Pentose Phosphate Pathway and Glycogen* Metabolism

Glucose-6-phosphate is a key metabolite at the crossroad of four different pathways. First, under aerobic conditions and at low ATP (high ADP) concentrations, glucose-6-P will rapidly be oxidized to CO2 via pyruvate and acetyl-CoA. Second, when in need for biosynthetic activity, such as cell division with a great need for new nucleic acids, some of the glucose-6-P oxidation proceeds via ribulose-5-P in the pentose phosphate pathway. Third, phosphatases provide free glucose in liver that rapidly equilibrates across the hepatic cell membrane, a mechanism by which the liver controls blood glucose levels. Fourth, to store extra glucose for emergencies independent of sugar levels in the blood as glycogen in liver and muscle cells (carbohydrate loading).

Pentose Phosphate Pathway
(KEGG pathway MAP00030)

The pentose phosphate pathway (or cycle) converts glucose-6-phosphate to reducing equivalents (NADPH) and biosynthetic precursors (ribose) for the reductive biosynthesis of lipids and nucleic acids. The pathway can be modulated according to different metabolic requirements such as:

Pathway Mode Result Net Reaction
Oxidative branch Reducing power and pentoses 6 glucose-6-P + 12 NADP+ Þ 6 ribulose-5-P + 6 CO2 + 12 NADPH
Non-oxidative branch Glycolytic intermediates 6 ribulose-5-P Þ 5 glucose-6-P + Pi 
Both branches (cyclic) Reducing power 1 glucose-6-P + 12 NADP+ Þ 6 CO2 + 12 NADPH + Pi

The first step of the oxidative branch is catalyzed by Glucose-6-phosphate 1-dehydrogenase (E.C. and competes with  phosphoglucoisomerase (E.C. for glycolysis and phosphoglucomutase (E.C. for glycogen synthesis for its substrate. This linear branch involves two dehydrogenases, one which decarboxylates a C6 lactone intermediate to a C5 sugar. It generates the nucleotide precursor ribose-5-phosphate which is a component of important coenzymes ATP, CoA, NAD(P)+, FAD, and genetic material RNA, and DNA.

The second mode, or non-oxidative branch, of the pentose phosphate cycle includes several interconversion steps of C7, C4, and C3 ketoses and aldoses regenerating glucose-6-phosphate, fructose-6-phosphate, and glyceraldehyde-3-phosphate, all three being  metabolites of glycolysis/gluconeogenesis. This complex recycling of ribulose-5-P back to glucose-6-P is necessary for the complete anaerobic oxidation of one molecule of glucose to carbon dioxide and water and 12 molecules of NADPH (the last mode shown above).

All reactions of the non-oxidative branch are fully reversible, unlike the dehydrogenase reactions of the oxidative branch of the pentose phosphate pathway. The decarboxylation makes the oxidative reaction irreversible. Only plants and photosynthetic microorganisms have the enzymes necessary to reverse this pathway (Calvin cycle) using closely related, but not identical set of proteins. 

Glycogen metabolism
(KEGG Pathway MAP00500)

Glucose cannot accumulate in large numbers inside cells because an accumulation of charged glucose-6-P would have a strong osmotic effect essentially causing cells to swell. Instead, glucose is stored in form of the non-charged, water free glucose polymer glycogen. After a heavy intake of carbohydrates, one tenth of the liver mass may exist as glycogen. Within the first 12 to 24 hours after food withdrawal most of the bodies carbohydrate needs are met by this internal storage. After this period the body switches to gluconeogenesis to meet the carbohydrate needs, primarily fueled by amino acid metabolism, i.e. protein degradation. The normal glycogen content of liver varies between 2 and 8%.

Glycogenesis is the synthesis of glycogen glucose-6-P is isomerized to glucose-1-P by phosphoglucomutase and subsequently activated by UTP as an high energy biosynthetic precursor UDP-glucose.

                            UTP + glucose-1-P Þ UDP-glucose + PPi

The highly energy compound UDP-glucose is used to transfer a glucose unit to branches of glycogen. This reaction is catalyzed by glycogen synthetase ( E.C. The nucleotide of choice for glucose activation for glycogen synthesis in E.coli is ATP forming ADP-glucose from glucose-1-P.

Glycogenolysis or glycogen degradation uses phosphorylase (E.C. to remove glucose units from by phosphorylation (instead of hydrolysis) to form free glucose-1-P.

Glycogen synthesis and degradation are co-regulated through intracellular (allosteric) as well as extracellular (hormonal) signals. The intracellular regulation is mediated by the levels of ATP and AMP, while the hormonal control operates through posttranslational enzyme phosphorylation and dephosphorylation. The hormones glucagon and epinephrine stimulate glycogen degradation through enzyme phosphorylation inhibiting its synthesis. Insulin is an antagonist to glucagon and epinephrine stimulating glycogen synthesis via dephosphorylation of glycogen synthase (now active) and phosphorylase (now inactive). Thus, with a single switch, glycogen synthesis can be activated (inhibited) while its degradation is inhibited (activated).

In the absence of hormonal activation, cytoplasmic AMP activates phosphorylase b. ATP competes with AMP inhibits phosphorylase b. The phosphorylation of phosphorylase b by kinase, however, converts it to the fully active phosphorylase a independent of ATP and AMP levels. Thus hormonal control overrides a cellular (or local) control mechanism.

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