Thursday 16 February 2012

HMP Pathway

Pentose phosphate pathway


The Pentose Phosphate Pathway

The pentose phosphate pathway (also called the phosphogluconate pathway and the hexose monophosphate shunt) is a process that generates NADPH and pentoses (5-carbon sugars). There are two distinct phases in the pathway. The first is the oxidative phase, in which NADPH is generated, and the second is the non-oxidative synthesis of 5-carbon sugars. This pathway is an alternative to glycolysis. While it does involve oxidation of glucose, its primary role is anabolic rather than catabolic. For most organisms, it takes place in the cytosol; in plants, most steps take place in plastids.

 Outcome

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.

Aromatic amino acids, in turn, are precursors for many biosynthetic pathways, notably including the lignin in wood.

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.

In mammals, the PPP occurs exclusively in the cytoplasm, and is found to be most active in the liver, mammary gland and adrenal cortex in the human. However, the pathway is absent in skeletal muscle tissue. 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 absent, the H2O2 would be converted to hydroxyl free radicals by Fenton chemistry, which can attack the cell.

In a significant step, erythrocytes generate, through the pentose phosphate pathway, a large amount of NADPH used in the reduction of glutathione.

Hydrogen peroxide is also generated for phagocytes in a process often referred to as a respiratory burst.
 Phases
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.

Oxidative phase of pentose phosphate pathway. glucose-6-phosphate (1), 6-phosphoglucono-δ-lactone (2), 6-phosphogluconate (3), ribulose 5-phosphate (4).

The entire set of reactions can be summarized as follows:
Reactants     Products     Enzyme     Description
Glucose 6-phosphate + NADP+     → 6-phosphoglucono-δ-lactone + NADPH     glucose 6-phosphate dehydrogenase     Dehydrogenation. The hemiacetal hydroxyl group located on carbon 1 of glucose 6-phosphate is converted into a carbonyl group, generating a lactone, and, in the process, NADPH is generated.
6-phosphoglucono-δ-lactone + H2O     → 6-phosphogluconate + H+     6-phosphogluconolactonase     Hydrolysis
6-phosphogluconate + NADP+     → ribulose 5-phosphate + NADPH + CO2     6-phosphogluconate dehydrogenase     Oxidative decarboxylation. NADP+ is the electron acceptor, generating another molecule of NADPH, a CO2, and 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 pentose phosphate pathway's Nonoxidative phase (incorrect structure of ribose5P)


Reactants     Products     Enzymes
ribulose 5-phosphate     → ribose 5-phosphate     Ribulose 5-Phosphate Isomerase
ribulose 5-phosphate     → xylulose 5-phosphate     Ribulose 5-Phosphate 3-Epimerase
xylulose 5-phosphate + ribose 5-phosphate     → glyceraldehyde 3-phosphate + sedoheptulose 7-phosphate     transketolase
sedoheptulose 7-phosphate + glyceraldehyde 3-phosphate     → erythrose 4-phosphate + fructose 6-phosphate     transaldolase
xylulose 5-phosphate + erythrose 4-phosphate     → glyceraldehyde 3-phosphate + fructose 6-phosphate     transketolase

Net reaction: 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+. 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.

 
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