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15.2: Glycogenesis

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    The process of forming glycogen is called glycogenesis and it requires the activity of six enzymes (Figure \(\PageIndex{1}\)). Some of these, we have already discussed including the hexokinase that phosphorylates the 6'-OH of glucose and the phosphoglucomutase that converts glucose-6-phosphate to the glucose-1-phosphate isomer. In this section, we will discuss the remaining four enzymes and their role in glycogen biosynthesis. They are Glycogen Synthase, UDP-Glucose Pyrophosphorylase, Glycogenin, and Glycogen Branching Enzyme.

    Figure \(\PageIndex{1}\): Enzymes involved in Glycogenesis. Image from Mark Cidade

    Glycogen Synthase

    The activity of glycogen synthase (GS) is the predominant enzyme required during glycogenesis. This enzyme is also the key regulatory step in the process. In section 15.1, we have already seen how insulin signaling upregulates the activity of this enzyme by inhibiting phosphorylation by GSK-3. Other effectors include the allosteric binding of glucose-6-phosphate, which also increases the activity of the GS. In a later section, we will also see that the hormone glucagon can also regulate the activity of the GS through protein kinase A (PKA). In this situation, glycogen synthesis is downregulated and glycogen breakdown is amplified.

    Within glycogenesis the GS is responsible for building the majority of the main alpha 1 --> 4 chain linkages. The GS does require a primer of 4 -6 glucose residues linked together by alpha 1 --> 4 bonds to begin synthesis. GS can only form alpha 1 --> 4 linkages in the main chain, it CANNOT create the alpha 1 --> 6 branches inherent to the core structure of glycogen.

    To build the glycogen main chain, GS uses the glycogen primer + a glucose that has been activated through binding to a molecule of uridine diphosphate (UDP) at the 1-position for its substrates. Upon completion of one round of synthesis, the 1 position of the incoming UDP-glucose is bonded with the 4-position of the nascent glycogen molecule releasing the UDP as a leaving group.

    \[\text { Glycogen }_{(n)}+\text { UDP-glucose } \rightarrow \text { Glycogen }_{(n+1)}+\text { UDP }\]

    UDP-Glucose Pyrophosphorylase

    The formation of the UDP-glucose required for the synthesis of the main chain of glycogen is mediated by the UDP-glucose pyrophosphorylase (GalU or UGPase; EC GalU catalyze the reversible reaction of glucose 1-phosphate and UTP into UDP-glucose and inorganic pyrophosphate (PPi) (Figure \(\PageIndex{2}\)). Enzymes of the GalU family are ubiquitous and can be found among the tree of life.

    Figure \(\PageIndex{2}\): Formation of UDP-Glucose

    Like many other nucleotidyl transferases, also GalU requires divalent cations to promote the reaction (Figure \(\PageIndex{3}\)). In most cases magnesium ions are employed. The reaction mechanism follows a sequential bi-bi-mechanism starting with the binding of UTP to the active site, in presence of a magnesium ion, followed by the binding of glucose 1-phosphate. The octahedral coordination sphere of the magnesium positions the substrates in the right way and enables the nucleophilic attack of glucose 1-phosphate on UTP. A lysine, an aspartate and several water molecules within the active site help to stabilize the position of the substrates and cofactor for the proper nucleophilic attack of the phosphoryl oxygen of glucose 1-phosphate towards the α-phosphor atom of UTP. Finally, PPi is released from the GalU/Mg2+/UDP-glucose complex. UDP-Glucose then dissociates from the complex restoring the active site of the enzyme for another round of synthesis.

    Figure \(\PageIndex{3}\): Proposed Reaction Mechanism of UDP-Glucose Pyrophosphorylase. Image from Kumpf, A., et al. (2019) Int. J. Mol. Sci. 20(22) 5809;

    Glycogen Synthase

    UDP-glucose is then utilized by glycogen synthase (GS) to extend the main chain of glycogen by one glucose residue. In this reaction, the 4’-OH group of the glycogen main chain attacks the anomeric carbon of UDP-glucose (Figure \(\PageIndex{4}\)). The UDP functional group serves as a good leaving group allowing for the formation of the alpha 1 --> 4 bond.

    Figure \(\PageIndex{4}\): Formation of the Glycogen Mainchain by Glycogen Synthase. Image modified from Mikael Häggström


    Previously, we mentioned that GS requires a glycogen primer of 4 – 6 glucose residues to begin adding new residues to the main chain. This primer is provided by the small docking protein, Glycogenin. This protein is a homodimer that self-catalyzes glycosylation at amino acid Tyr-194. In this reaction, UDP-glucose is coordinated by a Mn2+ metal cofactor and critical aspartate residues (Figure \(\PageIndex{5}\)). The –OH group of Tyr-194 then mediates nucleophilic attack on the anomeric carbon of UDP-glucose. Thus, glycogenin is tethered to the reducing end of the glycogen molecule.

    Figure \(\PageIndex{5}\): Coordination of UDP-Glucose by Glycogenin. Critical apartic acid residues and a manganese ion cofactor are required for the coordination of UDP-glucose by glycogenin. Image from Hedberg Oldfors, C., Glamuzina, E., Ruygrok, P. and Anderson, L. (2016) J. Inhert. Met. Dis. 40(1) DOI: 10.1007/s10545-016-9978-1

    Glycogen Branching Enzyme

    The final enzyme, the glycogen branching enzyme (GBE), catalyses the hydrolytic cleavage of an α(1→4) glycosidic linkage and subsequent inter- or intra-chain transfer of the non-reducing terminal fragment to the C6 hydroxyl position of an α-glucan (Figure \(\PageIndex{6}\)). In this example, an inter-chain transfer is occurring. At the top of the scheme, above the arrow, you can see that the GBE enzyme transiently removes X-number of glucose residues (usually around 7) from one linear glycogen chain and then attaches it as an alpha 1 --> 6 branch to the other chain. In this process an additional non-reducing end is created which can act as primer site for Glycogen Phosphorylase (the main enzyme that breaks down glycogen). Thus, glucose residues can be released very quickly when needed.

    Figure \(\PageIndex{6}\): Formation of Glycogen alpha 1 --> 6 Branches. Image from van der Vlist, J., et al (2012) Polymers 4(1) 674-690. DOI: 10.3390/polym4010674


    Figure \(\PageIndex{7}\) provides a summary of the glycogenesis reactions required for the main chain biosynthesis. Overall, a summary of glycogenesis begins when glucose enters the cell through the GLUT4 transporter (or similar family member). Hexokinase phosphorylates the glucose and traps it in the cell. Phosphoglucomutase then converts glucose 6-phosphate into glucose 1-phosphate. This substrate is utilized by UDP-glucose pyrophosphorylase to generate UDP-glucose. Glycogen synthase (GS) uses UDP-glucose as a glucose donor to extend the alpha 1 --> 4 chain of glycogen with more glucosyl residues. Note that a primer of at least 4 glucose residues must be attached to glycogenin to serve as a substrate for GS. Finally, the glycogen branching enzyme (GBE) transfers chains of alpha 1 --> 4 glucose residues (~7) to the same or to a different glycogen residue to create an alpha 1 --> 6 linkage. This occurs approximately every 12 to 16 residues.

    Figure \(\PageIndex{7}\): Main Chain Biosynthesis During Glycogenesis


    1. Kumpf, A., Partzsch, A., Pollender, A., Bento, I., and Tischler, D. (2019) Two Homologous Enzymes of the GalU Family in Rhodococcus opacus 1CP-RoGalU1 and RoGalU2. Int. J. Mol. Sci. 20(22), 5809.

    15.2: Glycogenesis is shared under a not declared license and was authored, remixed, and/or curated by Henry Jakubowski.