WEEK 4 (HMP Shunt) Flashcards
What is the HMP shunt also known as?
Pentose phosphate pathway
In which molecule in Glycolysis does the reaction shunt away?
Glucose-6-Phosphate
What are the key things to remember about the HMP shunt?
- Occurs in the cytoplasm
- Main organs are LIVER, MAMMARY GLANDS, RBCs & ADRENAL CORTEX
- Goal is to produce NADPH
- 2 phases: Oxidative (irreversible, rate-limiting) & Reductive (reversible)
What does the HMP shunt synthesise?
- 2 molecules of NADPH
- Ribose-5-Phosphate
- CO2
Why is NADPH needed?
- Glutathione reduction (Free radical detoxification)
- Fatty acid synthesis
- Steroid hormone synthesis
Which organs use the HMP shunt to synthesis fatty acids?
- Liver
- Lactating mammary glands
- Adipose tissue
Which organs use the HMP shunt to synthesis Steroid hormones?
- Testes
- Ovaries
- Placenta
- Adrenal cortex
What requires NADPH to keep glutathione reduced?
RBCs
What are the irreversible oxidative reactions?
3 reactions that lead to formation of ribulose-5-phosphate, CO2 & 2 molecules of NADPH
Glucose-6-phosphate -> 6-Phosphoglucanolactone -> 6-Phosphogluconate -> Ribulose-5-phosphate
What is the enzyme that converts Glucose-6-Phosphate to 6-Phosphoglucanolactone?
Glucose-6-Phosphate Dehydrogenase
What is the enzyme that converts 6-Phosphoglucanolactone to 6-Phosphogluconate?
Glucanolactone Hydrolase
What is the enzyme that converts 6-Phosphogluconate to Ribulose-5-Phosphate?
6-Phosphogluconate Dehydrogenase
What are the Reversible non-oxidative reactions?
Reversible reactions that permit Ribulose-5-Phosphate to be converted to either RIBOSE-5-PHOSPHATE (needed for nucleotide synthesis) or to INTERMEDIATES OF GLYCOLYSIS (Fructose-6-Phosphate & Glyceraldehyde-3-Phosphate)
What are the properties of Transketolase?
- Transfers a carbon unit to create Fructose-6-Phosphate
- Requires thiamine (B1) as a co-factor
- Associated with WERNICKE-KORSAKOFF SYNDROME (memory disorder that results from vitamin B1 deficiency and is associated with alcoholism)
- Abnormal transketolase may predispose
- Affected individuals may have abnormal binding to thiamine
What are the uses of Hydrogen peroxide reduction?
- Co-factor in fatty acid & steroid synthesis
- Protection from oxidative damage
- Phagocytosis
- Used in “reductive” reactions (releases hydrogen to form NADP+)
How are Reactive Oxygen Species (ROS) formed?
- Continuously as by-products of aerobic metabolism
- Through reactions with drugs & environmental toxins
- When the level of antioxidants is diminished
All creating conditions of OXIDATIVE STRESS
What can highly reactive oxygen intermediates cause?
Serious chemical damage to DNA, Proteins and can lead to cell death
What is the function of Reduced Glutathione (G-SH)?
Reduced Glutathione (G-SH) can chemically detoxify H2O2 why by GLUTATHIONE PEROXIDASE forms OXIDISED GLUTATHIONE (G-S-S-G) which no longer has protective properties
How does the cell regenerate Reduced Glutathione (G-SH)?
In a reaction catalysed by GLUTATHIONE REDUCTASE using NADPH as a source of reducing equivalents. Additional enzymes (e.g SUPEROXIDE DISMUTASE & CATALASE) catalyse the conversion of other ROS (Reactive oxygen species) to harmless products.
What is able to reduce and detoxify ROS in the lab?
Antioxidant chemicals & a number of intracellular reducing agents
(e.g ASCORBATE, VITAMIN E & B-CAROTENE)
What is Phagocytosis and what are its properties?
PHAGOCYTOSIS = Ingestion by receptor-mediated endocytosis of microorganisms, foreign particles & cellular debris
- Neutrophils & Macrophages
- Generate H2O2 to kill bacteria
What are the 2 mechanisms of Phagocytosis?
- OXYGEN-INDEPENDENT KILLING (uses pH changes in PHAGOLYSOSOMES & LYSOSOMAL ENZYMES to destroy pathogens)
- OXYGEN-DEPENDENT SYSTEM (uses NADPH OXIDASE, SUPEROXIDE DISMUTASE & MYELOPEROXIDASE)
Describe CGD-Chronic Granulomatous Disease
- Loss of function of NADPH oxidase
- Phagocytes cannot generate H2O2
- Phagocytes use despite enzyme deficiency
- Catalase (-) bacteria generate their own H2O2
- Catalyse (+) bacteria breakdown H2O2 -> Host cells have no H2O2 to use -> Recurrent infections
Which 5 organisms cause almost all CGD infections?
- Staph aureus
- Pseudomonas
- Serratia
- Nocardia
- Aspergillus
What are the properties of Nitric Oxide?
- Mediator
- Endothelium-derived relaxing factor that causes vasodilation by relaxing vascular smooth muscle
- Neurotransmitter -> Prevents platelet aggregation -> Plays an essential role in macrophage function
What are the properties of Nitric Oxide synthesis?
- 3 NOS isozymes
- 2 are CONSTITUTIVE, CALCIUM-CALMODULIN-DEPENDENT enzymes that are found primarily in ENDOTHELIUM & NEURAL TISSUE and constantly produce very low levels of NO for vasodilation and neurotransmission
- INDUCIBLE, CA2+ INDEPENDENT ENZYME can be expressed in many cells as an early defence against pathogens
Describe the physiology behind Glucose-6-Phosphate
NADPH is necessary to keep GLUTATHIONE reduced which detoxifies free radicals and peroxides -> Decrease in NADPH in RBCs leads to HEMOLYTIC ANEMIA due to poor RBC defines against oxidising agents -> Infection can cause HEMOLYSIS -> Inflammatory response produces FREE RADICALS that diffuse into RBCs -> Oxidative damage
What are the properties of Glucose-6-Phosphate Dehydrogenase deficiency?
- X-linked recessive disorder
- Most common human enzyme deficiency
- Increased malarial resistance
- HEINZ BODIES (oxidised haemoglobin precipitated in RBCs)
- BITE CELLs (Result from the Phagocytic removal of Heinz bodies by splenic macrophages)
