Pentose Phosphate Pathway

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The pentose phosphate pathway is the major source for the NADPH required for anabolic processes. There are three distinct phases each of which has a distinct outcome. Depending on the needs of the organism the metabolites of that outcome can be fed into many other pathways. Gluconeogenesis is directly connected to the pentose phosphate pathway. As the need for glucose-6-phosphate (the beginning metabolite in the pentose phosphate pathway) increases so does the activity of gluconeogenesis.

Introduction

The main molecule in the body that makes anabolic processes possible is NADPH. Because of the structure of this molecule it readily donates hydrogen ions to metabolites thus reducing them and making them available for energy harvest at a later time. The PPP is the main source of synthesis for NADPH. The pentose phosphate pathway (PPP) is also responsible for the production of Ribose-5-phosphate which is an important part of nucleic acids. Finally the PPP can also be used to produce glyceraldehyde-3-phosphate which can then be fed into the TCA and ETC cycles allowing for the harvest of energy. Depending on the needs of the cell certain enzymes can be regulated and thus increasing or decreasing the production of desired metabolites. The enzymes reasonable for catalyzing the steps of the PPP are found most abundantly in the liver (the major site of gluconeogenesis) more specifically in the cytosol. The cytosol is where fatty acid synthesis takes place which is a NADPH dependent process.

Oxidation Phase

The beginning molecule for the PPP is glucose-6-P which is the second intermediate metabolite in glycolysis. Glucose-6-P is oxidized in the presence of glucose-6-P dehydrogenase and NADP⁺. This step is irreversible and is highly regulated. NADPH and fatty acyl-CoA are strong negative inhibitors to this enzyme. The purpose of this is to decrease production of NADPH when concentrations are high or the synthesis of fatty acids is no longer necessary.
The metabolic product of this step is gluconolactone which is hydrolytrically unstable. Gluconolactonase causes gluconolactone to undergo a ring opening hydrolysis. The product of this reaction is the more stable sugar acid, 6-phospho-D-gluconate.
6-phospho-D-gluconate is oxidized by NADP⁺in the presence of 6-phosphogluconate dehydrogenase which yields ribulose-5-phosphate.
The oxidation phase of the PPP is solely responsible for the production of the NADPH to be used in anabolic processes.

Isomerization Phase

Ribulose-5-phosphate can then be isomerized by phosphopentose isomerase to produce ribose-5-phosphate. Ribose-5-phosphate is one of the main building blocks of nucleic acids and the PPP is the primary source of production of ribose-5-phosphate.
If production of ribose-5-phosphate exceeds the needs of required ribose-5-phosphate in the organism, then phosphopentose epimerase catalyzes a chiralty rearrangement about the center carbon creating xylulose-5-phosphate.
The products of these two reactions can then be rearranged to produce many different length carbon chains. These different length carbon chains have a variety of metabolic fates.

Rearrangement Phase

There are two main classes of enzymes responsible for the rearrangement and synthesis of the different length carbon chain molecules. These are transketolase and transaldolase.
Transketolase is responsible for the cleaving of a two carbon unit from xylulose-5-P and adding that two carbon unit to ribose-5-P thus resulting in glyceraldehyde-3-P and sedoheptulose-7-P.
Transketolase is also responsible for the cleaving of a two carbon unit from xylulose-5-P and adding that two carbon unit to erythrose-4-P resulting in glyceraldehyde-3-P and fructose-6-P.
Transaldolase is responsible for cleaving the three carbon unit from sedoheptulose-7-P and adding that three carbon unit to glyceraldehyde-3-P thus resulting in erythrose-4-P and fructose-6-P.
The end results of the rearrangement phase is a variety of different length sugars which can be fed into many other metabolic processes. For example, fructose-6-P is a key intermediate of glycolysis as well as glyceraldehyde-3-P.

References

Garrett, H., Reginald and Charles Grisham. Biochemistry. Boston: Twayne Publishers, 2008.
Raven, Peter. Biology. Boston: Twayne Publishers, 2005.

Problems

Where does the PPP take place and why there?
The PPP has three main phases, what are the outcomes of those phases?
What is Ribose-5-phosphate and why is it important?
In the isomerization phase of the PPP there are two enzymes that catalyze two different reactions. How are the out comes of these two reactions different? (Hint: What is being changed in these reactions?)
Name all eight enzymes in the PPP and briefly describe the processes.

Contributors

Darik Benson, University California Davis