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The Pentose Phosphate Pathway (also called Phosphogluconate Pathway, or Hexose Monophosphate Shunt) is an alternative pathway to glycolysis, in which NADP+ is the electron acceptor and NADPH is produced for the synthesis of fatty acids and steroids and the synthesis of a pentose sugar (ribose) for nucleotide and nucleic acid formation. It occurs in the cytosol. Tissues like the mammary gland, adrenal cortex, adipose tissue, and liver involved in lipid biosynthesis are rich in enzymes for the pentose phosphate pathway. 30% oxidation of glucose occurs in the liver via this pathway.
A variation of the pentose phosphate pathway called the Calvin cycle is used by plants to fix CO2 in Photosynthesis. The overall reaction of Hexose Monophosphate Shunt is&nbsp;
<img style="display: block; margin-left: auto; margin-right: auto;" src="https://vediphlie-aws.s3.ap-south-1.amazonaws.com/PENTOSE_PHOSPHATE_PATHWAY_bacc57fe97.PNG" alt="PENTOSE PHOSPHATE PATHWAY" />
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<img style="display: block; margin-left: auto; margin-right: auto;" src="https://vediphlie-aws.s3.ap-south-1.amazonaws.com/Pentose_Phosphate_pathway_c3b85a4367.PNG" alt="Pentose Phosphate pathway" />
The reactions of the pathway are divided into two phases. An oxidative non-reversible phase and a non-oxidative reversible phase. In an oxidative on reversible phase, glucose-6-phosphate undergoes dehydrogenation and decarboxylation to yield a pentose, ribulose-5-phosphate and In non-oxidative reversible phase, ribulose-5- phosphate is converted back to glucose-6-phosphate.&nbsp;
<h2 style="text-align: justify;">1. Oxidative Phase -</h2>
The oxidative phase of the pentose phosphate pathway is composed of three steps:-
Glucose 6 phosphates (G6P) the metabolite that arises through the action of Hexokinase on glucose or from glycogen is considered the starting point of the pentose phosphate pathway.
In oxidative on the reversible phase of the pathway oxidation and decarboxylation of glucose-6-phosphate occurs, producing the 5-C sugar ribulose-5-phosphate.
Glucose-6-phosphate Dehydrogenase is an NADP-dependent enzyme that catalyzes the dehydrogenation of glucose-6-phosphate, to 6-phosphogluconolactone. It catalyzes the net transfer of a hydride ion to NADP+&nbsp;from C1 of G-6-P to form 6-phosphogluconolactone. These enzymes are specific to NADP and are strongly inhibited by NADPH.
G6PD is the committed step in the Pentose Phosphate Pathway because 6‐Phosphoglucono‐lactone has no other metabolic fate except to be converted to 6‐phosphogluconate.
6-Phosphogluconolactonase hydrolysis of the ester linkage (lactone) resulting in ring-opening of and form product 6-phosphogluconate. Although ring opening occurs in the absence of a catalyst, 6-Phosphogluconolactonase speeds up the reaction, decreasing the lifetime of the highly reactive, and thus potentially toxic, 6-phosphogluconolactone.&nbsp;
Phosphogluconate Dehydrogenase catalyzes the oxidative decarboxylation of 6-phosphogluconate, to yield the 5-C ketose ribulose-5-phosphate. The hydroxyl at C3 (two Carbon of the product) is oxidized to a ketone. This promotes loss of the carboxyl at C1 as CO2. NADP+ again serves as an oxidant and NADPH is produced.
The net result is the oxidation of one carbon to CO2 and production of two moles of NADPH and the synthesis of a mole of pentose phosphate.
The overall reaction of oxidative phase is -&nbsp;
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<h2>2. Nonoxidative Phase -</h2>
In non-oxidative reversible phase recycling of pentose phosphates to glucose, 6-phosphate occurs. In this ribulose 5- phosphate is first epimerized to xylulose-5-phosphate: Enzymes used are Ribulose-5-phosphate Epimerase, Ribulose-5-phosphate Isomerase, Transketolase, and Transaldolase. Epimerase interconverts the stereoisomers ribulose-5-phosphate and xylulose-5-phosphate. Isomerase converts the ketose ribulose-5-phosphate to the aldose ribose-5-phosphate.
Both reactions involve deprotonation to form an enediolate intermediate, followed by specific deprotonation to yield the product. Both reactions are reversible. In a series of reactions six five-carbon sugars, phosphate converts to five-six carbon sugar-phosphate, and six molecules of CO2 have produced.&nbsp;
Unique enzymes to the pentose phosphate pathway activity in these interconversions of sugars: transketolase and transaldolase. Transketolase and Transaldolase catalyze the transfer of two carbon (2&ndash;C) and three carbon (3&ndash;C) molecular fragments respectively. Transketolase catalyzes the transfer of a two-carbon fragment from a ketose donor to an aldose acceptor i.e transfers a two-carbon fragment from xylulose-5-phosphate to either ribose-5-phosphate or + erythrose-4-phosphate. It utilizes as prosthetic group thiamine pyrophosphate (TPP), a derivative of vitamin B1. H readily dissociates from the C between N and S in the thiazolium ring of thiamine pyrophosphate.
Completion of the reaction is by reversal of these steps. The two-carbon fragment condenses with one of the aldoses erythrose-4-phosphate (4-C) or ribose-5-phosphate (5-C) to form a six-carbon or seven carbon ketose-phosphate product. Transfer of the two carbon fragments to the five-carbon aldose ribose-5-phosphate yields sedoheptulose-7- phosphate. Transfer instead to the four-carbon aldose erythrose-4-phosphate yields fructose-6-phosphate. Transaldolase catalyzes the transfer of a three-carbon dihydroxyacetone moiety, from sedoheptulose-7-phosphate to glyceraldehyde-3-phosphate. Aldol cleavage results in the release of erythrose-4-phosphate.
Completion of the reaction occurs by reversal, as the carbanion attacks instead the aldehyde carbon of the 3-carbon aldose glyceraldehyde-3-phosphate to yield the 6-carbon fructose-6-phosphate. The structure of E. coli Transaldolase, crystallized with a modified active-site intermediate. The structure of human Transaldolase has also been determined, and it exhibits a similar barrel structure.
The flow of intermediates containing 15 C atoms through Pentose Phosphate Pathway reactions by which 5-C sugars are converted to 3-C and 6-C sugars is summarized in the diagram at right and balance sheet below.&nbsp;
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Glucose-6-phosphate may be regenerated from either the 3 carbon product glyceraldehyde-3-phosphate or the 6 carbon product fructose-6-phosphate, via enzymes of Gluconeogenesis.
Depending on the relative needs of a cell for ribose-5-phosphate, NADPH, and ATP, the Pentose Phosphate Pathway can operate in various modes, to maximize different products. There are three major scenarios:-
1. Ribulose-5-phosphate may be converted to ribose-5-phosphate, a substrate for the synthesis of nucleotides and nucleic acids. The pathway also produces some NADPH.
2. Glyceraldehyde-3-phosphate and fructose-6-phosphate, formed from the 5-carbon sugar phosphates, may be converted to glucose-6-phosphate for re-entry into the linear portion of the Pentose Phosphate Pathway, maximizing the formation of NADPH.
3. Glyceraldehyde-3-phosphate and fructose-6-phosphate, formed from the 5-carbon sugar phosphates, may enter Glycolysis, for the synthesis of ATP. The pathway also produces some NADPH.
Ribose-1-phosphate generated during catabolism of nucleosides also enters the Glycolytic pathway in this way, after first being converted to ribose-5-phosphate. Thus the Pentose Phosphate Pathway serves as an entry into Glycolysis for both 5-carbon and 6-carbon sugars.
<h2 style="text-align: justify;">3. Regulation -</h2>
The first step of the phosphopeptide pathway is the irreversible committed step. This reaction is catalyzed by glucose6-phosphate dehydrogenase. This step is of course allosterically regulated. The product of this reaction NADPH is a strong inhibitor. So when the cytosol concentration of NADPH is high, the enzyme&rsquo;s activity is low. It is also allosterically regulated by fatty acid acyl esters of coenzyme A. The transcription of the gene for this enzyme is under hormonal regulation.&nbsp;
<img style="display: block; margin-left: auto; margin-right: auto;" src="https://vediphlie-aws.s3.ap-south-1.amazonaws.com/Regulation_of_pentose_phosphate_pathway_bc3c85804c.PNG" alt="Regulation of pentose phosphate pathway" />
Fig.: Regulation of pentose phosphate pathway
When erythrocytes are exposed to chemicals that generate high levels of superoxide radicals, GSH (Reduced Glutathione) is required to reduce these damaging compounds. Glutathione Peroxidase catalyzes the degradation of organic hydroperoxides by reduction, as two glutathione molecules are oxidized to a disulfide GSSG. The Pentose phosphate pathway is responsible for maintaining high levels of NADPH in red blood cells for use as a reductant in the glutathione reductase reaction. Regulation of the G6PD activity controls flux through the glycolytic pathway and pentose phosphate pathways.
The synthesis of glucose 6‐phosphate dehydrogenase is induced by the increased insulin/glucagon ratio after a high carbohydrate meal Insulin, which is secreted in response to hyperglycemia, induces the synthesis of G-6-P&nbsp;&nbsp;
<img style="display: block; margin-left: auto; margin-right: auto;" src="https://vediphlie-aws.s3.ap-south-1.amazonaws.com/Regulation_of_G6_PD_activity_through_glycolytic_and_pentose_phosphate_pathway_66d50c4828.PNG" alt="Regulation of G6PD activity through glycolytic and pentose phosphate pathway" />
Fig.: Regulation of G6PD activity through glycolytic and pentose phosphate pathway
dehydrogenase and 6‐phosphogluconate dehydrogenase increase the rate of glucose oxidation by pentose phosphate pathway ring fasting.
Mutations present in some populations cause a deficiency in glucose 6‐phosphate dehydrogenase, with consequent impairment of NADPH production. Detoxification of H2O2 is inhibited, and cellular damage results ‐ lipid peroxidation leads to erythrocyte membrane breakdown and hemolytic anemia.
Most G6PD deficient individuals are asymptomatic ‐ only in combination with certain environmental factors (sulfa antibiotics, herbicides, antimalarials, divicine) do clinical manifestations occur.

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The Pentose Phosphate Pathway also called Phosphogluconate Pathway or Hexose Monophosphate Shunt is an alternative pathway to glycolysis. 

Pentose Phosphate Pathway - Oxidative & Nonoxidative Phase, Regulation

The Pentose Phosphate Pathway also called Phosphogluconate Pathway or Hexose Monophosphate Shunt is an alternative pathway to glycolysis. In the Pentose Phosphate Pathway topic of Biochemistry; we will cover the oxidative phase of the pentose phosphate pathway, non-oxidative reversible phase recycling of pentose phosphates, Regulation of phosphopeptide pathway etc. 

Pentose Phosphate Pathway

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