FACULTY OF MEDICINE

MEDICAL BIOCHEMISTRY

PENTOSE PHOSPHATE PATHWAY

DR. METE ÖZKOÇ
 ATP is the cell’s «energy currency»; its exergonic cleavage is coupled to many otherwise endergonic cell functions
 But ATP is not only currency, also reducing power is kind of currency for the cell!
 Many endergonic reactions, notably the reductive biosynthesis of fatty acids and cholesterol, require NADPH in
addition to ATP.
 Please note that: Even though their close chemical resemblance, NADPH and NADH are not metabolically
interchangeable
 Whereas NADH uses the free energy of metabolite oxidation to synthesize ATP, NADPH uses the free energy of
metabolite oxidation for reductive biosynthesis
 NADPH is generated by the oxidation of glucose-6-P via an alternative pathway to glycolysis, the pentose
phosphate pathway (PPP). Also this pathway known as hexose monophosphate pathway.
 Tissues most heavily involved in lipid biosynthesis (liver, mammary glands, adipose tissue, and adrenal cortex) are
rich in pentose phosphate pathway enzymes.
 The overall reaction of the PPP is:

3 G6P + 6 NADP+ + 3 H2O → 6 NADPH + 3 CO2 + 2 F6P + GA3P

▪ The pentose phosphate pathway consist three stages:
▪ NADPH producing (Oxidative reactions)
▪ Isomerization of pentoses (Non-oxidative reactions)
▪ Recovering of glycolytic intermediates (Non-oxidative reactions)

▪ The pathway provides:

▪ Reducing agent NADPH
▪ Ribose-5-phosphate
STAGE 1: OXIDATIVE REACTIONS (PRODUCING NADPH)

3x
STAGE 2: ISOMERIZATION AND EEPIMERIZATION OF RU5P

 The relative amounts R5P and Xu5P produced from Fu5P depend on the
need of the cell
 For example, R5P is an essential precursor in the biosynthesis of
nucleotides.
 Accordingly, R5P production is relatively high in rapidly dividing cells, in
which the rate of DNA synthesis is increased.
 If the pathway is being used solely for NADPH production, Xu5P and R5P
are produced in a 2:1 ratio for conversion to glycolytic intermediates in
the third stage of pentose phosphate pathway.
STAGE 3: CARBON-CARBON BOND CLEAVAGE AND FORMATION

▪ In this stage of PPP there are only transaldolase

and transketolase reactions
▪ Whereas transketolase only catalyze the 2C unit
transfer reactions, transaldolase only catalyze 3C
unit transfer reactions
▪ For the activity of Transketolase TPP is required
REGULATION OF PENTOSE PHOSPHATE PATHWAY

 The principle products of the pentose phosphate pathway are R5P and NADPH
 Transaldolase and -ketolase reactions convert excess R5P to glycolytic intermediates when the metabolic need for
NADPH exceeds that of R5P in nucleotide biosynthesis
 The resulting GA3P and F6P can be consumed through glycolysis and oxidative phosphorylation or recycled by
gluconeogenesis to form G6P
 If the need of R5P is higher than NADPH, F6P and GA3P can be diverted from the glycolytic pathway for use in
the synthesis of R5P by reversal of transaldolase and transketolase reactions.
 The flux of the metabolic pathway is controlled by the G6P dehydrogenase reaction. This step is the control point of
the pathway.
 NADP+ is regulating the enzyme activity. As the ratio of the NADP+/NADPH ratio of the cytosol is 1/100 the ratio
has to be kept stable
 When the NADPH is consumed the ratio will be change to NADP+ side which means NADP+ concentrations will
increase and the increased NADP+ concentrations also will increase the G6P dehydrogenase activity
 Glucose 6-phosphate dehydrogenase enzyme is an important enzyme and its deficiency causes Favism,
which leads to hemolytic anemia.
 Favism is the occurrence of hemolytic anemia as a result of the consumption of fava beans
 The biggest reason for this is to ensure the continuity of glutathione (GSH), which is an antioxidant
molecule.
 NADPH is needed to sustain GSH and the only source of NADPH of erythrocytes is the pentose
phosphate pathway.
 If the G6P dehydrogenase enzyme, which catalyzes the first step of the pentose phosphate pathway, is
lack, NADPH will not be produced as this pathway will be interrupted and therefore the continuity of
GSH will not be ensured.
 Since consuming fava beans will increase the oxidant capacity in erythrocytes, if the continuity of GSH is
not ensured, there will be no molecules to take part in reducing the oxidant capacity and it will cause the
membrane structure to break down with oxidative damage and cause hemolysis.