HMP Shunt B&B

Question 1

what is synthesized via the HMP shunt?

Answer 1

HMP (hexose monophosphate shunt) = PPP (pentose phosphate pathway)

diverts glucose-6-phosphate (glycolysis) into synthesis of
1. NADPH
2. ribose 5-phosphate

all reactions occur in cytosol

Question 2

Wernicke-Korsakoff syndrome

Answer 2

abnormal transketolase - unable to bind thiamine (B1) (cofactor)

recall transketolase converts ribose-5-phosphate (HMP shunt product) to fructose-6-phosphate (funnels back into glycolysis/gluconeogenesis)

associated with alcohol use disorder —> thiamine deficiency

Question 3

what is the function of the transketolase enzyme in the HMP shunt?

Answer 3

HMP (aka PPP) shunts glucose-6-phosphate into ribose-5-phosphate

ribose-5-phosphate is converted to fructose-6-phosphate by transketolase, funneling back into the glycolysis/gluconeogenesis pathway

Question 4

what are the uses of NADPH? (3)

Answer 4

NADPH is used in reductive reactions

1. co-factor in fatty acid and steroid synthesis
2. phagocytosis via respiratory burst (NADPH oxidase)
3. protection from oxidative damage (via glutathione production)

Question 5

what 3 enzymes are required for phagocytic respiratory burst?

Answer 5

phagocytes generate H2O2 for “oxygen dependent” killing of bacteria, using 3 enzymes:

1. NADPH oxidase
2. superoxidase dismutase
3. myeloperoxidase

Question 6

from what kinds of bacteria do patients with chronic granulomatous disease get recurrent infections?

Answer 6

chronic granulomatous disease: LOF of NADPH oxidase —> phagocytes cannot generate H2O2

susceptible to catalase (+) bacteria which break down H2O2 - staph. aureus, Pseudomonas, Serratia, Nocardia, Aspergillus

[catalase (-) bacteria generate H2O2, which phagocytes can “steal” for use]

Question 7

what metabolic pathway is affected in glucose-6-phosphate dehydrogenase deficiency?

Answer 7

glucose-6-phosphate dehydrogenase diverts glucose-6-phosphate (glycolysis) into HMP shunt to generate NADPH, which is required for glutathione synthesis in RBC (protection against ROS)

absence of NADPH —> RBC hemolysis following exposure to trigger (infection, drugs, fava beans)

Question 8

what are the classic triggers of hemolysis due to glucose-6-phosphate dehydrogenase deficiency? (3)

Answer 8

absence of NADPH —> RBC hemolysis, triggered by:

1. infection - macrophages generate ROS
2. fava beans - contain oxidants
3. drugs - sulfa drugs, INH, anti-malarials (quinidine), aspirin

Question 9

how is glucose-6-phosphate dehydrogenase (G6PD) deficiency inherited and what are the classic signs?

Answer 9

X-linked R (males), lack of NADPH (required for RBC glutathione synthesis)

—> RBC hemolysis following trigger (infection, drugs, fava beans)

—> Heinz bodies (oxidized Hgb precipitates) and bite cells (phagocytic removal by splenic macrophages)

Question 10

what test can be used to diagnose glucose-6-phosphate dehydrogenase deficiency?

Answer 10

recall G6PD diverts glucose-6-phosphate (glycolysis) into HMP shunt to generate NADPH, which is required for glutathione synthesis in RBC

diagnose with fluorescent spot test - detects generation of NADPH from NADP (positive if no fluorescence)

Question 11

in which cellular compartment does the HMP shunt occur?

Answer 11

hexose monophosphate shunt (HMP), aka pentose phosphate pathway (PPP), aka phoshogluconate pathway

occurs in cytosol, alternative glucose metabolism

produces NADPH (reductive biosynthetic and detox rxns) and ribose 5-phosphate (nucleotide synthesis or conversion to glycolysis intermediate)

Question 12

what are the 2 phases of the HMP shunt?

Answer 12

1. oxidative phase: irreversible steps (produces NADPH)
2. nonoxidative phase: reversible interconversion of sugars (produces ribose 5-phosphate)

Question 13

what is the regulatory enzyme of the pentose pathway (HMP shunt)?

Answer 13

glucose 6-phosphate dehydrogenase - first enzyme of oxidative phase (irreversible steps, produces NADPH)

activated by insulin

Question 14

how does Wernicke-Korsakoff Syndrome present?

Answer 14

caused by thiamine deficiency, associated with alcohol use disorder

—> decreased mental function, abnormal gait, paralysis of eye movements, severely impaired memory

[recall transketolase of HMP requires coenzyme thiamine pyrophosphate (TPP)]

Question 15

what are 2 other sources of NADPH besides HMP shunt for cells other than RBC?

(recall RBC only get NADPH from HMP)

Answer 15

1. malic enzyme: NADPH via conversion of malate to pyruvate
2. NNT (nicotinamide nucleotide transhydrogenase): converts NADH to NADPH