8. What is the relevance of HMP shunt pathway in RBCs?

Pentose phosphate pathway (aka hexose monophosphate shunt or phosphogluconate pathway)

The pentose phosphate pathway is an alternative route for the metabolism of glucose. It does not lead
to formation of ATP but has two major functions: (1) the formation of NADPH for synthesis of fatty
acids and steroids, and maintaining reduced glutathione for antioxidant activity, and (2) the synthesis
of ribose for nucleotide and nucleic acid formation.
Like glycolysis, the enzymes of the pentose phosphate pathway are cytosolic and occurs in the
following organs: adipose tissue, testis, lactating mammary gland, adrenal cortex, liver, RBCs. Unlike
glycolysis, oxidation is achieved by dehydrogenation using NADP+, not NAD+, as the hydrogen
acceptor. The sequence of reactions of the pathway may be divided into two phases: an irreversible
oxidative phase and a reversible nonoxidative phase. In the first phase, glucose- 6-phosphate
undergoes dehydrogenation and decarboxylation to yield a pentose, ribulose-5-phosphate. In the
second phase, ribulose-5-phosphate is converted back to glucose-6-phosphate by a series of reactions
involving mainly two enzymes: transketolase and transaldolase

The Oxidative Phase Generates NADPH

Dehydrogenation of glucose-6-phosphate to 6-phosphogluconate occurs via the formation of 6phosphogluconolactone, catalyzed by glucose 6-phosphate dehydrogenase, an NADP-dependent
Enzyme. The hydrolysis of 6-phosphogluconolactone is accomplished by the enzyme gluconolactone
hydrolase. A second oxidative step is catalysed by 6-phosphogluconate dehydrogenase, which
also requires NADP+ as hydrogen acceptor. Decarboxylation follows with the formation of the
ketopentose ribulose-5-phosphate
The Nonoxidative Phase Generates Ribose Precursors
This reversible phase will convert Ribulose 5-phospate back to glucose 6-phosphate by a series of
reactions involving mainly 2 enzymes:
transketolase and transaldolase. Ribulose-5 phosphate
substrate for 2 enzymes: (1)Ribulose 5-phosphate 3-epimerase, which alters configuration about C3,
forming epimer xylulose 5-Phosphate and (2)Ribose 5-phosphate ketoisomerase which converts
ribulose 5-Phosphate (ketopentose) to ribose 5-phosphate (aldopentose). Ribose 5-phosphateused for nucleotide and Nucleic acid synthesis. End Products of this Reaction (with the help of
transkelolase and transaldolase dependent reactions) are Fructose 6-P (C6) which will be converted
into glucose 6-P by phosphohexose isomerase and Glyceraldehyde 3-P (C3) Converted into glucose 6-P
by fructose 1,6-bisphosphatase (a gluconeogenic enzyme). If lack of this enzyme, Glyceraldehyde 3-P
will follow normal glycolytic pathway, forming pyruvate.
The role of PPP in erythrocytes

(G-SH, reduced glutathione; G-S-S-G, oxidized glutathione; Se, selenium-containing enzyme.)

In red blood cells, the pentose phosphate pathway is the sole source of NADPH for the reduction of
oxidized glutathione catalyzed by glutathione reductase, a flavoprotein containing FAD. Reduced
glutathione removes H2O2 in a reaction catalysed by glutathione peroxidase, an enzyme that
contains the selenium analog of cysteine (selenocysteine) at the active site. The reaction is important
since accumulation of H2O2 may decrease the life span of the erythrocyte by causing oxidative
damage to the cell membrane, leading to hemolysis. In other tissues, NADPH can also be generated by
the reaction catalyzed by the malic enzyme.