Tuesday, 28 October 2014

HMP pathway or Hexose Monophosphate Pathway or Pentose Phosphate Pathway

(Hexose monophosphate pathway)
(Pentose phosphate pathway)

·        Minor metabolic pathway of carbohydrates, it is also known as pentose phosphate pathway.
·        Glucose shunted through this pathway instead of going through the glycolytic pathway, so it is known as the shunt pathway.
·         In the glycolysis there are a few biphosphate intermediate but in this pathway there is monophosphate only hence this is called hexose monophosphate pathway.
·        About 10% of glucose molecules per day are entering in this pathway.
·         The liver and RBCs metabolise about 30% of glucose by this way.

Function of HMP
·       The major purpose of this pathway is generation of reduced NADPH and pentose phosphates for nucleotide synthesis.

Overview of the shunt pathway

The HMP shunt pathway has oxidative and non-oxidative phases. During the oxidative phase, glucose-6-phosphate is oxidized with the generation of 2 molecules of NADPH, and one molecule of pentose phosphate, with the liberation of one molecule of CO2. During the non-oxidative phase, the pentose phosphate is converted to intermediates of glycolysis.

A.    Oxidative phase

Step 1 of HMP phase
Glucose-6-phosphate is oxidized by NADP+ to produce 6-phosphoglucono lactone; the enzyme is glucose-6- phosphate dehydrogenase.
One molecule of NADPH is formed in the reaction.
Regulation is effected by this enzyme.

Step 2 of HMP phase
The lactone is hydrolyzed by lactonase to form 6-phosphogluconate. 

Step 3 of HMP phase
This is an oxidative step coupled with decarboxylation.
The enzyme is 6- phosphogluconate dehydrogenase.
Ribulose 5 phosphate is formed and a second molecule of NADPH is generated. 

B.    Non oxidative phase

Step 4: Isomerisation
The ribulose-5- phosphate is then isomerised to ribose-5 phosphate or epimerised to Xylulose-5-phosphate.

Step 5: Transketolase reaction
Transketolase is a thiamine pyrophosphate (TPP) enzyme.  It transfere two carbon unit with keto group from Xylulose-5 phosphate to ribose-5-phosphate to form 3 caron (glyceraldehyde-3-phosphate) and 7 carbon (sedoheptulose-7 phosphate).

Step 6: Transaldolase reaction
This reaction involves transfere of a 3 carbon unit from sedoheptulose-7-phostate to glyceraldehyde-3-phosphate to form fructose-6-phosphate.

Step 7: second transketolase reaction
In another transketolase reaction a 2C unit is transferred from Xylulose-5- phosphate to erythrose-4-phosphate to form fructose-6- phosphate and glyceraldehyde-3-phosphate.

Step 8: regeneration of glucose -6- phosphate
Two molecules of glyceraldehyde-3-phsphate formed in step 7 are condensed to form one fructose-6-phosphate 
Fructose-6-phosphate is then converted to glucose-6-phosphate (reversal of step 2 of glycolysis).

Importance of HMP

1-    It provides a way for oxidation of glucose by a mechanism other than CAC with no production of energy.
2-    It provides the cell with ribose-5-phosphate which is needed for nucleotides, nucleosides, nucleic acids and coenzymes biosynthesis.
3-    It is the main generator of reduced NADPH which is needed in reductive biosynthesis.
·         Synthesis of fatty acids, cholesterol, steroid hormones.
·         Hydroxylation of metabolic reactions as in tryptophan and phenylalanine metabolism.

Importance in RBCs
Red blood cells are liable for oxidative damage by H2O2 due to their role in O2 transport.
In RBCs H2O2 causes both oXidation of iron in hemoglobin to form methemoglobin and lipid peroxidation.
The major role of HMP in red blood cells is the production of NADPH, which protect these cells from oxidative damage by providing reduced glutathione for removal of H2O2.

Enzymes that catalyze antioxidant reactions:
Reduced glutathione, a tripeptide- thiol (glutamyl-cysteinyl-glycine) present in most cells, can chemically detoxify hedrogen peroxide. 
This reaction catalysed by glutathione peroxidase, forms oxidized glutathione.
The cell regenerates reduced glutathione in a reaction catalyzed by glutathione reductase using NADPH as a source of reducing electrons. Thus, NADPH indirectly provides electrons for the reduction of hydrogen peroxide. 
·        Hydrogen peroxide is one of a family of reactive oxygen intermediates that are formed from the partial reduction of molecular oxygen.
·        They are highly reactive and can cause serious chemical damage to DNA, proteins and unsaturated lipids.
·        Reactive oxygen intermediates have been implicated in a number of pathogenic processes, including cancer, inflammatory disease and aging.


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