Alternate Pathways to Carbohydrate Metabolism PDF

Alternate Pathways to Carbohydrate Metabolism Mahabubul Mowla Lecturer, DBB, USTC  Overview In addition to catabolism of glucose for the specific purpose of energy production in the form of ATP, several other pathways involving sugar metabolism exist in cel...

Alternate Pathways to Carbohydrate Metabolism Mahabubul Mowla Lecturer, DBB, USTC  Overview In addition to catabolism of glucose for the specific purpose of energy production in the form of ATP, several other pathways involving sugar metabolism exist in cells. One, the pentose phosphate pathway, known also as the hexose monophosphate shunt (HMP-shunt) or the 6-phosphogluconate pathway, is particularly important in animal cells.  Pentose Phosphate Pathway The Pentose Phosphate Pathway Has Two Phases: In the first stage, hexose is decarboxylated to pentose, followed by two oxidation reactions that lead to formation of NADPH. The pathway then continues and, by a series of transformations, six molecules of pentose undergo rearrangements to yield five molecules of hexose.  Oxidative Phase In this phase, NADPH is produced by the reduction of two molecules of NADP+. The energy for this production is utilised by the conversion of glucose-6-phosphate to ribulose-5-phosphate. The three steps of the oxidative phase of the HMP shunt are: 1. Glucose-6-phosphate is dehydrogenated to 6- phosphoglucono-δ-lactone in the presence of glucose 6- phosphate dehydrogenase. In this reaction, one molecule of NADP+ is converted into NADPH. 2. 6-phosphoglucono-δ-lactone is hydrolysed into 6- phosphogluconate in the presence of 6- phosphogluconolactonase. 3. 6-phosphogluconate is converted into ribulose 5- phosphate in the presence of 6-phosphogluconate dehydrogenase by oxidative decarboxylation. Pentose Phosphate Pathway  Non-oxidative Phase The non-oxidative phase can be summarised in five steps: 1. Ribulose-5-phosphate isomerises into ribose-5-phosphate in the presence of ribose-5-phosphate isomerase. 2. Another enzyme, phosphopentose epimerase, isomerises ribulose-5-phosphate into xylulose 5-phosphate at the same time. 3. Transketolase enzyme transfers a carbon group from ketose (xylulose-5-phosphate) to the aldose (ribose-5-phosphate), and the products obtained are glyceraldehyde 3-phosphate and sedoheptulose 7-phosphate. 4. Transaldolase again transfers a carbon group from sedoheptulose 7-phosphate (ketose) to glyceraldehyde 3-phosphate (aldose), and the products obtained are erythrose 4-phosphate and fructose 6-phosphate. 5. A carbon from xylulose 5-phosphate is transferred to erythrose 4-phosphate in the presence of transketolase to obtain glyceraldehyde 3-phosphate and fructose 6-phosphate. Interconversions of Pentose Phosphates Lead to Glycolytic Intermediates  Reaction of Transaldolase Transaldolase catalyzes a reaction similar to the aldolase reaction of glycolysis: a three-carbon fragment is removed from sedoheptulose 7-phosphate and condensed with glyceraldehyde 3-phosphate, forming fructose 6-phosphate and the tetrose erythrose 4-phosphate  Reaction of Transketolase Transketolase acts by forming fructose 6-phosphate and glyceraldehyde 3 phosphate from erythrose 4-phosphate and xylulose 5-phosphate Regulation of Pentose Phosphate Pathway When NADPH is forming faster than it is being used for biosynthesis and glutathione reduction, [NADPH] rises and inhibits the first enzyme in the pentose phosphate pathway. As a result, more glucose 6-phosphate is available for glycolysis.  Significance of HMP Shunt The HMP shunt pathway is significant because it provides important intermediated products for the synthesis of biomolecules. Some of the points of significance are: NADPH performs several functions in the body, such as: It takes part in the synthesis of steroids and fatty acids. It is an important component within phagolysosomes in the immune response. Glutathione is reduced by NADPH in the presence of glutathione reductase. This helps in quenching free oxygen radicals and peroxides from cells. Ribose-5-phosphate, which is used in the synthesis of nucleic acid and nucleotides, and erythrose-4-phosphate, which is used for the synthesis of aromatic amino acids. The glyceraldehyde 3-phosphate and fructose 6-phosphate produced in the pathway are intermediates for glycolysis and gluconeogenesis. Utilization of HMP-shunt intermediates NADPH formed in the oxidative phase is used to reduce glutathione, GSSG and to support reductive biosynthesis. The other product of the oxidative phase is ribose 5-phosphate, which serves as precursor for nucleotides, coenzymes, and nucleic acids. In cells that are not using ribose 5- phosphate for biosynthesis, the nonoxidative phase recycles six molecules of the pentose into five molecules of the hexose glucose 6- phosphate, allowing continued production of Deficiency of Glucose-6-phosphate Dehydrogenase (G6PD) G6PD deficiency is when the body is missing or doesn’t have enough of an enzyme called G6PD (glucose-6- phosphate dehydrogenase). This enzyme helps red blood cells work correctly. A lack of this enzyme can cause hemolytic anemia. This is when the red blood cells break down faster than they normally would. So instead of circulating for 90 days, the red blood cells are destroyed earlier. This results in a low number of red blood cells called anemia.  Causes of G6PD deficiency G6PD deficiency is inherited. It is caused by changes (mutations) to the G6PD gene. The gene is located on the X chromosome and is passed from parents to their children. Boys only get one copy of the X chromosome with the G6PD gene from their mothers, but girls get a copy from their mother and father. This makes girls less likely to have G6PD deficiency than boys because they have two sources of the enzyme.  Causes of G6PD deficiency G6PD deficiency is inherited. It is caused by changes (mutations) to the G6PD gene. The gene is located on the X chromosome and is passed from parents to their children. Boys only get one copy of the X chromosome with the G6PD gene from their mothers, but girls get a copy from their mother and father. This makes girls less likely to have G6PD deficiency than boys because they have two sources of the enzyme. Symptoms of G6PD deficiency Diagnosis & Treatment of G6PD Deficiency Healthcare provider can diagnose G6PD deficiency with a simple blood test. It may need this test if: Family comes from an area where this condition is common Have a family history of G6PD deficiency Have an unknown form of anemia Healthcare provider may repeat tests to make an accurate diagnosis. Treatment may include Prevention. Staying away from certain triggers that can set off hemolytic anemia, such as specific medicines, foods, and environmental exposures.These include: Aspirin, and products that have aspirin Certain antibiotics and antimalarial medicine Fava beans (develop favism which can cause severe hemolytic anemia) Moth balls (have a chemical called naphthalene)  Sorbitol Pathway Normally, glucose is processed by the glycolysis pathway and is utilized for ATP production and energy. When glucose levels become exorbitantly elevated, other pathways are upregulated to handle the glucose effectively The sorbitol or polyol pathway is a two-step metabolic pathway that converts glucose into fructose. This pathway is thought to play a prominent role in explaining the pathogenesis of complications in patients with end-stage diabetes.  Steps of Sorbitol Pathway The first step in the sorbitol pathway is the conversion of glucose to sorbitol via the enzyme aldolase reductase. This step utilizes a hydrogen group donated by NADPH. This is also the rate-limiting reaction of this entire pathway. The second step in this pathway is the conversion of sorbitol into fructose via the enzyme sorbitol dehydrogenase. This step donates a hydrogen group to NAD+, creating a byproduct of NADH. This step is reversible.  Function of Sorbitol Pathway Polyol pathway provide an alternate route of glucose metabolism when the high glucose levels overwhelm the primary glycolytic pathway. The polyol pathway also plays a prominent role in disrupting the redox balance of NADP+ and NADPH. Aldolase reductase utilizes an NADPH to drive the first step. This eventually results in a significant depletion of NADPH levels in the body. This decrease impairs several biochemical reactions. Glutathione reductase utilizes NADPH to alleviate the oxidative stress caused by free radicals in the human body. The second step in this pathway, requires NAD+ to drive the reaction forward. Sirtuins are histone deacetylases that are dependent on NAD+ for their function. The depletion of NAD+ impairs the sirtuin pathway, which is responsible for the deacetylation of proteins in the human body.  Sorbitol Pathway and Diabetes Mellitus The complications in a diabetic patient that can arise from the polyol pathway include lens swelling, osmotic imbalance, and peripheral neuropathy. The polyol flux is a key component in developing cataracts, especially in diabetic patients. The mechanism is likely due to the overproduction of free radicals and decreased ability to handle those radicals due to the suppressed glutathione reductase activity and the likely accumulation of sugar within the aqueous humor. Mechanisms for Complication Formation in Diabetic Patients Osmotic Hypothesis: Sorbitol and fructose are both membrane impermeable. In tissues without sorbitol dehydrogenase such as the retina, kidneys and Schwann cells, accumulation of sorbitol intracellularly draws fluid into the tissues leading to elevated osmotic stress. Metabolic flux hypothesis: There is a competition for NADPH between glutathione reductase and aldolase reductase. The depletion of NADPH and the surplus of NADH impaired several biochemical reactions such as lipid metabolism, growth factor formation, and protein kinase C activity.  Sorbitol Intolerance Sorbitol intolerance is a condition where the body has difficulty absorbing sorbitol, commonly used as a sweetener in sugar-free products. Symptoms include bloating, gas, diarrhea, and abdominal pain, which occur when sorbitol reaches the large intestine without being fully absorbed. Management typically involves limiting or avoiding sorbitol-containing foods and products. Individuals with irritable bowel syndrome (IBS) may be more susceptible to sorbitol intolerance.