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Pentose Phosphate Pathway
Copyright © 1999-2007 by Joyce J. Diwan. All rights reserved.
Pentose Phosphate Pathway
Pentose Phosphate Pathway Other names: Phosphogluconate Pathway Hexose Monophosphate Shunt The linear part of the pathway carries out oxidation and decarboxylation of the 6-C sugar glucose-6-P, producing the 5-C sugar ribulose-5-P.
to a carboxylic acid.6CH2OPO32 Glucose-6-phosphate Dehydrogenase OH NADP 1 H 4 5 O H 2 6 CH OPO 2 2 3 + NADPH + H 5 + O 6-Phosphogluconolactonase H 2 O H+ O 1 O 1C O OH HC 2 H H OH 3 4 H OH 3 H 2 HO 3CH HC OH 4 OH H OH HC 5 6 OH H OH H OH CH2OPO32 glucose-6-phosphate 6-phoshogluconolactone 6-phosphogluconate Glucose-6-phosphate Dehydrogenase catalyzes oxidation of the aldehyde (hemiacetal). at C1 of glucose-6-phosphate. in ester linkage (lactone). NADP+ serves as electron acceptor. .
. and thus potentially toxic. resulting in ring opening. The product is 6-phosphogluconate. 6-Phosphogluconolactonase speeds up the reaction. decreasing the lifetime of the highly reactive.6CH2OPO32 Glucose-6-phosphate Dehydrogenase OH NADP 1 H 4 5 O H 2 6 CH OPO 2 2 3 + NADPH + H 5 + O 6-Phosphogluconolactonase H 2 O H+ O 1 O 1C O OH HC 2 H H OH 3 4 H OH 3 H 2 HO 3CH HC OH 4 OH H OH HC 5 6 OH H OH H OH CH2OPO32 glucose-6-phosphate 6-phoshogluconolactone 6-phosphogluconate 6-Phosphogluconolactonase catalyzes hydrolysis of the ester linkage. Although ring opening occurs in the absence of a catalyst. 6-phosphogluconolactone.
This promotes loss of the carboxyl at C1 as CO2.O 1C O OH Phosphogluconate Dehydrogenase NADP+ NADPH + H+ 1CH2OH 2 HC 2 HO 3CH HC OH 4 C O OH OH HC CO2 2 3 HC 5 6 OH HC 4 5 CH2OPO 3 CH2OPO 32 6-phosphogluconate ribulose-5-phosphate Phosphogluconate Dehydrogenase catalyzes oxidative decarboxylation of 6-phosphogluconate. The OH at C3 (C2 of product) is oxidized to a ketone. . to yield the 5-C ketose ribulose-5-phosphate. NADP+ serves as oxidant.
functions as a reductant in anabolic (synthetic) pathways..g. e. + N R 2e + H + N R NADP+ NADPH NADPH. a product of the Pentose Phosphate Pathway. producing ATP. fatty acid synthesis. in which metabolites are oxidized. The resultant NADH is reoxidized by the respiratory chain. NAD+ serves as electron acceptor in catabolic pathways.H O C NH2 H H O C NH2 Reduction of NADP+ (as with NAD+) involves transfer of 2 e and 1 H+ to the nicotinamide moiety. .
NAD+ & NADP+ differ only in the presence of an extra phosphate on the adenosine ribose of NADP+. This difference has little to do with redox activity. It is a mechanism for separation of catabolic and synthetic pathways. but is recognized by substrate-binding sites of enzymes. Nicotinamide Adenine Dinucleotide O H O C NH2 O P O CH2 H H OH + N O H H OH NH2 N N nicotinamide O O P O O CH2 H H OH N O H N adenine esterified to Pi in NADP+ H OH .
to replenish NADPH. This enzyme is regulated by availability of the substrate NADP+. . Additional enzymes include an Isomerase. The rest of the pathway converts ribulose-5-P to the 5-C product ribose-5-P. As NADPH is utilized in reductive synthetic pathways. or to 3-C glyceraldehyde-3-P & 6-C fructose-6-P. Epimerase.Regulation of Glucose-6-phosphate Dehydrogenase: Glucose-6-phosphate Dehydrogenase is the committed step of the Pentose Phosphate Pathway. and Transaldolase. the increasing concentration of NADP+ stimulates the Pentose Phosphate Pathway. Transketolase.
Both reactions involve deprotonation to an endiolate intermediate followed by specific reprotonation to yield the product. CH2OH C O H OH Epimerase CH2OH C H H C C O OH OH HO H C C Isomerase converts the ketose ribulose-5-P to the aldose ribose-5-P.Epimerase interconverts stereoisomers ribulose-5-P and xylulose-5-P. CH2OPO32 xylulose-5phosphate HC H C C C O OH OH OH CH2OPO32 ribulose-5H phosphate Isomerase H CH2OPO32 ribose-5phosphate . Both reactions are reversible.
in each case from a ketose donor to an aldose acceptor. and Transaldolase actually transfers a ketol moiety (dihydroxyacetone). since Transketolase actually transfers an aldol moiety (glycoaldehyde). . However the traditional enzyme names are used here. E. D. Nicholson has suggested that the names of these enzymes should be changed.Transketolase & Transaldolase catalyze transfer of 2-C or 3-C molecular fragments respectively.
Pyruvate Dehydrogenase of Krebs Cycle also utilizes TPP as prosthetic group. Transketolase utilizes as prosthetic group thiamine pyrophosphate (TPP).Transketolase CH2OH C HO H C C O H OH H H HC C C C O OH OH OH H HC C O OH HO H H CH2OH C C C C C O H OH OH OH + H + H CH2OPO32 CH2OPO32 CH2OPO32 CH2OPO32 xylulose5-phosphate riboseglyceraldehyde. a derivative of vitamin B1. .sedoheptulose5-phosphate 3-phosphate 7-phosphate Transketolase transfers a 2-C fragment from xylulose5-P to either ribose-5-P or erythrose-4-P.
H+ dissociates from the C between N & S in the thiazolium ring.aminopyrimidine moiety N H3C N CH2 thiazolium H3C ring + N C H S O CH2 O P O O O P O O CH2 acidic H+ thiamine pyrophosphate (TPP) NH2 TPP binds at the active site in a “V” conformation. & serves as H+ acceptor. The aminopyrimidine amino group is near the dissociable H+. This H+ transfer is promoted by a Glu residue adjacent to the pyrimidine ring. .
H3C TPP CH2 2 CH2OPO2OPO 3 The thiazolium carbanion reacts with the carbonyl C of xylulose-5-P to form an addition compound. N H3C N CH2 + N C S xylulose-5-P CH2OH C HO H C C O H OH NH2 Transketolase H3C CH2 + N C N NH2 HO HO C C C S CH2OH H OH CH2 CH2OPO32 2 CH2OPO2OPO 3 N H3C subsequent cleavage active site intermediate H CH2OPO32 . N+ in the thiazole ring acts as an e sink. promoting C-C bond cleavage.
H3C 2 CH2 CH2OPO2OPO 3 The 2-C fragment + CH2 N condenses with N S C one of the aldoses HO C CH2OH subsequent H3C N NH2 erythrose-4-P (4-C) cleavage HO C H or ribose-5-P (5-C) active site H C OH to form a ketose-P intermediate CH2OPO32 product. . HO C H Completion is by H C OH reversal of these CH2OPO32 Transketolase steps. C CH2OH A 2-C fragment C O H3C N NH2 remains on TPP.H3C 2 CH2 CH2OPO2OPO 3 The 3-C aldose TPP + glyceraldehyde-3-P CH2 N xylulose-5-P N S is released.
Transketolase CH2OH C HO H C C O H OH H H HC C C C O OH OH OH H HC C O OH HO H H CH2OH C C C C C O H OH OH OH + H + H CH2OPO32 CH2OPO32 CH2OPO32 CH2OPO32 xylulose5-phosphate riboseglyceraldehyde. .sedoheptulose5-phosphate 3-phosphate 7-phosphate Transfer of the 2-C fragment to the 5-C aldose ribose-5-phosphate yields sedoheptulose-7-phosphate. Transfer of the 2-C fragment instead to the 4-C aldose erythrose-4-phosphate yields fructose-6-phosphate.
from sedoheptulose-7-phosphate to glyceraldehyde-3-phosphate.glyceraldehyde.fructose7-phosphate 3-phosphate 4-phosphate 6-phosphate Transaldolase catalyzes transfer of a 3-C dihydroxyacetone moiety. Transaldolase has an a.b barrel structure. .CH2OH C HO CH HC HC HC H2C OH OH OH HC O Transaldolase H2C C HC O OH OPO32 HC HC H2C O OH OH HO CH HC OH OH OPO32 OH O + HC H2C + HC H2C OPO32 OPO32 sedoheptulose.erythrose.
the e-amino group of a lysine residue reacts with the carbonyl C of sedoheptulose-7-P to form a protonated Schiff base intermediate.Enz-Lys NH2 HO CH2OH C CH HC OH OH OH OPO32 HC O OH OH OPO32 Enz-Lys OH O Enz-Lys H N + HO CH2OH C CH HC HC HC H2C OH OH OH OPO32 CH2OH H N + HO C C H + H+ Schiff base intermediate sedoheptulose7-phosphate HC H2C HC erythrose-4phosphate HC HC Transaldolase H2C In Transaldolase. .
as the carbanion attacks instead the aldehyde carbon of the 3-C aldose glyceraldehyde-3-P to yield the 6-C fructose-6-P. . Schiff base intermediate CH HC OH OH OH OPO32 sedoheptulose7-phosphate HC H2C HC The Schiff HC base erythrose-4phosphate HC stabilizes the HC carbanion H2C Transaldolase on C3.Enz-Lys NH2 HO CH2OH C O H Enz-Lys N + HO OH CH2OH C CH HC HC HC H2C O OH OH OPO32 Enz-Lys H N + HO OH OH OH OPO32 CH2OH C C H + H+ Aldol cleavage releases erythrose-4phosphate. Completion of the reaction is by reversal.
The diagram at right summarizes flow of 15 C atoms through Pentose Phosphate Pathway reactions by which 5-C sugars are converted to 3-C and 6-C sugars. IS = Isomerase EP = Epimerase TK = Transketolase TA = Transaldolase (3) ribulose-5-P IS EP ribose-5-P TK (2) xylulose-5-P glyceraldehyde-3-P sedoheptulose 7 P fructose-6.P erythrose-4-P TK TA fructose-6-P glyceraldehyde-3-P .
The balance sheet below summarizes flow of 15 C atoms through Pentose Phosphate Pathway reactions by which 5-C sugars are converted to 3-C and 6-C sugars. C5 + C5 C3 + C7 (Transketolase) C3 + C7 C6 + C4 (Transaldolase) C5 + C4 C6 + C3 (Transketolase) ____________________________ 3 C5 2 C6 + C3 (Overall) Glucose-6-phosphate may be regenerated from either the 3-C glyceraldehyde-3-phosphate or the 6-C fructose-6-phosphate. via enzymes of Gluconeogenesis. .
the Pentose Phosphate Pathway can operate in various modes. and ATP. a substrate for synthesis of nucleotides and nucleic acids.Depending on needs of a cell for ribose-5-phosphate. There are three major scenarios: 2 NADP+ 2 NADPH + CO2 glucose-6-P ribulose-5-P ribose-5-P Pentose Phosphate Pathway producing NADPH and ribose-5-phosphate Ribulose-5-P may be converted to ribose-5-phosphate. to maximize different products. The pathway also produces some NADPH. NADPH. .
. & glyceraldehyde-3-P Pentose Phosphate Pathway producing maximum NADPH Glyceraldehyde-3-P and fructose-6-P may be converted to glucose-6-P for reentry to the linear portion of the Pentose Phosphate Pathway.2 NADP+ 2 NADPH + CO2 glucose-6-P ribulose-5-P ribose-5-P fructose-6-P. maximizing formation of NADPH.
& glyceraldehyde-3-P to Glycolysis for production of ATP Pentose Phosphate Pathway producing NADPH and ATP Glyceraldehyde-3-P and fructose-6-P.2 NADP+ 2 NADPH + CO2 glucose-6-P ribulose-5-P ribose-5-P fructose-6-P. may enter Glycolysis for ATP synthesis. formed from 5-C sugar phosphates. . The pathway also produces some NADPH.
after first being converted to ribose-5-phosphate. & glyceraldehyde-3-P to Glycolysis for production of ATP Pentose Phosphate Pathway producing NADPH and ATP Ribose-1-phosphate generated during catabolism of nucleosides also enters Glycolysis in this way. . Thus the Pentose Phosphate Pathway serves as an entry into Glycolysis for both 5-carbon & 6-carbon sugars.2 NADP+ 2 NADPH + CO2 glucose-6-P ribulose-5-P ribose-5-P fructose-6-P.
One role of glutathione is degradation of hydroperoxides. Hydroperoxides can react with double bonds in fatty acids of membrane lipids. . Its functional group is a cysteine thiol. that arise spontaneously in the oxygen-rich environment in red blood cells.O H 3N + O N H CH CH2 SH C N H CH2 COO H C CH2 CH2 C COO -glutamyl-cysteinyl-glycine Glutathione Glutathione is a tripeptide that includes a Glu linked by an isopeptide bond involving the side-chain carbonyl group. making membranes leaky.
. 2 GSH + ROOH GSSG + ROH + H2O Glutathione Peroxidase uses the trace element selenium as functional group. selenocysteine. The enzyme's primary structure includes an analog of cysteine. as two glutathione molecules (represented as GSH) are oxidized to a disulfide.O H 3N + O N H CH CH2 SH C N H CH2 COO H C CH2 CH2 C COO -glutamyl-cysteinyl-glycine Glutathione Glutathione Peroxidase catalyzes degradation of organic hydroperoxides by reduction. with Se replacing S.
Regeneration of reduced glutathione requires NADPH. due to inadequate [NADPH] within red blood cells. . The effect of partial deficiency of Glucose-6-phosphate Dehydrogenase is exacerbated by substances that lead to increased production of peroxides (e. the antimalarial primaquine).g. Glutathione Reductase catalyzes: GSSG + NADPH + H+ 2 GSH + NADP+ Genetic deficiency of Glucose-6-P Dehydrogenase can lead to hemolytic anemia.. produced within erythrocytes in the Pentose Phosphate Pathway.
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