pentose phosphate pathway, Lecture notes of Biochemistry

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The Pentose Phosphate Pathway – PPP

And other ways of Hexose Metabolism Molecular Biochemistry

OverviewOverview

 (^) It is an alternate route for the oxidation of glucose without direct consumption or generation of ATP.  (^) It takes place entirely in the cytoplasm.

Pentose Phosphate Pathway  (^) The pentose phosphate pathway is an alternative route for the metabolism of glucose.  (^) is a more complex pathway than glycolysis  (^) It does not lead to formation of ATP but has two major functions:  (^) (1) the formation of NADPH for synthesis of fatty acids and steroids, and maintaining reduced glutathione for antioxidant activity,  (^) (2) the synthesis of ribose for nucleotide and nucleic acid formation.  (^) Glucose, fructose, and galactose are the main hexoses absorbed from the gastrointestinal tract, derived from dietary starch, sucrose, and lactose, respectively.  (^) Fructose and galactose can be converted to glucose, mainly in the liver.

Importance ofImportance of pentosepentose phosphate pathway : phosphate pathway :  (^) Generation of NADPH

• (^) mainly used for reductive synthesis of fatty acids, cholesterol and steroid hormones.
• (^) hydroxylation reaction in metabolism of phenylalanine and tryptophan.
• (^) production of reduced glutathione in erythrocytes and other cells.  (^) Production of ribose residues

1. used for nucleotide,
2. nucleic acid,
3. and coenzyme biosynthesis

Uses of NADPH

 (^) The oxidative portion of the pentose phosphate pathway consists of three reactions that lead to the formation of ribulose 5-phosphate, CO2, and two molecules of NADPH for each molecule of glucose 6- phosphate oxidized.

1. This portion of the pathway is particularly important in the liver, lactating mammary glands, and adipose , which are active in the NADPH-dependent biosynthesis of fatty acids and 2. in the testes, ovaries, placenta and adrenal cortex , which are active in the NADPH-dependent biosynthesis of steroid hormones and in
2. erythrocytes, which require NADPH to keep glutathione reduced.

REACTIONS OF THE PENTOSE PHOSPHATE PATHWAY OCCUR IN THE CYTOSOL  (^) Like glycolysis, the enzymes of the pentose phosphate pathway are cytosolic.  (^) Unlike glycolysis , oxidation is achieved by dehydrogenation using NADP+, not NAD+, as the hydrogen acceptor.  (^) The sequence of reactions of the pathway may be divided into two phases:

1. an irreversible oxidative phase and
2. a reversible nonoxidative phase.  (^) In the first phase, glucose-6-phosphate undergoes dehydrogenation and decarboxylation to yield a pentose, ribulose-5-phosphate.  (^) In the second phase, ribulose-5-phosphate is converted back to glucose-6-phosphate by a series of reactions involving mainly two enzymes: transketolase & transaldolase.

Pentose Phosphate Pathway  (^) 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.  (^) 6-Phosphogluconolactonase catalyzes hydrolysis of the ester linkage, resulting in ring opening.  (^) The product is 6-phosphogluconate. H O O H H H O H O H CH 2 O PO (^3) 2  H H O H H O O H H H O H O H CH 2 O PO (^3) (^2)  H O 3 2 4 5 6 1 1 6 5 4 3 2 C HC CH HC HC CH 2 O PO (^3) (^2)  O O  O H HO O H O H N A D P H + H

NADP

• (^) H 2 O H + 1 2 3 4 5 6 G lucose- 6 - phosphate D ehydrogenase 6 - P hospho - glucono- lactonase glucose- 6 - phosp hate 6 - p ho shogluconolactone 6 - pho sphogluconate

NADP

+

serves as electron acceptor.

Formation of ribulose 5-phosphateFormation of ribulose 5-phosphate  (^) 6-Phosphogluconolactone is hydrolyzed by 6- phosphogluconolactone hydrolase. (or gluconolactone hydrolase.)  (^) The reaction is irreversible and not rate-limiting.  (^) The oxidative decarboxylation of the product, 6- phosphogluconate is catalyzed by 6-phosphogluconate dehydrogenase, which also requires NADP+ as hydrogen acceptor.  (^) This irreversible reaction produce s :

1. a pentose sugar–phosphate (ribulose 5-phosphate), Ketopentose (by decarboxylation)
2. CO2 (from carbon 1 of glucose), and
3. a second molecule of NADPH.

NADPH producing reactionsNADPH producing reactions

 (^) Glucose-6-P dehydrogenase  (^) 6-P-gluconate dehydrogenase

NADPH & NADHNADPH & NADH

 (^) NADPH , a product of the Pentose Phosphate Pathway, functions as a reductant in anabolic (synthetic) pathways, e.g., fatty acid synthesis.  (^) NAD+^ serves as electron acceptor in catabolic pathways, in which metabolites are oxidized.  (^) The resultant NADH is reoxidized by the respiratory chain, producing ATP.

REVERSIBLE NONOXIDATIVE REACTIONSREVERSIBLE NONOXIDATIVE REACTIONS  (^) The nonoxidative reactions of the pentose phosphate pathway occur in all cell types synthesizing nucleotides and nucleic acids.  (^) These reactions catalyze the interconversion of sugars containing three to seven carbons.  (^) These reversible reactions permit ribulose 5-phosphate (produced by the oxidative portion of the pathway)

1. to be converted either to ribose 5-phosphate (needed for nucleotide synthesis,)
2. or to intermediates of glycolysis—fructose 6-phosphate and glyceraldehyde 3-phosphate.  (^) Many cells that carry out reductive biosynthetic reactions have a greater need for NADPH than for ribose 5-phosphate.

The Nonoxidative Phase Generates Ribose Precurs

 (^) Ribulose-5-phosphate is the substrate for two enzymes.  (^) Ribulose-5-phosphate 3-epimerase alters the configuration about carbon 3, forming the epimer xylulose 5-phosphate , also a ketopentose.  (^) Ribose-5-phosphate keto-isomerase converts ribulose 5-phosphate to the corresponding aldopentose, ribose-5-phosphate, which is used for nucleotide and nucleic acid synthesis.

• (^) Epimerase interconverts stereoisomers ribulose-5-P and xylulose-5-P.
• (^) Isomerase converts the ketose ribulose-5-P to the aldose ribose-5- P.
• (^) Both reactions are reversible. C C C CH 2 OPO 32  O H OH H OH CH 2 OH C C C CH 2 OPO 3 2  O HO H H OH CH 2 OH C C C CH 2 OPO 3 2  OH H OH H OH HC (^) O H ribulose- 5 - phosphate xylulose- 5 - phosphate ribose- 5 - phosphate Epimerase Isomerase

Phase 2 Reactions:Phase 2 Reactions:  (^) Transketolase transfers the two-carbon units  (^) The reaction requires Mg2+ and thiamin diphosphate (vitamin B1) as coenzyme.  (^) Transketolase catalyzes the transfer of the two-carbon unit from xylulose-5-phosphate to ribose-5-phosphate, producing the seven-carbon ketose sedoheptulose-7- phosphate and the aldose glyceraldehyde-3-phosphate.  (^) These two products then undergo transaldolation.  (^) Transaldolase catalyzes the transfer of a three carbon moiety (carbons 1–3) from the ketose sedoheptulose-7-phosphate onto the aldose glyceraldehyde-3-phosphate to form the ketose fructose 6-phosphate and the four-carbon aldose erythrose 4-phosphate.