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Pentose-Phosphate Pathway
pentose phosphate pathway
Overview
Background
- The pentose phosphate pathway (aka hexose monophosphate shunt (HMP shunt)) divides into 3 oxidative steps and series of nonoxidative isomerizations and transketolase reactions, which can produce a wide variety of products.
- It occurs with the cytosol of the cell (just like glycolysis); the pentose phosphate pathway and glycolysis are intimately related.
Overview
- The pentose phosphate pathway (PPP) is essential for the generation of NADPH and ribose 5-phosphate.
- NADPH is a critical reducing agent: it is an essential electron donor in the management of oxidative stress.
- NADPH is important for RBC reduction of glutathione as well as the reductive biosynthesis of fatty acids and cholesterol.
- Digestive, endocrine, hematologic, and reproductive tissues all rely on a high ratio of NADPH to NADP+ to reduce oxidative radicals.
- Ribose 5-phosphate provides the pentose sugar for nucleotides (eg, DNA) and various coenzymes (eg NADH). Remember that nucleotides comprise a pentose sugar, phosphate group, and nitrogenous base (they are the building blocks of RNA and DNA).
- Rapidly dividing cells rely on the PPP for the generation of nucleotides.
Stoichiometric Equation of the PPP
The stoichiometry for its most essential mode:
- The reactants are glucose 6-phosphate + 2 NADP+ + H2O
- The products are ribulose 5-phosphate + 2 NADPH + H2 + CO2
Glucose 6-phoshate and Glycolysis
- Glucose 6-phosphate is the first intermediary product in glycolysis. Thus, the PPP and glycolysis are intimately related (in glycolysis, glucose is converted to glucose 6-phosphate and ultimately to pyruvate).
Oxidative Steps
Step 1: Dehydrogenation of Glucose 6-Phosphate
Glucose 6-Phosphate
- Glucose 6-phosphate is a ringed structure: the ring comprises 5 carbons and 1 oxygen.
- A sixth carbon is bound to carbon 5.
- We include the hydroxyls and hydrogens on each carbon, as well as the phosphate group on carbon 6. We use select colors for the oxygen within the ring and the hydrogens on carbon 1, so we can follow their movement throughout the pathway.
Dehydrogenation of Glucose 6-phosphate
- Step 1: glucose 6-phosphate dehydrogenase catalyzes a dehydrogenation reaction to produce 6-phosphoglucono-delta-lactone.
- This is a dehydrogenation reaction, so we can predict that 6-phosphoglucono-delta-lactone will be similar in appearance to glucose 6-phosphate but with fewer hydrogens.
- Indeed, carbon 1 loses its hydrogen and forms a double bond to oxygen.
- NADP+ is reduced to NADPH; it picks up a hydrogen carrying two high-energy electrons to form NADPH and an additional hydrogen is lost.
- NADPH is an important oxidative stress reducer.
- For accounting purposes, we include the other hydrogen which is split off from glucose 6-phosphate during this dehydrogenation reaction; this accounts for one of the hydrogens in the stoichiometric equation we laid out at the beginning.
Dehydrogenation Reaction
- Start at Glucose 6-phosphate: at carbon 1, one of the hydrogens is split from the molecule and binds to NADP+ to form NADPH; the other hydrogen is also removed; and the oxygen forms a double bond to carbon.
Step 2: Hydrolysis of 6-phosphoglucono-delta-lactone
Hydrolysis of 6-phosphoglucono-delta-lactone
- Step 2: a lactonase catalyzes a hydrolysis reaction, which produces 6-phosphogluconate.
- This is a hydrolysis reaction, so we can anticipate that it will involve the rupture of a chemical bond. Indeed, show that the ring structure is broken between carbon 5 and the neighboring oxygen.
So, we show this linear molecule, now:
- Carbon 1 is bound to two oxygen atoms.
- Line of carbons 2, 3, 4, and 5.
- The phosphate group attached to carbon 6.
- We highlight the hydroxyl attached to carbon 5 because, as we'll show in a moment, it is added during the hydrolysis reaction.
Hydrolysis Reaction
- Start with 6-phosphoglucono-delta-lactone:
- A water molecule is introduced with a hydroxyl bind to carbon 5.
- The bond between carbon 5 and the neighboring oxygen is broken.
- Again, for accounting purposes, we show that a hydrogen is lost in the reaction.
Step 3: Decarboxylation of 6-phosphogluconate
Decarboxylation of 6-phosphogluconate
- Step 3: 6-phosphogluconate dehydrogenase catalyzes this decarboxylation reaction.
- The product is ribulose 5-phosphate plus carbon dioxide, which is released from the 6-phosphogluconate.
- Ribulose 5-phosphate is a 5-carbon, linear molecule.
- Carbon 1 has a hydroxyl and two hydrogens attached and that carbon 2 has a double bond to oxygen.
- The other carbons are the same as in the previous molecule but are numbered one less than in the reactant (because CO2 was release).
- Importantly, this is a second opportunity for the reduction of NADP+ to NADPH.
- As we indicated in our stoichiometric equation, 2 NADPH are produce for every molecule of glucose 6-phosphate that undergoes the PPP.
Decarboxylation reaction
- Start with 6-phosphogluconate:
- The carbon dioxide is released at carbon 1.
- NADP+ is reduced to NAPDH.
- This leads carbon 3 to form a double bond with oxygen and to lose a hydrogen.
- The product is ribulose 5-phosphate; the carbon numbering changes:
- Carbon 2 now becomes carbon 1.
- Carbon 3 becomes carbon 2. And so on.
Nonoxidative Steps
Isomerization of Ribulose 5-phosphate to Ribose 5-phosphate
Isomerization of Ribulose 5-Phosphate
- The PPP has many potential products.
- Let's address the production of ribose 5-phosphate, since it is critical for the formation of nucleotides and a selection of coenzymes.
- Via our first nonoxidative reaction, phosphopentose isomerase catalyzes a rearrangement (an isomerization) of ribulose 5-phosphate to ribose 5-phosphate.
- Ribose 5-phosphate differs from ribulose 5-phosphate in that carbon 1 bears the double-bonded oxygen and carbon 2 bears a hydroxyl.
- Carbons 1 and 2 are the targets of the isomerization.
Ribose 5-phosphate provides the nucleotide pentose sugar
- Ribose 5-phosphate is an essential component of nucleotides, including ATP and DNA and RNA, and also coenzymes, including NADH, FAD, and coenzyme A.
Additional Pentose Phosphate Pathway Products
Additional Products
For reference, we list out additional potential products of the pentose phosphate pathway:
- Xylulose 5-phosphate
- Sedoheptulose 7-phosphate
- Glyceraldehyde 3-phosphate
- Fructose 6-phosphate
- Erythrose 4-phosphate
Transketolase and Transaldolase Reactions
- In our overview, we established the most essential mode of the pentose phosphate pathway; however, because of the interconnection with the glycolytic pathway, cells have the ability of up-regulating or down-regulating the production ratio of products. The PPP relies on transketolase and transaldolase to accomplish these up- and down-regulations.
Transketolase Reactions: 2-carbon transfer
- Transketolase reactions are thiamine-dependent (its prosthetic group is thiamine) and are responsible for 2-carbon transfers of glycoaldehyde from a ketose donor to an aldose acceptor.
- For example:
- Via a transketolase reaction, xyulose 5-phosphate, which is simply an epimer of ribulose 5-phosphate, (a 5-carbon molecule) reacts with ribose 5-phosphate (another 5-carbon molecule) to form glyceraldehyde 3-phosphate (a 3-carbon molecule) and sedoheptulose 7-phosphate (a 7-carbon molecule).
- Thus, the total carbon atoms at the beginning is 10 (5 + 5) and at the end is 10 (3 + 7). A 2-carbon transfer.
- We can imagine that 2 carbon atoms are removed from the xyulose (C5) to form the glyceraldehyde (C3) and 2 carbons are added to the ribose (C5) to form the sedoheptulose (C7).
Transaldolase Reactions: 3-carbon transfer
- Transaldolase reactions are responsible for 3-carbon transfers of a dihydroxyacetone unit from a ketose donor to an aldose acceptor. Transaldolase is NOT thiamine dependent (it does NOT contain a prosthetic group).
- For example:
- Via a transaldolase reaction, glyceraldehyde 3-phosphate (a 3-carbon molecule) reacts with sedoheptulose 7-phosphate (a 7-carbon molecule) to form fructose 6-phosphate (a 6-carbon molecule) and erythrose 4-phosphate (a 4-carbon molecule).
- Thus, the total carbon atoms at the beginning is 10 (3 + 7) and at the end is 10 (3 + 7). A 3-carbon transfer.
- We can imagine that 3 carbon atoms are added to the glyceraldehyde (C3) to form the fructose (C6) and 3 carbons are removed from the sedoheptulose (C7) to form the eryhtrose (C4).
Glycolytic Effect
- As mentioned earlier, digestive, endocrine, reproductive digestive, endocrine, hematologic, and reproductive tissues all rely on a high ratio of NADPH to NADP+ to reduce oxidative radicals; whereas, rapidly dividing cells rely on the PPP for the generation of nucleotides, so we can predict which products various organ systems will generate.
- Take a digestive organ cell, for example, we'll assume that it requires high amounts of NADPH for fatty acid synthesis. In this case, the PPP will up-regulate the production of glyceraldehyde 3-phosphate and fructose 6-phosphate because they are reversibly linked to glycolysis.
Clinical Correlation: glucose 6-phosphate dehydrogenase deficiency
glucose 6-phosphate dehydrogenase deficiency
Hemolytic Anemia from NADPH deficiency
- As a clinical correlation, denote that glucose 6-phosphate dehydrogenase deficiency results in hemolytic anemia from NADPH deficiency.
- Red blood cells rely on glutathione to protect them against oxidative species. Glutathione relies on NADPH for its reductive regeneration.
- Thus, NADPH deficiency leaves the erythrocytes with a deficiency of protective glutathione and the cells lyse from the build-up of the reactive oxygen species.