A patient with G6PD deficiency takes an antimalarial drug that generates reactive oxygen species inside red blood cells. Why do these cells lyse when cells from a person without G6PD deficiency do not?
AG6PD-deficient cells lack the enzymes to directly detoxify the drug's reactive intermediates
BWithout G6PD, cells cannot make NADPH, so they cannot regenerate reduced glutathione and are defenseless against oxidative damage
CG6PD is required for ATP synthesis, and without ATP red blood cells cannot maintain membrane integrity
DThe drug inhibits ribose synthesis, preventing DNA repair in red blood cells
G6PD is the first and rate-limiting enzyme of the oxidative phase of the PPP. It produces NADPH, which is the essential cofactor for glutathione reductase — the enzyme that regenerates reduced glutathione (GSH) from oxidized glutathione (GSSG). Reduced glutathione is the primary antioxidant in red blood cells. Without NADPH from the PPP, and given that red blood cells lack mitochondria and cannot generate NADPH from other sources, oxidative stress overwhelms their defenses. Hemoglobin and membrane lipids are damaged, causing hemolysis. This is why the PPP's antioxidant role — not just its nucleotide synthesis role — is clinically critical.
Question 2 Multiple Choice
A textbook describes the pentose phosphate pathway as 'an alternative glucose oxidation pathway that generates energy.' What is fundamentally wrong with this description?
ANothing — the PPP does generate some NADH that can be used for ATP synthesis
BThe PPP is not regulated, so it cannot function as an alternative to glycolysis
CThe PPP's primary products are NADPH and ribose-5-phosphate, not ATP — it is a biosynthetic support pathway, not an energy-generating one
DThe PPP does not actually metabolize glucose-6-phosphate
The PPP produces NADPH (not NADH) and ribose-5-phosphate — neither of which directly generates ATP. NADPH is a cytoplasmic reducing coenzyme used in biosynthetic reactions and antioxidant defense; unlike NADH, it cannot feed electrons into the mitochondrial electron transport chain for ATP synthesis. The pathway is regulated by NADPH availability (via G6PD inhibition), not by ATP/AMP energy charge — a clear signal that its biological purpose is biosynthetic support. Calling it an 'energy pathway' conflates two distinct metabolic currencies: NADPH (biosynthetic reductant) and NADH (energetic reductant).
Question 3 True / False
The non-oxidative phase of the pentose phosphate pathway can generate ribose-5-phosphate from glycolytic intermediates without producing any NADPH.
TTrue
FFalse
Answer: True
The non-oxidative phase uses transketolase and transaldolase to reversibly interconvert sugar phosphates. It can run from glycolytic intermediates (fructose-6-phosphate and glyceraldehyde-3-phosphate) toward ribose-5-phosphate without any oxidation steps — and therefore without NADPH production. This flexibility is essential for rapidly dividing cells (e.g., tumor cells, embryonic cells) that need large amounts of ribose for nucleotide synthesis but don't have elevated antioxidant demand. The two phases serve independent metabolic goals and can operate uncoupled from each other.
Question 4 True / False
The pentose phosphate pathway and glycolysis are regulated by the same mechanism: both are inhibited when cellular ATP levels are high.
TTrue
FFalse
Answer: False
Glycolysis is regulated primarily by energy charge — high ATP inhibits phosphofructokinase, slowing glycolysis when energy is ample. The PPP is regulated by a completely different signal: the NADPH/NADP⁺ ratio. When NADPH is abundant, it inhibits glucose-6-phosphate dehydrogenase (G6PD), slowing the oxidative phase. When biosynthesis or oxidative stress consumes NADPH, NADP⁺ rises, relieving G6PD inhibition and accelerating the pathway. ATP levels do not directly control G6PD. This distinction reflects the pathways' different purposes: glycolysis responds to cellular energy needs; the PPP responds to biosynthetic redox demand.
Question 5 Short Answer
Why does the pentose phosphate pathway branch off at glucose-6-phosphate rather than at a later glycolytic intermediate? Name the two principal products the PPP provides that glycolysis cannot.
Think about your answer, then reveal below.
Model answer: Glucose-6-phosphate is the first committed metabolite after glucose enters the cell — a metabolic branch point before any ATP-generating steps have occurred. Branching here allows the cell to divert glucose toward biosynthetic support before committing it to energy production. If the branch point were later (e.g., at pyruvate), the cell would have already spent glucose's biosynthetic potential on ATP generation. The two principal products glycolysis cannot supply: (1) NADPH — the cytoplasmic reducing coenzyme required for fatty acid synthesis, cholesterol synthesis, steroid hormone synthesis, and glutathione regeneration for antioxidant defense; (2) ribose-5-phosphate — the five-carbon sugar backbone of all nucleotides (ATP, GTP, NAD, FAD, and the building blocks of DNA and RNA). Together, these two products support the biosynthetic and protective functions that are essential for cell growth and survival under oxidative stress.