Chapter 3 of 5 - Glycogenesis Course
From glucose trapping and mutase steps to UDP-glucose, glycogen synthase, and branching - the enzyme sequence that builds glycogen matches the chemistry you need for exams and clinical biochemistry.
Glycogenesis is carried out by a coordinated set of enzymes that act in sequence: glucose is phosphorylated, rearranged to glucose-1-phosphate, activated as UDP-glucose, then polymerized and branched into glycogen. Each step has a dedicated catalyst, and flux through the pathway is controlled mainly at glycogen synthase, the rate-limiting step.
The primer for new glycogen comes from glycogenin and glycogen architecture, which you should connect mentally with the synthase step below.
Both enzymes phosphorylate glucose to glucose-6-phosphate (G6P), trapping glucose inside the cell. Hexokinase I-III are widely expressed, have a low Km for glucose (high affinity), and are product-inhibited by G6P, so they work well when glucose is scarce. Glucokinase (hexokinase IV) is prominent in liver and pancreatic beta cells, has a high Km, and is not inhibited by G6P. In hepatocytes it acts as a glucose sensor: it phosphorylates glucose strongly only when blood glucose is high, matching hepatic uptake and glycogenesis to the fed state.
Phosphoglucomutase interconverts G6P and glucose-1-phosphate (G1P). The reaction is reversible and proceeds through a bisphosphate intermediate on the enzyme: a catalytic serine is transiently phosphorylated, and glucose-1,6-bisphosphate shuttles the phosphate between the C1 and C6 positions of the substrate. Mutase deficiency (e.g., muscle phosphoglucomutase deficiency) impairs glycogen turnover in affected tissues.
This enzyme forms the activated sugar nucleotide: G1P + UTP → UDP-glucose + PPi. Inorganic pyrophosphatase rapidly cleaves PPi to 2 Pi, which is highly favorable thermodynamically and makes the pyrophosphorylase step effectively irreversible in vivo. Every glucose unit committed to glycogen passes through UDP-glucose.
Glycogen synthase is the rate-limiting enzyme of glycogenesis. It transfers glucose from UDP-glucose to the non-reducing end of a growing chain, forming alpha-1,4-glycosidic bonds. It cannot initiate a new polymer and requires a primer, typically the short glucosyl chain on glycogenin. The enzyme exists as GSa (active, dephosphorylated) and GSb (less active, phosphorylated), with hormonal signals and phosphatases/kinases determining how much synthase is in the active form.
Linear alpha-1,4 chains would pack poorly and be poor substrates for rapid release. Branching enzyme cleaves an oligosaccharide block of about seven glucose residues from the interior of a chain that must be at least about 11 residues long and reattaches it via an alpha-1,6 linkage, creating a branch point. A new branch is placed so it is at least four residues away from an existing branch, yielding the tree-like glycogen architecture optimal for simultaneous phosphorylase access at many ends.
Quick Check
Which enzyme is the rate-limiting step of glycogenesis?
Storing one glucose molecule in glycogen costs one UTP per glucose added at the synthase step, because UDP-glucose pyrophosphorylase consumes UTP when it makes UDP-glucose. In energy bookkeeping this is often equated to about one ATP equivalent, since UTP is regenerated from UDP using ATP and nucleoside diphosphate kinase in the cell.
The hexokinase/glucokinase step already spent one ATP to make G6P from glucose, so the full pathway from free glucose to glycogen uses two high-energy phosphates per glucose stored (one ATP at trapping, one UTP at activation). The hydrolysis of PPi to 2 Pi after the pyrophosphorylase reaction is essential: it prevents PPi buildup and pulls synthesis of UDP-glucose forward.
Fill in the Blank
Glycogen synthase exists in two forms:________(active, dephosphorylated) and GSb (inactive, phosphorylated). Insulin promotes the active form by activating protein phosphatase 1.
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