Pentose phosphate pathway (PPP) or hexose monophosphate pathway (HMPP)

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Presentation transcript:

Pentose phosphate pathway (PPP) or hexose monophosphate pathway (HMPP) Ferchmin 2019 Pentose phosphate pathway (PPP) or hexose monophosphate pathway (HMPP) Index by slide numbers 3) Pathway description 4) NAD+ and NADP 5) Oxidative step of PPP 6) Glucose-6-Phosphate Dehydrogenase Deficiency 7) Nonoxidative step of PPP 8) Regulation of PPP 9) Function of PPP 10-13) Glutathione, and its role as antioxidant. Selenocystein The pentose phosphate pathway (PPP) or the hexose monophosphate pathway (HMPP) consists of reactions in which G6P is metabolized to ribose-5-phosphate and reduced NADPH is generated. PPP was called pentose shunt because when glycolysis was the only known glucose pathway there was an unexpected “leakage" of glucose out of glycolysis. The PPP is an alternative metabolic pathway for glucose determined by the metabolic requirements.

Objectives or what you ought to learn from this file Learn the two phases of the PPP, the oxidative and the isomerization part. Learn the regulatory enzymes of PPP. Understand how the PPP provides reducing power for glutathione and anabolic reactions Understand the clinical aspect of the deficiency of glucose-6-phosphate dehydrogenase In general terms the objectives of all my lectures are explained in the slide 4 of this PPTX. That is: For every pathway you ought to know: 1) Purpose of the pathway. (Adaptive value for the organism). 2) Molecules going in and coming out? (The starting metabolites and the final products). 3) Place where it happens (organs, types of cell, subcellular compartments). 4) Regulatory enzymes. (Metabolic conditions that stimulate or inhibit the pathway). 5) Organization of the pathway and the formulas of the compounds involved. (The map of the pathway). 6) Relationship with other pathways. (Shared metabolites, enzymes and regulations). 7) Later, you will have to visualize each pathway interacting with other pathways in normal and in pathological conditions.

Pentose phosphate pathway (PPP) or shunt is also known as the hexose monophosphate pathway and consists of two parts: 1) Glucose-6-P undergoes two oxidations by NADP+, and the second is an oxidative decarboxylation that forms a pentose-P. 2) The P-pentoses that are formed during the first part are either rearranged into glucose-6-P or used for nucleotide synthesis. The PPP is different from glycolysis because it does not generate or consume ATP but produces reduced NADPH+H+. In glycolysis, there was no net oxidation/reduction only rearrangement of the redox state of the carbons of glucose, but in PPP the carbon #1 of glucose is oxidized to CO2. The primary regulatory enzyme is glucose-6-phosphate dehydrogenase which uses NADP+ as coenzyme.

Comparison of NAD with NADP Although both coenzymes look deceptively similar, they have a different metabolic role. NADP+ is involved in anabolic functions while NAD+ in catabolic pathways. The third figure shows the shared molecular mechanism of oxidation-reduction of their nicotinamide moiety. The rule of thumb is that NAD is the redox coenzyme for catabolic reactions (like feeding the respiratory electron chain) while NADP is mainly involved in synthetic reactions. NADP is phosphorylated in carbon 2 of the adenosine nucleotide.

GPDH deficiency is relatively common in persons with roots from regions with endemic malaria. The rate-limiting enzyme is glucose-6-phosphate dehydrogenase (G6PD) and is stimulated by glucose-6-phosphate, and NADP+ and inhibited by the product NADPH. In the PPP, no ATP is produced or used up. The first carbon to be modified is carbon 1 which is oxidized and released as CO2. The next oxidation is done by the 6-phosphogluconate dehydrogenase (which is not regulated) on the carbon 3. This is a completely different plan than glycolysis where glucose is metabolized by targeting carbons 3 and 4 and where there is a rearrangement of the oxidation state of carbons but no net redox of the whole molecule. In glycolysis followed by TCA (Kreb’s) cycle the first Cs to be converted to CO2 are # 3 and 4. In PPP is C #1.

Glucose-6-Phosphate Dehydrogenase Deficiency Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an inherited condition caused by a defect or defects in the gene that codes for glucose-6-phosphate dehydrogenase (G6PD). It can cause hemolytic anemia, variable in severity from life-long anemia, to rare bouts of anemia to total unawareness of the condition. The episodes of hemolytic anemia can be triggered by common medicines, oxidants, infection, or by eating fava beans or other foods. G6PD deficiency is the most common human enzyme deficiency in the world, with about 400 million people living with it. It is most prevalent in people of African, Mediterranean, and Asian ancestry. The incidence in different populations varies from zero in South American Indians to less than 0.1% of Northern Europeans to about 50% of Kurdish males. In the United States, it is most common among African American males; about 11 to 14% are G6PD-deficient. G6PD deficiency is a sex-linked recessive trait. Thus, males have only one copy of the G6PD gene, but females have two copies. Recessive genes are masked in the presence of a gene that encodes normal G6PD. Accordingly, females with one copy of the gene for G6PD deficiency are usually normal, while males with one copy express the phenotype. G6PD is present in all human cells but is particularly important to red blood cells. It is required to make NADPH in red blood cells and maintain the RBC reduced. It is also required to make glutathione. Glutathione and NADPH both help protect red blood cells against oxidative damage. Thus, when G6PD is defective, and the demand for NADPH is too high oxidative damage to red blood cells readily occurs causing hemolysis and hemolytic anemia. G6PD deficiency compatible with survival is advantageous because the Plasmodium falciparum requires a well reduced erythrocyte. There are more than 100 different known forms of G6PD enzyme molecules encoded by defective G6PD genes, yet not one of them is completely inactive. Suggesting that the activity of G6PD is indispensable for supporting life. Many G6PD defective enzymes are deficient in their stability rather than their initial ability to function. Since red blood cells lack nuclei, they, unlike other cells, cannot synthesize new enzyme molecules to replace defective ones. Hence, we expect young red blood cells to have new, functional G6PD and older cells to have non-functioning G6PD. This explains why episodes of hemolytic anemia are frequently self-limiting; new red blood cells are generated with enzymes able to afford protection from oxidation.

2) Nonoxidative steps of pentose phosphate shunt transketolase requires thiamine pyrophosphate (vitamin B1) transketolase requires thiamine pyrophosphate (vitamin B1) The isomerization reactions have a dual role. a) Regeneration of glucose-6P after the decarboxylation of carbon 1. b) Provide ribose for the synthesis of nucleotides and RNA and DNA. The molecules in the isomerization part of PPP seem to be in equilibrium. Therefore, starting from glucose-6-P it is possible to synthesize ribose independently of the oxidative part of the PPP. Xylulose-5-P activates the phosphoprotein phosphatase 2A (PP2A), which activates phosphofructokinase-2. The product of the latter, 2,6-diphospho-fructose, is an activator of glycolysis as we have seen in the lecture about glycolysis. I would be absurd to demand from you to memorize the isomerizations reactions, however, transketolase is important because the impairment of its activity has a real medical relevance. Transketolase depends on the vitamin B1, thiamine. Alcoholism, deficiency of B1 and impairment of the activity of transketolase contribute to a neurological disease called Wernicke-Korsakov. Wernicke neurological disorder results from severe deficiency of thiamine (vitamin B1), and Korsakoff's psychosis is a chronic neurologic consequence of Wernicke encephalopathy. So, do not disregard the transketolase relevance. The nonoxidative steps of the PPP are identical to the dark reactions of plant photosynthesis and were elucidated using for the first time 14CO2 in biochemistry. Positive regulator of hepatic glycolysis

GSSG is oxidized and GSH reduced glutathione GSSG is oxidized and GSH reduced glutathione. This will be discussed in the next page Although glutathione is not part of the PPP it is a regulator of glucose-6-P dehydrogenase and is reduced by the NADPH+H+ generated in the PPP. Glutathione is a tripeptide comprised of three amino acids (cysteine, glutamic acid, and glycine) present in most mammalian tissues. Glutathione acts as an antioxidant, a free radical scavenger, and a detoxifying agent. Glutathione is also essential as a cofactor for the enzyme glutathione peroxidase, in the uptake of amino acids, and in the synthesis of leukotrienes. As a substrate for glutathione S-transferase, this agent reacts with many harmful chemical species, such as halides, epoxides, and free radicals, to form harmless inactive products. In erythrocytes, these reactions prevent oxidative damage through the reduction of methemoglobin and peroxides. Glutathione is also involved in the formation and maintenance of disulfide bonds in proteins and the transport of amino acids across cell membranes.

(CH2O)n [2H]n  (CH2)n + H2O FUNCTIONS OF PPP 1) Formation of NADPH needed for reduction of carbohydrates to fatty acids (CH2O)n [2H]n  (CH2)n + H2O PPP accounts for 50 % of glucose utilization in adipocytes. In liver 5 to 30 % of glucose is metabolized by PPP. At the onset of lactation there is an explosive increase of PPP in the mammary glands to produce the lipids need for the milk. 2) Protect the cells against oxidation by ROS (reactive oxygen species). NADPH protects erythrocytes from destruction by oxygen over-exposure. The main roles of glycolysis in erythrocytes is to provide ATP for hexokinase to provide for ion pumps and to sustain the PPP active. 3) Synthesis of ribose for nucleotide and nucleic acid synthesis. A combination of oxidative and nonoxidative branches of the PPP are active according to the metabolic state of the cells. PPP enzymes are found in the cytosol, the same compartment where glycolytic and most gluconeogenic enzymes and shared intermediate of the three pathways are found..

Notice the unusual bonds between cysteine and glutamate. Glutathione synthesis is not ribosomal and glutathione is not directly encoded in DNA. Notice the unusual bonds between cysteine and glutamate. What is wrong with this bond?

Link between hexose monophosphate pathway and reduction of peroxides The sketch below is not an actual reaction but a schematic illustration of the transferences of reducing power from PPP to the glutathione reductase and glutathione peroxidase. Hydrogen peroxide (H2O2) is one member of the family of reactive oxygen species (ROS). Reactive oxygen species (ROS) are formed from partial reduction of molecular O2 i.e. adding electrons to oxygen leading to the formation of superoxide, hydrogen peroxide and hydroxyl radical. ROS are formed continuously from aerobic metabolism of drugs and environmental toxins or diminished antioxidants. All these lead to oxidative stress. ROS cause damage to DNA, protein and unsaturated lipids of the cells including cell membranes.. They are implicated in cancer, chronic inflammatory, various diseases and aging.

Proposed mechanism of glutathione peroxidase Glutathione peroxidase has selenocystein a rare amino acid that contains selenium. The story of selenocystein incorporation into proteins is mystifying. There are many antioxidants that neutralize the oxygen reactive species (ROS). Among them are: vitamins C and E and recently the tomato red pigment, lycopene. Lycopene, became notorious for reportedly preventing prostate cancer and retinal macula degeneration. Proposed mechanism of glutathione peroxidase Reactive oxygen species, such as superoxide and hydrogen peroxide, are generated in all cells by mitochondrial and enzymatic sources. These reactive species can cause oxidative damage to DNA, proteins, and membrane lipids. Glutathione peroxidase is an intracellular antioxidant enzyme that reduces peroxides and limits its harmful effects. However, certain reactive oxygen species, such as hydrogen peroxide, are also essential for growth factor-mediated signal transduction, mitochondrial function, and maintenance of normal thiol redox-balance. Therefore, reductive stress can diminish cell growth. Newer evidence points to additional cellular and physiological effects caused by lack of cellular oxidants and accumulation of excess reducing equivalents, including changes in protein disulfide bond formation, diminished mitochondrial function and decreased cellular metabolism. A complete understanding of physiological conditions that may create reductive stress have not been elucidated

See the notes, if you will. This slide is a rehearsal of the role of PPP in adult erythrocytes See the notes, if you will. PPP in the mature erythrocyte produces NADPH and ribose 5-phosphate from Glc-6-P. Erythrocytes are dependent on NADPH for glutathione reduction, and on the ribose 5-P, which is utilized in nucleotide resynthesis (Salvage-recycling). Glucose 6-phosphate dehydrogenase (Glc-6-D) deficiency is the most common genetic enzymopathy known in humans, and it is particularly prevalent among individuals of Mediterranean, Asian, and African descent where malaria was or is now endemic. Patients with this hereditary trait, are susceptible to hemolysis, and lipid peroxidation, that may be triggered by drugs so innocently looking drugs such as sulfonamides, primaquine, Tylenol, and foodstuffs like fava beans, or other substances. Several hundred variants of this enzyme have been identified in erythrocytes. A life compatible deficiency of Glc-6-PD in erythrocytes protects people from infestations of falciparum malaria since it requires reduced glutathione for optimal growth.  When an episode of hemolysis occurs oldest erythrocytes are lysed but new, often immature, cells with new set of enzymes are produced. Hemolysis stops, and the patient improves until a new episode happens. Immature erythrocytes are called reticulocytes.