HMP Shunt and Its Significance- Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

HMP Shunt

Pentose phosphate, also known as hexose monophosphate, is another essential body product created in this pathway. Rather than producing glycogen, ribose-5-phosphate and nicotinamide adenine dinucleotide phosphate (NADPH) are produced in a process called the HMP shunt. During this pathway, oxidative and non-oxidative phases take place, each of which includes a series of reactions. It is also known that enzyme or co-factor deficiencies can have potentially fatal consequences on patients who are affected by HMP shunts.

The HMP shunt is also referred to as the phospho-gluconate pathway or the pentose phosphate pathway. TCA cycle and glycolysis utilize this pathway. It is anabolic in nature because it involves NADPH synthesis and pentoses synthesis. Cellular cytosol contains enzymes responsible for HMP shunt. Highly glycolytic tissues, like skeletal muscle and non-lactating mammary gland, are not nearly as active as adrenal gland, liver, erythrocytes, testis, adipose tissue, and lactating mammary gland. NADPH is essential to most of them.

There are two phases in total for the reactions for HMP shunt such as oxidative and non-oxidative phase.

Phase of Oxidation:

The following are the steps in this phase:

• NADPH is formed when glucose 6phosphate is irreversibly oxidized by glucose 6-phosphate dehydrogenase.
• Hydrolysis of 6-phosphoconolactone by gluconolactone hydrolase yields 6-phosphogluconate irreversibly.
• 6phosphogluconate dehydrogenase reduces NADP to NADPH by oxidizing 6-phosphogluconate irreversibly to 3-keto-6-phosphate. Afterward, ribulose 5-phosphate is formed by decarboxylation of 3-keto-6-phosphogluconate.

Non-oxidative Phase:

• During the early part of this phase, ribulase is isomerized to ribose 5-phosphate, which is needed to synthesize nucleotides. Later, fructose 6-phosphate and glyceraldehyde 3-phosphate are formed from ribulose and ribose phosphate.
• It isomerizes ribulose 5-phosphate into ribose 5-phosphate using phospho-pentose isomerase.
• It is also responsible for isomerizing ribulose 5-phosphate into xylulose 5-phosphate with phospho-pentose 3-epimerase.
• The enzyme converts Xylulose 5-phosphate into glyceraldehyde 3-phosphate and sedoheptulose 7-phosphate by transferring the C2 group from a ketose (Xylulose 5-phosphate).
• In the process of trans-aldolase action, sedoheptulose (7-phosphate) is converted to erythrose 4-phosphate and fructose 6-phosphate, resulting in erythrose and fructose, respectively.
• In the reaction, transketolase converts erythrose 4-phosphate into glyceraldehyde 3-phosphate and fructose 6-phosphates by transferring carbons from another xylulose 5-phosphate.
• Two xylulose 5-phosphate molecules and three glucose 6-phosphate molecules are converted into one ribose 5-phosphate molecule and one glyceraldehyde 3-phosphate molecule.

Significance

• A unique pathway in the human body, HMP shunt generates important products, including pentose and NADPH, which are needed for biosynthetic reactions and for numerous other functions.
• In muscles requiring more energy, this pathway is less active, since it employs NADP+ instead of NAD+.
• By generating NADPH, the pathway generates electrons that are utilized in the synthesis of fatty acids, steroids, cholesterol, etc., so that the pathway is more active in the liver, testes, adipocytes, etc.
• In leucocytes, this pathway increases during phagocytosis, where NADPH is generated by NADPH oxidase that is used to produce superoxide radicals and destroy phagocytosed materials.
• It is glutathione reductase that is responsible for reducing oxidized glutathione by NADPH generated by this pathway in erythrocytes
• Incorporating ribose into nucleic acids and nucleotides through the pathway synthesis of ribose 5-phosphate.
• It is through this pathway that pentose (ribose and xylulose) is converted into glyceraldehyde 3-phosphate and fructose 6-phosphate for the following processes -- glycolysis or gluconeogenesis.
• As part of this pathway, xylulose 5-phosphate activates phosphoprotein phosphatase, thereby regulating glycolysis and gluconeogenesis.

Gluocse-6-phospahte (G6PD) Deficiency

Glucose-6-phosphate dehydrogenase deficiency, a genetic disorder of red blood cells, affects oxygen transport to the body's tissues. A deficiency in glucose-6-phosphate dehydrogenase results in premature breakdown of red blood cells in those with the condition. Hemolysis is the process of red blood cell destruction. Hemolytic anemia is caused by red blood cells being destroyed faster than they can be replaced, and is linked to glucose-6-phosphate dehydrogenase deficiency. An individual with this condition develops paleness, yellowish skin, whites of the eyes, dark urine, fatigue, rapid heartbeat, and shortness of breath.

Most commonly, hemolytic anemia is caused by infections or medications (such as antibiotics) when a person with glucose-6-phosphate dehydrogenase deficiency has glucose-6-phosphate dehydrogenase deficiency. As well as hemolytic anemia, the pollen from fava plants can cause a reaction known as favism. Jaundice in new born may also be caused by glucose-6-phosphate dehydrogenase deficiency. There are some people, however, who experience no signs or symptoms and are not aware that they suffer from this disorder.

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