STEPTRACKERBIOCHEMISTRY + HEMATOLOGY + IMMUNOLOGY | CARBOHYDRATE METABOLISM | HIGH-YIELD REVIEW

HMP Shunt & NADPH

The pentose phosphate pathway makes ribose for nucleotides and NADPH for building, detoxifying and killing — and G6PD runs the gate.

FOCUS ON
Oxidative phase (irreversible): G6PD (rate-limiting) makes NADPH. Nonoxidative phase (reversible): transketolase (needs B1) shuffles sugars → ribose-5-P or back to glycolysis. No ATP made or used. Active in RBCs, liver, adrenal cortex, lactating breast. NADPH uses: glutathione reduction (RBC), fatty acid and steroid synthesis, respiratory burst (NADPH oxidase), CYP450, nitric oxide synthase.
PART · USE
WHAT HAPPENS
WHERE
CLUE · DISEASE
G6PD (oxidative phase)
rate-limiting
G6P → 6-phosphogluconolactone, makes NADPH; then 6-PG DH makes a second NADPH → ribulose-5-P
Cytosol
+ NADP⁺ · − NADPH · ↑ by insulin
Transketolase (nonoxidative)
Reversible transfer of carbons → ribose-5-P, or F-6-P + G3P back to glycolysis
Cytosol; needs TPP (B1)
RBC transketolase activity tests thiamine status
Glutathione defense
NADPH → glutathione reductase keeps glutathione reduced → glutathione peroxidase (selenium) neutralizes H₂O₂
RBCs
Only NADPH source in RBCs = HMP shunt
G6PD deficiency
XR · most common enzyme deficiency
↓ NADPH → oxidant stress denatures Hb → Heinz bodies → splenic macrophages bite them → bite cells
Episodic hemolysis
Triggers: infection (most common), fava beans, sulfonamides, primaquine, dapsone, nitrofurantoin, rasburicase · protects against malaria
Respiratory burst
NADPH oxidase: O₂ → superoxide → (SOD) H₂O₂ → (myeloperoxidase + Cl⁻) HOCl bleach
Neutrophils, macrophages
Defect = chronic granulomatous disease
Chronic granulomatous disease
XR (mostly)
NADPH oxidase defect → can't kill catalase-positive organisms (they destroy their own H₂O₂)
Recurrent infections with S aureus, Aspergillus, Burkholderia cepacia, Serratia, Nocardia; granulomas
Abnormal dihydrorhodamine flow test (or nitroblue tetrazolium)
Myeloperoxidase deficiency
Can't make HOCl
Usually mild; ↑ Candida infections
Normal DHR test
Biosynthesis
NADPH supplies reducing power for fatty acid, cholesterol and steroid synthesis
Liver, adrenal cortex, gonads, lactating mammary gland
Malic enzyme also makes NADPH in liver
Nucleotide synthesis
Ribose-5-P → PRPP
Dividing cells
Links HMP shunt to 1.02
Other NADPH users
CYP450 drug metabolism, nitric oxide synthase, DHFR, HMG-CoA reductase
Liver, endothelium
—

Mechanism — why G6PD deficiency causes hemolysis

G6PD ↓
→
↓ NADPH
→
↓ Reduced glutathione
→
Oxidant (drug, infection, fava)H₂O₂ builds up
→
Heinz bodies → bite cellsIntra- and extravascular hemolysis

The respiratory burst step by step

ENZYME
PRODUCT
DEFICIENCY
NADPH oxidase
Superoxide (O₂⁻)
CGD
Superoxide dismutase
H₂O₂
(Familial ALS: SOD1)
Myeloperoxidase
HOCl (bleach)
MPO deficiency
Catalase / glutathione peroxidase
Detoxify H₂O₂
Bacteria with catalase evade CGD killing

How it's tested

COMMON CONFUSIONHeinz bodies are denatured hemoglobin (seen with supravital stain); bite cells are what remains after the spleen removes them.
THE TRAPTesting G6PD during an acute hemolytic episode can be falsely normal — the oldest, most deficient cells have already lysed; retest weeks later.
YOUR APPROACHNADPH problem → in RBC (hemolysis) or in phagocyte (CGD)? → trigger or organism → confirm test.

If you see… think…

Rate-limiting enzyme of the HMP shunt → G6PD
Hemolysis after primaquine or dapsone → G6PD deficiency
Heinz bodies and bite cells → oxidative hemolysis (G6PD)
HMP enzyme needing thiamine → transketolase
Recurrent S aureus and Aspergillus abscesses in a boy → chronic granulomatous disease
Abnormal dihydrorhodamine test → NADPH oxidase defect (CGD)
Organisms that cause trouble in CGD → catalase-positive
Only source of NADPH in RBCs → HMP shunt
Tissues with very active HMP shunt → liver, adrenal cortex, RBCs, lactating breast
Enzyme making bleach in neutrophils → myeloperoxidase