Pentose Phosphate Pathway: Source of NADPH for Reductive Biosynthesis

Introduction to Pentose Phosphate Pathway
The pentose phosphate pathway (Hexose monophosphate pathway) is the metabolic pathway that occurs in the cytosol and generates NADPH that is utilized in various biosynthetic pathways. This pathway can be broadly classified into two categories i.e oxidative steps and non-oxidative steps. In the oxidative stage of pentose phosphate pathway, the glucose-6-phosphate is converted to five carbon ribulose-5 phosphate and generation of NADPH. During the non-oxidative stage, the interconversion of pentose sugars and hexose sugars are catalyzed by isomerases and aldolases. The fate of these reversible steps depends on the anabolic and energy status of the cells. The two main functions of the pentose phosphate pathway are
a) Provide NADPH for biosynthetic pathways
b) Provide pentose sugars for nucleotide synthesis

Oxidative Stage of Pentose Phosphate Pathway
The oxidative stage of pentose phosphate pathway is a stepwise oxidation-reduction reaction followed by decarboxylation.
-The first step of the pentose phosphate pathway is the conversion of glucose-6-phosphate to 6-phosphogluconolactone and generation of NADPH from NADP+. This oxidation-reduction coupled reaction is catalyzed by enzyme glucose-6-phosphate dehydrogenase (G6PD). G6PD is a rate-limiting enzyme of the pentose phosphate pathway.
-The second step is the hydrolysis of 6-phosphogluconolactone to 6-phosphogluconate catalyzed by enzyme gluconolactone hydrolase.
-The third enzyme 6-phosphogluconate dehydrogenase catalyzed an oxidation-reduction reaction of pentose phosphate pathway to yield 3-keto-6-phosphogluconate which is non-enzymatically decarboxylated to form ribulose-5-phosphate. During this conversion, the second NADPH is generated. Altogether, the conversion of glucose-6-phosphate to ribulose-6-phosphate yields two NADPH which is used for various biosynthetic and physiological processes of the cells.

Figure 1: Oxidative Stage of the Pentose Phosphate Pathway.

1) Glucose-6-phosphate dehydrogenase; 2) Gluconolactone hydrolase; 3) 6-phosphogluconate dehydrogenase; 4) nonenzymatic decarboxylation

Non-oxidative Stage of Pentose Phosphate pathway:
Once the ribulose-5-phosphate is formed, the series of reversible steps can result in the formation of six sugars. Transketolase and transaldolases are the enzymes that catalyze a series of reversible reaction to convert pentose sugar into fructose-6-phosphate which can again re-enter glycolysis or pentose phosphate pathway depending on the cellular demand of ATP and NADPH.
-First, the ribulose-5-phosphate is converted into xylulose 5-phosphate and ribose-5-phosphate catalyzed by enzyme 3-epimerase and keto-isomerase respectively.
-Second, the xylulose-5-phosphate and ribose-5-phosphate are converted into glyceraldehyde-3-phosphate and sedoheptulose by enzyme Transketolase. Transketolase is a thiamine contained enzyme that transfers 2 carbons from keto-sugars to aldo-sugar (or vice-versa).

Figure 2: Non-oxidative Stage of the Pentose Phosphate Pathway

-Third, the glyceraldehyde-3-phosphate and sedoheptulose are converted to fructose-6-phosphate and erythrose-4-phosphate catalyzed by enzyme Transaldolase. Transaldolase transfers 3 carbons from keto-sugar to aldo-sugar.
-Lastly, another 2 carbons from xylulose-5-phosphate (keto-sugar) to erythrose-4-phosphate to yield fructose-6-phosphate and glyceraldehyde.
Overall, three pentose sugars are utilized to form 2 fructose-6-phosphate and 1 glyceraldehyde-3-phosphate.

Cellular demand for ATP, NADPH, and pentose sugar modulate pentose phosphate pathway
-Scenario 1: When ribose-5-phosphate and NADPH are the prime need of the cells (especially dividing cells), most of the glucose-6-phosphate is converted into pentose sugar and NADPH. The oxidative reaction is most active during this state of cells.

-Scenario 2: When NADPH is required for other biosynthetic pathways, the pentose sugars are converted into fructose-6-phosphate which can be re-converted into glucose-6-P by glycolytic enzyme phosphoglucoisomerase. The glucose-6-phosphate thus formed re-enters into the pentose phosphate pathway. In this mode, one glucose-6-phosphate can generate 12 NADPH (please derive how !!!).

-Scenario 3: When NADPH and ATP are required (for example erythrocytes) 3 glucose-6-phosphate is converted into pentose phosphate pathway and generate 6 NADPH. The 3 pentose sugar formed during the oxidative stage is converted into 2 fructose-6-phosphate and 1 glyceraldehyde-3-phosphate. These can enter glycolysis to form additional ATPs and NADH.

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