A team led by CMFI Principal Investigator Karl Forchhammer has elucidated the origin of a key regulator in bacterial metabolism. Responsible for its production is an enzyme that has been detected in numerous bacterial species, including members of the human microbiome and pathogens. The findings could be useful in combating pathogenic bacteria.
Carbon metabolism is one of the central metabolic processes common to many living organisms. The storage of sugars also plays a central role in this process.
Animals (including humans) but also bacteria, can store sugar in cells as a polymer in the form of glycogen and mobilize it again when energy demand increases (Figure 1). A key reaction in both storage and mobilization is the rearrangement of phosphate residues on the sugar molecules. These rearrangement reactions are catalyzed by the Phosphohexomutase (PHM) group of enzymes. (Figure 2)
The large family of PHM enzymes can be divided into several subgroups. They all function on the same principle, but are specialized for different phosphate sugars as substrates. For the phosphate rearrangement reactions to occur, the enzymes must first be activated. This is done by the molecule glucose-1,6-bisphosphate. This molecule attaches a phosphate group to the reaction center of the enzymes, thereby placing them in an active state. How this activator molecule is formed in humans and other vertebrates has been the subject of research for some time and is largely understood: Responsible for the formation of the molecule is an enzyme (PGM-2) that also belongs to the PHM family, but does not occur outside vertebrates. Its central role in metabolism is shown by the fact that a defect in this enzyme results in a deficiency of G16bP. This deficiency leads, among other things, to neurodevelopmental disorders in newborns. In bacteria, it has been known for decades that G16bP plays an important role in sugar metabolism, but how this molecule is formed has now been shown for the first time.
"The research results have filled a significant gap in our knowledge of bacterial sugar metabolism, which is otherwise considered well understood," said Niels Neumann, CMFI doctoral student and lead author of the study.
The enzyme that produces G16bP in bacteria belongs to another subgroup of the PHM family that has been little studied. It uses a different pathway to produce G16bP than is the case in vertebrates.
Using the cyanobacterium Synechocystis, as well as the human intestinal bacterium Bacteroides salyersiae, the researchers were able to show that this enzyme is present in numerous bacterial species, including representatives of the human microbiome and pathogenic species.
Neumann N, Friz S, Forchhammer K. Glucose-1,6-Bisphosphate, a Key Metabolic Regulator, Is Synthesized by a Distinct Family of α-Phosphohexomutases Widely Distributed in Prokaryotes. mBio. Jul 20:e0146922. (2022) doi: 10.1128/mbio.01469-22.