PENTOSE PHOSPHATE PATHWAY Hexose monophosphate pathway Learning objectives
PENTOSE PHOSPHATE PATHWAY (Hexose monophosphate pathway) Learning objectives: • List the two phases (oxidative and non-oxidative) of the pentose phosphate pathway • List key enzymes involved in the pathway Glucose 6 -phosphate dehydrogenase Transketolase Transaldolase • List key compounds involved in the pathway: Glucose 6 -phosphate NADPH Ribose 5 -phosphate Glyceraldehyde 3 -phosphate Fructose 6 -phosphate • Discuss functions of the pentose phosphate pathway in cell metabolism
The cell needs “reducing power” for biosynthesis and protection against oxidative stress. The “reducing power” is NADPH : H- NAD+ NADP+ H H NADPH
The cell needs ribose 5 -phosphate for synthesis of nucleotides used in DNA, RNA, NAD+, NADP+, FAD, and Coenzyme A PO 32 --OH 2 H OH O H H H OH OH Ribose 5 -phosphate CH 2 OH Ι H - C – OH Ι H – C – OH Ι CH 2 OPO 32 Ribose 5 -phosphate The pentose phosphate pathways provides both NADPH and ribose 5 -phosphate
+ lactonase Phosphopentose epimerase CO 2 Ribose 5 -phosphate isomerase
Glucose 6 -phosphate dehydrogenase CH 2 OPO 32 O H H OH H CH 2 OPO 32 H OH + NADP+ H OH OH 6 -Phosphoglucono-δ-lactone CH 2 OPO 32 O H OH H H O + NADPH + H+ OH H OH Glucose 6 -phosphate H O H Lactonase O + H 2 O OH H OH 6 -Phosphoglucono-δ-lactone COOΙ H – C – OH Ι HO – C – H + H+ Ι H – C – OH Ι CH 2 OPO 326 -Phosphogluconate
COOΙ H – C – OH CH 2 OH 6 -Phosphogluconate Ι Ι dehydrogenase HO – C – H C–O Ι Ι H – C – OH + NADP+ H – C – OH + NADPH + CO 2 Ι Ι H – C – OH Ι Ι CH 2 OPO 326 -Phosphogluconate Ribulose 5 -phosphate
Stoichiometry for oxidative phase of pentose phosphate pathway Glucose 6 -phosphate + 2 NADP+ + H 2 O → Ribulose 5 -phosphate + 2 NADPH + 2 H+ + CO 2
te a ph s ho se p 5 - era se om o ib is CH 2 OH R Ι C–O Ι H – C – OH Ι CH 2 OPO 32 - CHO Ι H - C – OH Ι H – C – OH Ι CH 2 OPO 32 Ribose 5 -phosphate Ph osp ep hope ime nt ras ose e Ribulose 5 -phosphate CH 2 OH Ι C–O Ι HO – C – H Ι H – C – OH Ι CH 2 OPO 32 Xylulose 5 -phosphate
CHO Ι H - C – OH Ι H – C – OH Ι CH 2 OPO 32 Ribose 5 -phosphate + CH 2 OH Ι C–O Ι HO – C – H Ι H – C – OH Ι CH 2 OPO 32 Xylulose 5 -phosphate Transketolase CH 2 OH Ι C–O Ι HO – C – H Ι H - C – OH Ι H – C – OH Ι CH 2 OPO 32 Sedoheptulose 7 -phosphate + CHO Ι H – C – OH Ι CH 2 OPO 32 Glyceraldehyde 3 -phosphate
CH 2 OH Ι C–O Ι HO – C – H Ι H - C – OH Ι H – C – OH Ι CH 2 OPO 32 - CHO Ι H – C – OH Ι CH 2 OPO 32 Erythrose 4 -phosphate Transaldolase Sedoheptulose 7 -phosphate + CHO Ι H – C – OH Ι CH 2 OPO 32 Glyceraldehyde 3 -phosphate + CH 2 OH Ι C–O Ι HO – C – H Ι H – C – OH Ι CH 2 OPO 32 Fructose 6 -phosphate
CHO Ι H – C – OH Ι CH 2 OPO 32 Erythrose 4 -phosphate + CH 2 OH Ι C–O Ι HO – C – H Ι H – C – OH Ι CH 2 OPO 32 Xylulose 5 -phosphate Transketolase CH 2 OH Ι C–O Ι HO – C – H Ι H – C – OH Ι CH 2 OPO 32 Fructose 6 -phosphate + CHO Ι H – C – OH Ι CH 2 OPO 32 Glyceraldehyde 3 -phosphate
Xylulose 5 -phosphate Sedoheptulose Transaldolase Transketolase 7 -phosphate Erythrose 4 -phosphate Ribose 5 -phosphate Glyceraldehyde 3 -phosphate Fructose 6 -phosphate Transketolase Fructose 6 -phosphate Glyceraldehyde 3 -phosphate Stoichiometry for non-oxidative phase of pentose phosphate pathway 3 Pentose 5 -phosphate 2 Fructose 6 -phosphate + Glyceraldehyde 3 -phosphate Stoichiometry for the whole pentose phosphate pathway 3 Glucose 6 -phosphate + 6 NADP+ + 3 H 2 O → 2 Fructose 6 -phosphate + Glyceraldehyde 3 -phosphate + 6 NADPH + 6 H+ + 3 CO 2
Glucose 6 -phosphate dehydrogenase CH 2 OPO 32 O H H OH H CH 2 OPO 32 O H H OH + NADP+ OH H OH Glucose 6 -phosphate H H O + NADPH + H+ OH H OH 6 -Phosphoglucono-δ-lactone The first step in the pentose phosphate pathway is the main regulatory step of the pathway + NADPH (Competitive inhibitor of the enzyme) Insulin (enhances expression of the enzyme leading to enhanced flux through pathway in the well-fed state)
Different outcomes of the pentose phosphate pathway The needs for NADPH and ribose 5 -phosphate are balanced: Glucose 6 -phosphate + 2 NADP+ + H 2 O → Ribose 5 -phosphate + 2 NADPH + 2 H+ + CO 2 The cell needs more NADPH than ribose 5 -phosphate: Glucose 6 -phosphate + 12 NADP+ + 7 H 2 O → 12 NADPH + 12 H+ + 6 CO 2 + Pi The cell needs more ribose 5 -phosphate than NADPH: 5 Glucose 6 -phosphate + ATP → 6 Ribose 5 -phosphate + ADP
In addition to the pentose pathway, NADPH can be generated by the malic enzyme Malic enzyme + NADP+ + NADPH + + CO 2 Malate is generated in the mitochondria by the TCA (Krebs) cycle. Erythrocytes which lack mitochondria are thus particularly susceptible to oxidative damage Defective glucose 6 -phosphate dehydrogenase is the most common enzymatic defect in humans affecting hundreds of millions of people. Hemolytic anemia can occur if the individual experience oxidative stress, e. g. when treated with oxidant drugs or contract a severe infection.
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