Pentose Phosphate Pathway

 Pentose Phosphate Pathway 

Introduction

The pentose phosphate pathway, also called the phosphogluconate oxidative pathway, Warburg-Dickens-Lippmann path and the hexose monophosphate shunt (HMP Shunt) is a metabolic pathway parallel to Glycolysis. It generates  NADPH and pentoses (5-carbon sugars) as well as ribose 5-phosphate, a precursor for the synthesis of nucleotides. 

While the pentose phosphate pathway does involve oxidation of glucose, its primary role is anabolic rather than catabolic. This pathway takes place in liver, testis, mammary glands, adrenal cortex and white blood cells (leucocytes) but this pathway is especially important in red blood cells (erythrocytes).

Phases

There are two distinct phases in this pathway. The first is the oxidative phase, in which NADPH is generated, and the second is the non-oxidative synthesis of 5-carbon sugars. For most organisms, the pentose phosphate pathway takes place in the cytosol.

The primary results of the pathway are:

·         The generation of reducing equivalents, in the form of NADPH, used in reductive biosynthesis reactions within cells (e.g. fatty acid synthesis).

·         Production of ribose 5-phosphate (R5P), used in the synthesis of  nucleotides and nucleic acids.

·         Production of erythrose 4-phosphate (E4P) used in the synthesis of aromatic amino acids.

Dietary pentose sugars derived from the digestion of nucleic acids may be metabolized through the pentose phosphate pathway, and the carbon skeletons of dietary carbohydrates may be converted into glycolytic/gluconeogenic intermediates. The PPP is one of the three main ways the body creates molecules with reducing power, accounting for approximately 60% of NADPH production in humans.

One of the uses of NADPH in the cell is to prevent oxidative stress. It reduces glutathione via glutathione reductase, which converts reactive H₂O₂ into H₂O by glutathione peroxidase. If glutathione reductase is absent, the H₂O₂ would be converted to hydroxyl free radicals by Fenton chemistry, which can attack the cell.

Erythrocytes generate a large amount of NADPH through the pentose phosphate pathway to use in the reduction of glutathione. Hydrogen peroxide is also generated for phagocytes in a process often referred to as a respiratory burst.

Oxidative phase

In this phase, two molecules of NADP⁺ are reduced to NADPH, utilizing the energy from the conversion of glucose-6-phosphate into ribulose 5-phosphate.

The overall reaction for this process is-

Glucose 6-phosphate + 2 NADP⁺ + H₂O → ribulose 5-phosphate + 2 NADPH + 2 H⁺ + CO₂

Non-oxidative phase

The overall reaction for this process is

3 ribulose-5-phosphate → 1 ribose-5-phosphate + 2 xylulose-5-phosphate → 2 fructose-6-phosphate + glyceraldehyde-3-phosphate

Regulation

Glucose-6-phosphate dehydrogenase is the rate-controlling enzyme of this pathway. It is allosterically stimulated by NADP⁺ and strongly inhibited by NADPH. The ratio of NADPH: NADP⁺ is normally about 100:1 in liver cytosol^. This makes the cytosol a highly-reducing environment. An NADPH-utilizing pathway forms NADP⁺, which stimulates Glucose-6-phosphate dehydrogenase to produce more NADPH.

This step is also inhibited by acetyl CoA.G6PD activity is also post-translationally regulated by Cytoplasmic deacetylase SIRT2 where the substances move in the same direction. SIRT2-mediated deacetylation and activation of G6PD stimulates oxidative branch of PPP to supply cytosolic NADPH to counteract oxidative damage or support de novo lipogenesis.

Functions of Pentose Phosphate Pathway

1.     Synthesis of Pentose from hexoses (glucose or fructose)

2.     Synthesis of nucleotides through pentoses

3.     Glucose or fructose may be oxidized in this pathway too

4.     NADPH₂ formed in this pathway may be utilized in fat and steroid synthesis

5.     36 ATPs per molecule of glucose are produced in mitochondria through this pathway. This process is independent of Krebs’s Cycle.

6.     This pathway may produce glucoronic acid and Ascorbic acid (vitamin C)