Glycolysis is the core of cellular metabolism. While it is often represented as a single straight line that leads directly into the Krebb’s cycle, there are many offshoots and branching pathways. While we think of glycolysis as mainly producing ATP, there are also many other useful metabolites that can be produced from glucose. The Pentose Phosphate Pathway is an alternative rout for turning Glucose-6-phosphate into fructose-6-phosphate for use in the second phase of glycolysis. It is a unique pathway that doesn’t make or use any ATP, but instead shunts Glucose-6-phosphate away from the preparatory phase of glycolysis to generate large amounts of NADPH (a reducing agent and anti-oxidant) as well as material to synthesize nucleic acids. Any sugars that don’t get used for nucleic acid synthesis are returned to the second phase of glycolysis.
The Pentose Phosphate pathway can be broken into the oxidative phase, and the non-oxidative phase. The oxidative phase is a two-step process where glucose-6-phosphate is oxidized to Co2 and ribulose-5-phosphate, and NADP+ is reduced to NADPH. This step can be triggered by oxidative stress (because NADPH to neutralize free radicals) or a lack of ribose for DNA synthesis. The non-oxidative stage does not have any red/ox reactions but instead recycles the carbons in ribulose-5-phosphate to produce precursors for nucleic acid synthesis and fructose-6-phosphate to return to glycolysis. While the first stage is reasonably direct, the second stage is a non-linear, multistep process. The end result is to take six 5-carbon sugars(ribulose) from the first stage and turn them into five 6-carbon sugars (fructose). To simplify the diagram, we elected to leave out enzymes and the rules for rearrangements, hydrolysis, synthesis occurring in each step. Instead, the diagram is only intended to help students keep track of which carbons move to which sugars on each step.
Ok, lets follow 6 glucose-6-phosphate molecules as they travel through the Pentose Phosphate Pathway. One way to represent that is to write it into one big equation like this:
6 Glucose-6-phosphate → 6-CO2+12NADPH+5Fructose-6-phosphate
However, most of the reaction is a mirror image of itself, so it is easier to think about the reaction as two half cycles represented like this:
3 Glucose-6-phosphate → 3-CO2+6NADPH+2.5Fructose-6-phosphate
The oxidative phase happens in two steps: glucose-6-phosphate to 6-phosphogluconate, and then 6-phosphogluconate to ribulose-5-phosphate and CO2. each step generates a NADPH for every glucose. At the start of the non-oxidative phase the ribose is converted to either xylose-5-phosphate, or ribose-5-phosphate. If no ribose is used for nucleic acid synthesis, the ratio of xylose to ribose will be 2:1.
2 xyulose+1 ribose → 2.5 fructose
The main action of the pathway happens between the ribose-5-phosphate and one xyulose-5-phosphate, while the other xyluose-5-phosphate only comes in at the end. The first Xyluose-5-phosphate will be cut below the aldehyde, and two carbons will be transferred to the top of the ribulose-5-phosphate, forming the seven carbon sedheptulose-7-phosphate and the remaining 3 carbons from the first Xyluose-5-phosphate become glyceraldehyde-3-phosphate. Three carbons are then cut from the ketone end of Sedheptulose-7-phosphate and attached to the keytone end of Glyceraldehyde-3-phosphate making one fructose-6-phosphate and leaving one Erythrose-4-Phosphate. Erythrose-4-phosphate can be used to synthesize nucliotides, or it can react with the second xylulose-5-phosphate to make a second fructose-6-phosphate and a glyceraldehyde-3-phosphate. After two cycles complete, the two glyceraldehyde-3-phosphates can rearrange to form the last Fructose-6-phosphate.
NADPH is an important electron donor, it can provide reductive power to fuel energy consuming processes, and also donate electrons to neutralize free radicals, particularly the oxygen radical. To fill these roles, the concentration of NADPH in the cell must be much higher than the concentration of NAD+. The pentose phosphate can appears early in evolutionary history because it can quickly convert large amounts of NAD+ into NADPH and doesn’t need ATP or other outside energy sources to do it.