The HMP Shunt Flashcards
What is the HMP shunt?
- the hexosemonophosphate shunt (AKA the pentose phosphate pathway)
- this is a cycle that takes glucose-6-phosphate and uses it to generate NADPH (for reducing power) and ribose (used in DNA and RNA synthesis)
- basic reaction: G6P –> –> –> –> –> fructose-6-phosphate + NADPH
Which four pathways can glucose-6-phosphate enter?
- glycolysis, glycogenesis, gluconeogenesis, and the HMP shunt
What is NADPH?
- a reducing agent that can be used to put electrons ON TO certain molecules (ie: it does not generate ATP)
- it is involved in anabolic processes
Which enzyme converts glucose-6-phosphate into ___________?
- glucose-6-phosphate dehydrogenase (G6PD) converts G6P into 6-phosphogluconolactone to generate 1 NADPH
- (G6PD transfers and electron from G6P to NADP to form NADPH)
What happens to 6-phosphogluconolactone?
- it gets converted into ribulose-5-phosphate to generate another NADPH (and also CO2)
What happens to ribulose-5-phosphate?
- ribulose is used in nucleotide synthesis
- it can also enter glycolysis/gluconeogenesis by being converted into fructose-6-phosphate
Which enzyme converts ribulose-5-phosphate into fructose-6-phosphate? What does it need to function?
- transketolase
- this enzyme requires thiamine pyrophosphate (TPP) from vitamin B1 (thiamine)
- 4 enzymes require TPP, other 3: pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and branched chain ketoacid dehydrogenase (these 3 require the full “Tender Loving Care From Nancy”)
What disease develops from a mutated transketolase?
- Wernicke-Korsakoff disease
- the mutated transketolase has a decreased affinity for TPP, making it largely non-functional
- clinical effects are on the brain: CNS encephalopathy and psychiatric symptoms
- treat by giving excess thiamine to increase the chance of TPP successfully binding to transketolase
What disease is very similar to Wenicke-Korsakoff disease?
- Beriberi disease
- the issue here is based on thiamine deficiency, rather than a mutated transketolase
- this results in malfunctioning of not only transketolase, but also of PDH, alpha-KG dehydrogenase, and branched chain ketoacid dehydrogenase
- common in chronic malnourished alcoholics
What are specific functions of NADPH?
- depends on the location of the NADPH
- in the liver, NADPH is used for biosynthesis
- in neutrophils/macrophages, NADPH is used for oxidative burst
- in erythrocytes, NADPH is used to detox free radicals generated in the RBC
NADPH in neutrophils/macrophages
- used to generate the oxidative burst
- NADPH oxidase transfers electrons from NADPH onto O2 to form superoxide (O2.-)
- superoxide forms hydrogen peroxide (H2O2), which form hypochlorite (HOCl.)
NADPH in erythrocytes: where do the free radicals in the RBCs come from?
- used to detox free radicals generated by the RBC
- free radicals in the RBC come from 2 sources:
1) occasionally, O2 spontaneously picks up electrons for form superoxide
2) occasionally, O2 bound to Hb takes an electron from the iron and generates superoxide and MetHb (this occurs in 0.5 - 3.0% of our RBCs every day)
NADPH in erythrocytes: mechanism of detox
- NADH (not NADPH!) donates an electron to MetHb via MetHb reductase to return Hb back to normal
- glutathione (in its reduced form) donates an electron to hydrogen peroxide (H2O2) to form H2O; in order to return the now oxidized glutathione back to its reduced form, NADPH donates an electron!
Glucose-6-phosphate dehydrogenase deficiency
- prevents the HMP shunt from working, so no NADPH can be generated in cells
- major clinical effects: immunodeficiency (no oxidative burst), heinz bodies (denatured Hb from free radical damage), hemolytic anemia (via membrane damage from free radicals)
How can we distinguish G6PD deficiency from chronic granulomatous disease?
- (CGD = NADPH oxidase deficiency)
- in G6PD we have immunodeficiency, heinz bodies, and hemolytic anemia
- in CGD we only have immunodeficiency
