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HMP pathway- Lecture-1
Characteristics of HMP pathway
1) All the reactions of this pathway take place in the cytosol.
2) It does not lead to formation of ATP but has two major functions: (a) The formation of NADPH for synthesis of fatty acids and steroids, and (b) the synthesis of ribose for nucleotide and nucleic acid formation.
3) HMP pathway is highly active in rapidly dividing cells and in tissues where there is a great requirement of NADPH.
4) Cells of the liver, adipose tissue, adrenal cortex, testis and lactating mammary gland have high levels of the PPP enzymes. In fact 30% of the oxidation of glucose in the liver occurs via the PPP.
5) Erythrocytes utilize the reactions of the PPP to generate large amounts of NADPH used in the maintenance of membrane integrity
6) In skeletal, muscle, this pathway is less active.
7) All the intermediates of this pathway are in the mono phosphate form contrary to glycolysis where bisphosphate forms of intermediates are also there.
Overview of HMP pathway
This pathway consists of two phases: the oxidative (irreversible) phase and the nonoxidative (reversible) phase.
1) In the oxidative phase, there is oxidative decarboxylation of Glucose-6-P to form NADPH and Ribulose 5-phosphate. Ribulose is further isomerized to form Ribose-5-P. This five-carbon sugar and its derivatives are components of RNA and DNA, as well as ATP, NADH, FAD, and coenzyme A.
2) In the nonoxidative phase, the pathway catalyzes the interconversion of three-, four-, five-, six-, and seven-carbon sugars in a series of nonoxidative reactions that can result in the synthesis of five-carbon sugars for nucleotide biosynthesis or the degradation of excess five-carbon sugars into intermediates of the glycolytic pathway.
Over view of HMP pathway
Figure-1- HMP pathway consists of two phases, oxidative phase that leads to formation of Ribose-5-P by oxidative decarboxylation and Non oxidative phase that involves rearrangement process with the resultant formation of glycolytic intermediates. Glyceraldehyde-3-P(GAP) and Fr-6-P are intermediates of glycolysis. In other words, the glycolytic intermediates can also rearrange to form Pentoses due to reversible nature of this phase and this holds true in skeletal muscle.
Difference between Glycolysis and HMP pathway
|Occurrence||All cells of the body||Active in liver, adipose tissue, adrenal cortex, thyroid, erythrocytes, testis, and lactating mammary glands.|
|Glucose Oxidation(Coenzyme)||Oxidation is achieved by dehydrogenation using NAD+ as the hydrogen acceptor.||Oxidation is achieved by dehydrogenation using NADP+ as the hydrogen acceptor.|
|CO2 production||CO2 is not produced||CO2 is produced|
|Pentose production||Pentoses are not produced||Pentoses are produced|
|Intermediates||Can be in the bisphosphate form- such as Fr 1,6 bisphosphate , 1,3 bisphosphoglycerate or 2,3 bisphosphoglycerate etc.||Never in bisphosphate form. Always in mono phosphate form that is why called Hexose mono phosphate pathway.|
|Energy||ATP is utilized as well as produced. ATP is a major product of glycolysis||ATP is neither utilized nor produced.Glycolytic intermediates may enter glycolytic pathway to produce energy|
|Biological Significance||Energy production both in aerobic and anaerobic conditions||NADPH is required for reductive biosynthesis and pentoses are required forsynthesis of coenzymes and nucleotides.|
|Clinical Significance||Hemolytic anemia in Pyruvate kinase and Hexokinase deficiency||Hemolytic anemia in Glucose-6-P dehydrogenase deficiency|
Reactions of HMP pathway
1) Oxidative Phase
- The oxidative phase of the pentose phosphate pathway starts with the dehydrogenation of glucose 6-phosphate at carbon 1, in a reaction catalyzed by glucose 6-phosphate dehydrogenase (Figure 2).
- Unlike glycolysis, oxidation is achieved by dehydrogenation using NADP+, not NAD+, as the hydrogen acceptor.
- This enzyme is highly specific for NADP+; the Km for NAD+ is about a thousand times as great as that for NADP+.
- The product is 6-phosphoglucono-δ-lactone, which is an intramolecular ester between the C-1 carboxyl group and the C-5 hydroxyl group.
- The next step is the hydrolysis of 6-phosphoglucono- δ -lactone, by a specific lactonase to give 6-phosphogluconate.
- This six-carbon sugar is then oxidatively decarboxylated by 6-phosphogluconate dehydrogenase to yield Ribulose 5-phosphate.
- NADP+ is again the electron acceptor.
- The final step in the synthesis of ribose 5-phosphate is the isomerization of Ribulose 5-phosphate by phosphopentose Isomerase (Figure-2)
Figure 2- Reactions of oxidative phase of HMP pathway. 2 molecules of NADPH and one of CO2 are produced in the oxidative phase. Glucose-6-P dehydrogenase is the key regulatory enzyme of this pathway.
The Nonoxidative Phase
Ribulose 5-phosphate is the substrate for two enzymes. Ribulose 5-phosphate 3-epimerase (Phosphopentose epimerase) alters the configuration about carbon 3, forming the epimer Xylulose 5-phosphate, also a ketopentose. (Figure 3)
Ribose 5-phosphate keto Isomerase (Phosphopentose isomerase) converts Ribulose 5-phosphate to the corresponding aldopentose, ribose 5-phosphate, which is the precursor of the ribose required for nucleotide and nucleic acid synthesis.(Figure 3)
Figure 3- Interconversion of pentoses. Ribulose-5-P is converted to by phosphopentose isomerase to form Ribose-5-P. It is aldose ketose isomerization. It is also converted to Xylulose-5-P by epimerization. The reaction is catalyzed by Phosphopentose epimerase.
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