Transcript PENTOSE PHOSPHATE PATHWAY (Hexose monophosphate pathway)

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
PO32--OH2
H
OH
O
H
H
H
OH
OH
Ribose 5-phosphate
CH2OH
Ι
H - C – OH
Ι
H – C – OH
Ι
H – C – OH
Ι
CH2OPO32Ribose 5-phosphate
The pentose phosphate pathways provides both NADPH and ribose 5-phosphate
+ lactonase
Phosphopentose
epimerase
CO2
Ribose 5-phosphate
isomerase
Glucose 6-phosphate
dehydrogenase
CH2OPO32O
H
H
OH
H
CH2OPO32H
OH
+ NADP+
H
OH
OH
H
OH
6-Phosphoglucono-δ-lactone
CH2OPO32O
H
OH
H
H
O + NADPH + H+
OH
H
OH
Glucose 6-phosphate
H
O
H
Lactonase
O + H2 O
OH
H
OH
6-Phosphoglucono-δ-lactone
COOΙ
H – C – OH
Ι
HO – C – H
+ H+
Ι
H – C – OH
Ι
H – C – OH
Ι
CH2OPO326-Phosphogluconate
COOΙ
H – C – OH
CH2OH
6-Phosphogluconate
Ι
Ι
dehydrogenase
HO – C – H
C–O
Ι
Ι
H – C – OH + NADP+
H – C – OH + NADPH + CO2
Ι
Ι
H – C – OH
H – C – OH
Ι
Ι
CH2OPO32CH2OPO326-Phosphogluconate
Ribulose 5-phosphate
Stoichiometry for oxidative phase of pentose phosphate pathway
Glucose 6-phosphate + 2 NADP+ + H2O →
Ribulose 5-phosphate + 2 NADPH + 2 H+ + CO2
CH2OH
Ι
C–O
Ι
H – C – OH
Ι
H – C – OH
Ι
CH2OPO32-
Ribulose 5-phosphate
CHO
Ι
H - C – OH
Ι
H – C – OH
Ι
H – C – OH
Ι
CH2OPO32Ribose 5-phosphate
CH2OH
Ι
C–O
Ι
HO – C – H
Ι
H – C – OH
Ι
CH2OPO32Xylulose 5-phosphate
CHO
Ι
H - C – OH
Ι
H – C – OH
Ι
H – C – OH
Ι
CH2OPO32Ribose 5-phosphate
+
CH2OH
Ι
C–O
Ι
HO – C – H
Ι
H – C – OH
Ι
CH2OPO32Xylulose 5-phosphate
Transketolase
CH2OH
Ι
C–O
Ι
HO – C – H
Ι
H - C – OH
Ι
H – C – OH
Ι
H – C – OH
Ι
CH2OPO32Sedoheptulose 7-phosphate
+
CHO
Ι
H – C – OH
Ι
CH2OPO32Glyceraldehyde 3-phosphate
CH2OH
Ι
C–O
Ι
HO – C – H
Ι
H - C – OH
Ι
H – C – OH
Ι
H – C – OH
Ι
CH2OPO32-
CHO
Ι
H – C – OH
Ι
H – C – OH
Ι
CH2OPO32Erythrose 4-phosphate
Transaldolase
Sedoheptulose 7-phosphate
+
CHO
Ι
H – C – OH
Ι
CH2OPO32Glyceraldehyde 3-phosphate
+
CH2OH
Ι
C–O
Ι
HO – C – H
Ι
H – C – OH
Ι
H – C – OH
Ι
CH2OPO32Fructose 6-phosphate
CHO
Ι
H – C – OH
Ι
H – C – OH
Ι
CH2OPO32Erythrose 4-phosphate
+
CH2OH
Ι
C–O
Ι
HO – C – H
Ι
H – C – OH
Ι
CH2OPO32-
Transketolase
CH2OH
Ι
C–O
Ι
HO – C – H
Ι
H – C – OH
Ι
H – C – OH
Ι
CH2OPO32Fructose 6-phosphate
+
CHO
Ι
H – C – OH
Ι
CH2OPO32Glyceraldehyde 3-phosphate
Xylulose 5-phosphate
Xylulose
5-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 H2O →
2 Fructose 6-phosphate + Glyceraldehyde 3-phosphate + 6 NADPH + 6H+ + 3CO2
Glucose 6-phosphate
dehydrogenase
CH2OPO32O
H
H
OH
H
OH
H
CH2OPO32O
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+ + H2O → Ribose 5-phosphate + 2 NADPH + 2 H+ + CO2
The cell needs more NADPH than ribose 5-phosphate:
Glucose 6-phosphate + 12 NADP+ + 7H2O → 12 NADPH + 12 H+ + 6 CO2 + 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
O-
O
C
O-
O
H C
OH
CH2
+ NADP+
C
C
O
+ NADPH + H+ + CO2
CH3
C
O
Malic enzyme
O-
Pyruvate
Malate
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.