Pentose Phosphate Pathway and Nicotinamide Adenine Dinucleotide Phosphate Flashcards
NADPH can be used for:
1) Cellular respiration
2) Synthesis of fructose
3) Synthesis of lactose
ONLY 1 and 2
Where does the pentose phosphate pathway (or hexose monophosphate shunt) occur?
In cytosol
What does the PPP include?
3 irreversible oxidative reactions, followed by a series of reversible sugar interconversions
- No ATP consumed/produced
- C1 of G-6-P released as CO2
Why would the PPP be taken?
1) You are in need of NADPH (2 NADPHs are produced)
2) You are in need of ribose (for nucleotides)
What does the oxidative portion of the PPP consist of?
3 irreversible reactions that lead to formation of ribulose 5-phosphate, CO2, and 2 NADPH for each G-6-phosphate
- Important in the liver, lactating mammary glands, and adipose tissue for the NADPH-dependent biosynthesis of fatty acids
- Also important in the testes, ovaries, placenta, adrenal cortex for the NADPH-dependent biosynthesis of steroid hormones
- And important in RBCs for the NADPH to keep glutathione reduced
What is the 1st irreversible oxidative reaction?
Dehydrogenation of glucose 6-phosphate by GLUCOSE 6-PHOSPHATE DEHYDROGENASE (G6PD)
- Irreversible, committed and main regulated step of PPP
- NADPH is a potent competitive inhibitor of G6PD
- Insulin upregulates G6PD expression
What is the 2nd irreversible oxidative reaction?
Formation of ribulose 5-phosphate: 6-Phosphogluconolactone hydrolyzed by 6-phosphogluconolactone hydrolase
-Irreversible and not rate limiting
What is the 3rd irreversible oxidative reaction?
Oxidative decarboxylation by 6-phosphogluconate dehydrogenase
-Irreversible reaction produces a pentose sugar-phosphate (ribulose 5-phosphate), CO2 (from C1 of glucose), and second molecule of NADPH
What do the reversible nonoxidative reactions catalyze?
The interconversion of sugars containing 3-7 carbons
- Permit ribulose 5-P to be converted either to ribose 5-P (nucleotide synthesis) or intermediates of glycolysis (fructose 6-P -> G6P and glyceraldehyde 3-P)
- Occur in all cell types synthesizing nucleotides and nucleic acids
How many carbon units does a transketolase transfer?
2
How many carbon units does a transaldolase transfer?
3
How does NADPH differ from NADH?
Only by phosphate on ribose
-High-energy molecule destined for reductive biosynthesis, rather than electron for transfer to oxygen
What are 5 uses of NADPH?
1) Reductive biosynthesis
2) Reduction of H2O2
3) Cytochrome P450 monooxygenase system
4) Phagocytosis by white blood cells
5) Synthesis of nitric oxide
How is NADPH used in reactive biosynthesis?
Fatty acids and chain elongation, cholesterol and steroids, NTs, nucleotides, superoxide
How is NADPH used in cytochrome P450 monooxygenase system?
Biosynthesis of steroid hormones, detoxification of foreign compounds (xenobiotics), alcohol
How is NADPH used in phagocytosis by WBCs?
- Receptor-mediated endocytosis of microorganisms, foreign particles, and cellular debris by cells such as neutrophils and macrophages (monocytes)
- Important defense mechanism, particularly in bacterial infections
- O2 independent (use pH changes in phagolysosomes and lysosomal enzymes to destroy pathogens)
- O2 dependent mechanisms for killing bacteria
What is the O2-dependent mechanism for killing bacteria with NADPH?
- NADPH oxidase and myeloperoxidase (MPO) work together in killing bacteria
- MPO system: most potent of bactericidal mechanisms
- After internalization of bacteria, NADPH oxidase reduces O2 to O2 radical
- “Respiratory burst”: rapid consumption of O2
- O2 radical converted to H2O2 by superoxide dismutase
- Peroxide + chloride -> hypochlorous (HOCl) aka monster killer (what is inside bleach)
In general is H202 bad for us?
Not a free radical but can turn into one; ROS are formed continuously as byproducts of aerobic metabolism, reactions with drugs and environmental toxins, or wen level of antioxidants is diminished -> oxidative stress
- Damage to DNA, proteins, lipids, cell membranes
- Implicated in cancer, inflammatory disease, and aging
How does NADPH reduce H2O2?
Reduced glutathione (G-SH; a tripeptide-thiol present in most cells) is used by glutathione peroxidase to reduce the peroxide to water -The oxidized glutathione (G-S-S-G) produced is no longer protective -> regenerated/reduced by glutathione reductase, using NADPH as the source of electrons
What are some natural detoxifiers of ROS?
Ascorbate, vitamin E, beta-carotene
-if part of diet, not supplements
What is nitric oxide (NO)?
Important free radical glass; Mediator in broad array of systems; its synthesis requires NADPH
- Endothelium-derived relaxing factor: vasodilation by relaxing vascular smooth muscle
- Acts as a NT
- Prevents platelet aggregation
- Helps mediate macrophage bactericidal activity
- Very short half-life
- Reacts with O2 and O2 radical -> nitrates, nitrites, RNS
NO is made from what?
Made from arginine and O2 by 3 different NADPH-dependent NO synthases (NOS):
1) endothelial (eNOS) - constantly produce very low levels of NO for vasodilation
2) neuronal (nNOS) - constantly produce very low levels of NO for neurotransmission
3) inducible (iNOS) - produces large amount of NO for defense against pathogens
What does G6PD deficiency cause?
Impairs the ability of the cell to form the NADPH that is essential for the maintenance of G-SH pool -> cells most affected are RBC because they do not have additional source of NADPH
