymes for the microsomal for the liver microsomal, Cytochrome-P450 Mono-Oxygenase system. This is the major pathway for the hydroxylation of Aromatic and Aliphatic compounds such as Steroid alcohols and many drugs.
- In Phagocytosis mechanism, NADPH + H+ is very important in Respiratory Burst.
- Ribose-5-Phosphate is the precursor molecule for nucleotide synthesis. The concentration of Ribose-5-Phosphate is optimized by the enzyme Glucose-6-Phosphate dehydrogenase in HMP shunt.
- Hexose MonoPhosphate shunt provides Ribose-5-Phosphate for the Purine biosynthesis by the level of Ribose-5-Phosphate is regulated by Glucose-6-Phosphodehydrogenase.
Producing Glycolytic Intermediate
- In the Hexose Monophosphate Shunt Pathway, few molecules of Glycolytic intermediates are produced these are directly involved in Glycolysis. The molecules are Glyceraldehyde-3-Phosphate and Fructose-6-Phosphate.