Pentose Phosphate Pathway Dr. Abir Alghanouchi Biochemistry department Sciences college
The pentose phosphate pathway is an alternate route for the oxidation of glucose where ATP (energy) is neither produced nor utilized. The pentose phosphate pathway takes place entirely within the cytoplasm (because NADP + is used as a hydrogen acceptor) and is also known as the hexose monophosphate shunt or phosphogluconate pathway Is basically used for the synthesis of NADP and D ribose.
The PPP can be divided into two phases The irreversible oxidative phase: generates NADP which is required for many biosynthetic pathways and for detoxification of reactive oxygen species. The nonoxidative phase: interconverts 3, 4, 5, 6 and 7 monosaccharides to produce ribose 5P for nucleotide synthesis, and also to regenerate glucose 6P to maintain NADP production by the oxidative phase.
The irreversible oxidative phase Three enzymatic reactions in the oxidative phase G6PD is the committed step in the Pentose Phosphate Pathway because 6 Phosphoglucono lactone has no other metabolic fate except to be converted to 6 phosphogluconate.
4 6 2 OPO 3 5 3 O 2 Glucose-6-phosphate Dehydrogenase 6 2 OPO 3 NADP + + 5 NADP + O 1 4 Mg 2+ 3 2 Glucose 6 phosphate Dehydrogenase catalyzes oxidation of the aldehyde at 1 of glucose 6 phosphate, to a carboxylic acid This enzyme requires Mg 2+ et NADP + (serves as electron acceptor) as coenzymes NADP is a potent competitive inhibitor of this enzyme NADP/NADP + increase inhibits the reaction NADP/NADP + decrease stimulate the reaction 1 6-P gl lac glucose-6-phosphate 6-phoshogluconolactone e O
phate se 6-Phosphoglucono- O 6 1 2 OPO 3 + + lactonase 5 O 2 O + 2 O 3 4 O 1 4 O 3 2 5 2 OPO 6 3 6-phoshogluconolactone O 6-phosphogluconate 6 Phosphogluconolactonase catalyzes hydrolysis of 6 phosphogluconolactone The product is 6 phosphogluconate It is irreversible but not rate limiting
O O 1 2 3 4 5 6 O 2 OPO 3 6-phosphogluconate Phosphogluconate Dehydrogenase NADP + NADP + + O 2 2 Phosphogluconate Dehydrogenase catalyzes oxidative decarboxylation of 6 phosphogluconate, to yield the 5 ketose ribulose 5 phosphate The at 3 (2 of product) is oxidized to a ketone This promotes loss of the carboxyl at 1 as O 2 NADP + serves as oxidant 1 2 3 4 5 O 2 OPO 3 ribulose-5-phosphate
The reversible non oxidative phase In nonoxidative phase, ribulose 5 P is converted back to G 6 P by a series of reactions involving especially two enzymes 1.Transketolase 2.Transaldolase
Epimerase inter converts stereoisomers ribulose 5 P and xylulose 5 P Epimerase O 2 O Isomerase converts the ketose ribulose 5 P to ribose 5 P which is used in nucleotide, nucleic acid biosynthesis Both reactions are reversible 2 O 2 OPO 3 ribulose-5- phosphate Isomerase 2 OPO 3 xylulose-5- phosphate O 2 OPO 3 ribose-5- phosphate
Transketolase Transfers a 2 fragment from xylulose 5 P to either ribose 5 P or erythrose 4 P. Isomerase Epimerase Requires thiamine pyrophosphate (TPP), a derivative of vitamin B 1 as coenzyme and Mg 2+ as cofactor Transketolase Transaldolase Epimerase transketolase
Transketolase 2 O 2 O O O O + + O 2 OPO 3 2 OPO 3 2 OPO 3 2 OPO 3 xylulose- ribose- glyceraldehyde- sedoheptulose- 5-phosphate 5-phosphate 3-phosphate 7-phosphate Transfer of the 2 fragment to the 5 ribose 5 phosphate yields sedoheptulose 7 phosphate Transfer of the 2 fragment instead to 4 erythrose 4 phosphate yields fructose 6 phosphate
2 O Transaldolase 2 O O O O 2 OPO 3 O + + 2 OPO 2 OPO 3 3 2 OPO 3 sedoheptulose- glyceraldehyde- erythrose- fructose- 7-phosphate 3-phosphate 4-phosphate 6-phosphate Transaldolase catalyzes transfer of a 3 from sedoheptulose 7 phosphate to glyceraldehyde 3 P
SUMMARY: The balance sheet below summarizes flow of 15 atoms Through PPP reactions by which 5 sugars are converted to 3 and 6 sugars. TK 5 + 5 3 + 7 TA 7 + 3 4 + 6 TK 4 + 5 3 + 6 3 5 2 6 + 3 (Overall) TK: Transketolase TA: Transaldolase Xylulose-5-PO 4 Sedoheptulose-7-PO 4 Ribose-5-PO 4 Erythrose-4-PO 4 Glyceraldehyde-3-PO 4 Fructose-6-PO 4
Differences between MP shunt and glycolysis MP pathway Glycolysis Location Oxidation of glucose In -------------------- certain cells In ------------------- all cells - Occurs in the first -------------------- Phosphorylation occurs -------------------- reaction first then oxidation oenzyme Energy O 2 Pentoses NADP -------------------- + No -------------------- energy production Produced -------------------- Produced -------------------- NAD ------------------- + 2 -------------------- or 8 ATP Not -------------------- produced Not -------------------- produced
Importance of Pentose Phosphate Pathway 2 NADP + 2 NADP + O 2 glucose-6-p ribulose-5-p ribose-5-p Pentose Phosphate Pathway producing NADP and ribose-5-phosphate Ribulose 5 P may be converted to ribose 5 phosphate, a substrate for synthesis of nucleotides, nucleic acids and coenzymes The pathway also produces some NADP
2 NADP + 2 NADP + O 2 glucose-6-p ribulose-5-p ribose-5-p fructose-6-p, & glyceraldehyde-3-p Pentose Phosphate Pathway producing maximum NADP Glyceraldehyde 3 P and fructose 6 P may be converted to glucose 6 P, via enzymes of gluconeogenesis, for reentry to Pentose Phosphate Pathway, maximizing formation of NADP, which is need for reductive biosynthesis.
3 Glyceraldehyde 3 P and 6 fructose 6 P, formed from 5 sugar phosphates, may enter Glycolysis for ATP synthesis. 5 Ribose 1 phosphate generated during catabolism of nucleosides also enters Glycolysis in this way, after first being converted to ribose 5 phosphate Thus the Pentose Phosphate Pathway serves as an entry into Glycolysis for both 5 carbon & 6 carbon sugars.
0 2 0 2 2 O 2 2 GS NADP + Aerobic respiration Drugs, fava beans Superoxide radicals ydrogen peroxide glutathione peroxidase glutathione reductase pentose pathway Detoxification 2 2 O GSSG NADP + + Importance of PPP in RB When erythrocytes are exposed to chemicals that generate high levels of superoxide radicals, GS (Reduced Glutathione) is required to reduce these damaging compounds Glutathione Peroxidase catalyzes degradation of organic hydroperoxides by reduction, as two glutathione molecules are oxidized to a disulfide GSSG The PPP is responsible for maintaining high levels of NADP in red blood cells for use as a reductant in the glutathione reductase reaction.
The entry of glucose 6 phosphate into the pentose phosphate pathway is controlled by the cellular concentration of NADP NADP is a strong inhibitor of glucose 6 phosphate dehydrogenase (Rate Limiting Reaction) As NADP is used in various pathways, inhibition is relieved, and the enzyme is accelerated to produce more NADP
The synthesis of glucose 6 phosphate dehydrogenase is induced by the increased insulin/glucagon ratio after a high carbohydrate meal Insulin, which secreted in response to hyperglycemia, induces the synthesis of G6P dehydrogenase and 6 phosphogluconate dehydrogenase increasing the rate of glucose oxidation by PPP The synthesis of glucose 6 phosphate dehydrogenase is repressed during fasting
Mutations present in some populations causes a deficiency in glucose 6 phosphate dehydrogenase, with consequent impairment of NADP production Detoxification of 2 O 2 is inhibited, and cellular damage results lipid peroxidation leads to erythrocyte membrane breakdown and hemolytic anemia. Most G6PD deficient individuals are asymptomatic only in combination with certain environmental factors (sulfa antibiotics, herbicides, antimalarials, *divicine) do clinical manifestations occur. *toxic ingredient of fava beans
Uronic Acid Pathway Dr. Abir Alghanouchi Biochemistry department Sciences college
It is an alternative oxidative pathway for glucose in which glucose is converted into glucuronic acid Like the pentose phosphate pathway, Uronic Acid Pathway does not lead to generation of ATP It occurs in cytoplasm (mainly liver)
Importance of Uronic Acid Pathway This pathway produces glucuronic acid which is important for: Synthesis of substrates 1 Glycosaminoglycans (heparin, hyaluronic acid ) 2 Vitamin, L ascorbic acid (not in human) onjugation Reactions: UDP glucuronic acid is used for conjugation with many compounds to make them more soluble before excretion eg. steroid hormones and bilirubin Detoxification reactions: UDP glucuronic acid is used for conjugation with toxic compounds to make them less toxic eg. phenols
UDP glucuronate is converted to glucuronate then to L xylulose to D xylitol to D xylulose which then join PPP to complete its oxidation
Formation of UDP glucuronic acid Glucose 6 phosphate is isomerized to glucose 1 phosphate, which then reacts with uridine triphosphate (UTP) to form uridine diphosphate glucose (UDPGlc) in a reaction catalyzed by UDPGlc pyrophosphorylase UDPGlc is oxidized at carbon 6 by NAD dependent UDPGlc dehydrogenase in a two step reaction to yield UDP glucuronate
Formation of UDP glucuronic acid exokinase Glucose 6 (P) Phosphoglucomutase UDPGlc pyrophosphorylase Glucose UDPGlc dehydrogenase
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