Hexose monophosphate shunt | Online Biotech Notes

Hexose Monophosphate Shunt

The Hexose monophosphate pathway or HMP shunt is also called the pentose phosphate pathway or phosphogluconate pathway. This is an alternative pathway to glycolysis and the TCA cycle for the oxidation of glucose. However, HMP shunt is more anabolic, in nature since it is concerned with the biosynthesis of NADPH and pentoses.

HMP shunt—a unique multifunctional pathway

The pathway starts with glucose 6-phosphate. As such, no ATP is directly utilized or produced in the HMP pathway. It is a unique multifunctional pathway, since there are several interconvertible substances produced which may proceed in different directions in the metabolic reactions.

Location of the pathway

The enzymes of HMP shunt are located in the Cytosol. The tissues such as the liver, dipose tissue, adrenal gland, erythrocytes, testes, and lactating mammary gland, are highly active in HMP shunt. Most of these tissues are involved in the biosynthesis of fatty acids and steroids which are dependent on the supply of NADPH.

Reactions of the pathway

The sequence of reactions of HMP shunt (Fig.13.20) is divided into two phases:-

oxidative and non-oxidative.

Hexose Monophosphate Shunt

1. Oxidative phase: 

Glucose 6-phosphate dehydrogenase (G6PD) is an NADP-dependent enzyme that converts glucose 6-phosphate to 6-phosphogluconolactone. The latter is then hydrolysed by the gluconolactone hydrolase to 6-phosphogluconate. The next reaction involving the synthesis of NADPH is catalysed by a 6-phosphogluconate dehydrogenase to produce 3 keto 6-phosphogluconate which then undergoes decarboxylation to give ribulose 5-phosphate.

G6PD regulates HMP shunt.

The first reaction catalysed by G6PD is most regulatory in HMP shunt. This enzyme catalyses an irreversible reaction. NADPH competitively inhibits G6PD. It is the ratio of NADPH/NAD+ that ultimately determines the flux of this cycle.

2. Non-oxidative phase: 

The non-oxidative reactions are concerned with the interconversion of three, four, five, and seven carbon monosaccharides.

Ribulose 5-phosphate is acted upon by an epimerase to produce xylulose 5-phosphate while ribose 5-phosphate ketoisomerase converts ribulose 5-phosphate to ribose 5-phosphate.

The enzyme transketolase catalyses the transfer of two carbon moiety from xylulose 5-phosphate to ribose 5-phosphate to give a 3-carbon glyceraldehyde 3-phosphate and a 7-carbon sedoheptulose 7-phosphate. Transketolase is dependent on the coenzyme thiamine pyrophosphate (TPP) and Mg2+ ions.

Transaldolase brings about the transfer of a 3-carbon fragment (active dihydroxyacetone) from sedoheptulose 7-phosphate to glyceraldehyde 3- phosphate to give fructose 6-phosphate and four carbon erythrose 4-phosphate.

Transketolase acts on xylulose 5-phosphate and transfers a 2-carbon fragment (glyceraldehyde) from it to erythrose 4-phosphate to generate fructose 6-

phosphate and glyceraldehyde 3-phosphate.

Fructose 6-phosphate and glyceraldehyde 3-phosphate can be further catabolized through glycolysis and the citric acid cycle. Glucose may also be synthesized from these two compounds.

For the complete oxidation of glucose 6-phosphate to 6CO2, we have to start with 6 molecules of glucose 6-phosphate. Of these 6, 5 moles are regenerated with the production of 12 NADPH.

The overall reaction may be represented as

6Glucose 6phosphate + 12 NADP+  + 6 H20 --->  6Co2 + 12NADPH + 12H+ + Glucose 6- phosphate.

Significance of HMP shunt

HMP shunt is unique in generating two important products—pentoses and NADPH— needed for the biosynthetic reactions and other functions.

Importance of pentoses

In the HMP shunt, hexoses are converted into pentoses, the most important being ribose 5-phosphate. This pentose or its derivatives are useful for the synthesis of nucleic acids (RNA and DNA) and many nucleotides such as ATP, NAD+, FAD, and CoA.

Skeletal muscle is capable of synthesizing pentoses, although only the first few enzymes of HMP shunt are active. It, therefore, appears that the complete pathway of HMP shunt may not be required for the synthesis of pentoses.

Importance of NADPH

1. NADPH is required for the reductive biosynthesis of fatty acids and steroids, hence HMP shunt is more active in the tissues concerned with lipogenesis, e.g. adipose tissue, liver, etc.

2. NADPH is used in the synthesis of certain amino acids involving the enzyme

glutamate dehydrogenase.

3. There is a continuous production of H2O2 in the living cells which can chemically damage unsaturated lipids, proteins, and DNA. This is, however, prevented to a large extent through antioxidant (free radical scavenging) reactions involving NADPH. Glutathione mediated reduction of H2O2 is

given in the next column.

Glutathione (reduced, GSH) detoxifies H2O2, peroxidase catalyses this reaction. NADPH is responsible for the regeneration of reduced glutathione from the oxidized one.

4. Microsomal cytochrome P450 system (in the liver) brings about the detoxification of drugs and foreign compounds by hydroxylation reactions involving NADPH.

5. Phagocytosis is the engulfment of foreign particles, including microorganisms, carried out by white blood cells. The process requires the supply of NADPH.

6. Special functions of NADPH in RBC: NADPH produced in erythrocytes has special functions to perform. It maintains the concentration of reduced glutathione (reaction explained in 3) which is essentially required to preserve the integrity of the RBC membrane. NADPH is also necessary to keep the ferrous iron (Fe2+) of hemoglobin in a reduced state so that accumulation of methemoglobin (Fe3+) is prevented.

7. High concentration of NADPH in the lens of the eyes is necessary to preserve the transparency of the lenses.

Glucose 6-phosphate dehydrogenase deficiency

G6PD deficiency is an inherited sex-linked trait. Although the deficiency occurs in all the cells of the affected individuals, it is more severe in RBC. HMP shunt is the only means of providing NADPH in the erythrocytes.

Decreased activity of G6PD impairs the synthesis of NADPH in RBC. This results in the accumulation of methemoglobin and peroxides in erythrocytes leading to hemolysis.

Clinical manifestations in G6PD deficiency

Most of the patients with G6PD deficiency do not usually exhibit clinical symptoms. Some of them, however, develop hemolytic anemia if they are administered oxidant drugs or exposed to a severe infection. The drugs such as primaquine (antimalarial), acetanilide (antipyretic), sulfamethoxazole (antibiotic), or ingestion of fava beans (favism) produce hemolytic jaundice in these patients.

Severe infection results in the generation of free radicals (in macrophages)

which can enter RBC and cause hemolysis (due to decreased NADPH and reduced GSH).

G6PD deficiency and resistance to malaria

It is interesting to note that G6PD deficiency is associated with resistance to malaria (caused by Plasmodium falciparum). This is explained by the fact that the parasites that cause malaria are dependent on HMP shunt and reduced glutathione for their optimum growth in RBC. Therefore, G6PD deficiency—which is seen frequently in Africans—protects them from malaria, a common disease in this region. It is regarded as an adaptability of the people living in malaria-infected regions of the world.

Biochemical diagnosis can be done by detecting the reduced activity of G6PD in RBC. The management of G6PD deficiency includes avoiding oxidative stress and symptomatic treatment of hemolysis.

Wernicke-Korsakoff syndrome

This is a genetic disorder associated with HMP shunt. An alteration in transketolase activity that reduces its affinity (by tenfold or so) with thiamine pyrophosphate is the biochemical lesion. The symptoms of Wernicke-Korsakoff syndrome include mental disorder, loss of memory, and partial paralysis. The symptoms are manifested in vitamin-deficient alcoholics.

Related Topics:

• Glycolysis