Pentose Phosphate Pathway. Glycogenesis. Glycogenolysis

Pentose phosphate pathway

Cytosolic reactions. Has four main functions.

1. Generation of NADPH: which is involved in reductive biosynthesis pathways.

2. Source of pentoses from hexoses: in particular ribose-5-phosphate which is required in large amounts in nucleic acids and co-enzyme synthesis.

3. Allows for the oxidation of pentose carbon: by channeling it into glycolysis.

4. It is a source or erythrose: which is required for the biosynthesis of aromatic amino acids.

Three distinct phases

1. Oxidation

2. Isomerization

3. Sugar rearrangement

Phosphate products

From 3 glucose-6-phosphate:

3CO2, 6NADPH, 2 fructose-6-phosphate, Glyceraldehyde.

This pathway is active in tissue that synthesis fatty acids or sterols since large amounts of NADPH are required. There is little activity of the pentose phosphate pathway in muscle and brain.

Oxidative stage

The path of carbon in PPP.

Three molecules of a six carbon (18 C) compound are converted to three molecules of a five carbon sugar (ribulose-5-phosphate) (15 C), CO2 is released (3 C).

Nonoxidative stage

Three molecules of five carbon sugars (total 15C) are interconverted to produce two molecules of a six carbon sugar (fructose-6-phosphate) (total 12C) and one molecule of a three carbon compound (Glyceraldehyde 3-phosphate).

Importance of NADPH

To keep SH groups in proteins in a reduced state.

To reduce oxidized glutathione (eliminates reactive oxygen species such as H2O2, by reducing them in the process becomes oxidized itself). If left unchecked, the peroxides cause premature cell lysis as they cleave C-C bonds in phospholipid tails of membranes and also damage hemoglobin irreversibly.

Glucose-6-Phosphate dehydrogenase deficiency

In patients taking the anti-malaria drug, primaquine, hemolytic anemia can result if they have this deficiency. This is because the drug promotes peroxide formation. NADPH is insufficient to reduce glutathione. Glutathione levels are too low to reduce all the peroxide produced and this results in damage to the red blood cell membrane.

Glycogen

Is a storage carbohydrate with a relative mass of x10^6 daltons.

1. Storage sites: liver, approximately 6% by weight after a high carbohydrate diet. In muscles, rarely above 1%.

2. Functions: Liver glycogen maintains blood glucose levels within normal limits. Muscle glycogen is the source of hexose units for glycolysis in this tissue.

Glycogenesis

Occurs in 4 steps.

1. Primer.

2. Activation.

3. Elongation.

4. Branching.

Primer formation

Glycogenin.

When glycogen stores are empty, glycogenin acts as a primer protein. It auto adds glucose units to itself using UDP-glucose until a short chain (8 residues) is formed.

If glycogen is already present, glycogen synthase can elongate from existing chains.

Glucose activation

Phosphoglucomutase.

Glucose-6-phosphate - Glucose-1-phosphate.

UDP- glucose pyrophosphorylase.

G1P + UTP - UDP-glucose (high-energy donor of glucose).

UDP-glucose is the activated form of glucose that can now be attached.

Chain elongation

Glycogen synthase (rate limiting step).

Transfer glucose from UDP-glucose - growing glycogen chain. Adds glucose via alpha (1-4) glycosidic bonds. Glucose is always added at the non-reducing ends of glycogen. This allows multiple ends for rapid synthesis and breakdown.

Branching

Amylo-alpha(1-4)-alpha(1-6) transglucosidase.

Breaks a segment of 5-8 glucose residues from the chain. Reattaches it to a more inferior site, forming an alpha (1-6) bond.

Glycogenolysis

Glycogen breakdown involving 2 main enzymes.

1. Phosphorylase: breaks alpha (1-4) linkages and removes outer chains until four residues are left on the alpha (1-6) chain.

2. Alpha (1-4)-alpha(1-4)-glucantransferase: transfers three of the four residues on the alpha (1-6) chain, exposing the alpha (1-6) residue which is then cleaved by amylo-1,6-glycosides.

Thereafter, G-1-P is converted to G-6-P by phosphoglucomutase which in turn is converted to glucose by glucose phosphatase.

Control of glycogenesis and glycogenolysis

To prevent wastage of energy resources, glycogen synthesis and breakdown should be reciprocally regulated. Reciprocal regulation occurs through phosphorylation and dephosphorylation of key enzymes. The phosphorylation of glycogen phosphorylase and glycogen synthase is under hormonal regulation through cAMP dependent kinase. Hormones like glucagon and adrenaline promote phosphorylation of these enzymes whereas insulin has the opposite effect. Dephosphorylation can occur by specific phosphatases.

Phosphorylation

Activates glycogen phosphorylase and promotes glycogen breakdown.

Inactivates glycogen synthase and inhibits glycogen synthesis.

Dephosphorylation

Inactivates glycogen phosphorylase and inhibits glycogen breakdown.

Activates glycogen synthase and promotes glycogen synthesis.