Structural basis of glycogen metabolism in bacteria

Abstract

The evolution of metabolic pathways is a major force behind natural selection. In the spotlight of such process lies the structural evolution of the enzymatic machinery responsible for the central energy metabolism. Specifically, glycogen metabolism has emerged to allow organisms to save available environmental surplus of carbon and energy, using dedicated glucose polymers as a storage compartment that can be mobilized at future demand. The origins of such adaptive advantage rely on the acquisition of an enzymatic system for the biosynthesis and degradation of glycogen, along with mechanisms to balance the assembly and disassembly rate of this polysaccharide, in order to store and recover glucose according to cell energy needs. The first step in the classical bacterial glycogen biosynthetic pathway is carried out by the adenosine 5′-diphosphate (ADP)-glucose pyrophosphorylase. This allosteric enzyme synthesizes ADP-glucose and acts as a point of regulation. The second step is carried out by the glycogen synthase, an enzyme that generates linear α-(1→4)-linked glucose chains, whereas the third step catalyzed by the branching enzyme produces α-(1→6)-linked glucan branches in the polymer. Two enzymes facilitate glycogen degradation: glycogen phosphorylase, which functions as an α-(1→4)-depolymerizing enzyme, and the debranching enzyme that catalyzes the removal of α-(1→6)-linked ramifications. In this work, we rationalize the structural basis of glycogen metabolism in bacteria to the light of the current knowledge. We describe and discuss the remarkable progress made in the understanding of the molecular mechanisms of substrate recognition and product release, allosteric regulation and catalysis of all those enzymes.

The allosteric control mechanism of bacterial glycogen biosynthesis disclosed by cryoEM

“…[2][3][4] Glycogen and starch are large homopolymers composed by linear chains of α-(1→4)-glucose residues, containing α-(1→6)-linkages at branching points ( Figure 1A). 1,5 These chemical structures provide a high number of reactive-ends that facilitates rapid storage and recovery of glucose. 6 Glucose activation is the first step required to overcome the energy barrier for subsequent polymerization ( Figure 1B).…”

“…The classical pathway for bacterial glycogen biosynthesis involves the action of three enzymes: ADP-glucose pyrophosphorylase (AGPase), glycogen synthase (GS) and glycogen branching enzyme (GBE; Figure 1B). 5,[7][8][9] AGPase catalyzes the biosynthesis of the activated-sugar ADP-glucose ( Figures 1B-C), whereas GS generates a linear α-(1→4)-linked glucose chain, and the GBE produces α-(1→6)-linked glucan branches in the polymer. 5,[7][8][9] Glycogen degradation is carried out by glycogen phosphorylase (GP), which functions as a depolymerizing enzyme, and the glycogen debranching enzyme (GDE) that catalyzes the removal of α-(1→6)-linked ramifications ( Figure 1B).…”

“…5,[7][8][9] AGPase catalyzes the biosynthesis of the activated-sugar ADP-glucose ( Figures 1B-C), whereas GS generates a linear α-(1→4)-linked glucose chain, and the GBE produces α-(1→6)-linked glucan branches in the polymer. 5,[7][8][9] Glycogen degradation is carried out by glycogen phosphorylase (GP), which functions as a depolymerizing enzyme, and the glycogen debranching enzyme (GDE) that catalyzes the removal of α-(1→6)-linked ramifications ( Figure 1B). 5 Cell homeostasis requires precise and rapid mechanisms to sense the organism status to coordinate the metabolic network accordingly.…”

“…5,[7][8][9] Glycogen degradation is carried out by glycogen phosphorylase (GP), which functions as a depolymerizing enzyme, and the glycogen debranching enzyme (GDE) that catalyzes the removal of α-(1→6)-linked ramifications ( Figure 1B). 5 Cell homeostasis requires precise and rapid mechanisms to sense the organism status to coordinate the metabolic network accordingly. 10 To oversight the cell energy storage, glycogen and starch biosynthetic pathways are controlled by AGPase through cooperative and allosteric strategies.…”

“…[11][12][13][14] AGPase catalyzes the reversible condensation reaction between adenosine triphosphate (ATP) and glucose 1-phosphate (G1P) to produce ADP-glucose and pyrophosphate (PPi; Figure 1C). 5,15,16,17 Specifically, the oxygen on the phosphate group of G1P acts as a nucleophile attacking the α-PO 4 group of the nucleoside triphosphate, leading to the liberation of PPi ( Figure S1). 18 The reaction is held in the presence of the divalent metal cation Mg 2+ , which minimizes the charge repulsion between phosphate groups, favoring nucleophile activation.…”