Sugar Allocation to Metabolic Pathways is Tightly Regulated and Affects the Virulence of Streptococcus mutans

Abstract

Bacteria take up and metabolize sugar as a carbohydrate source for survival. Most bacteria can utilize many sugars, including glucose, sucrose, and galactose, as well as amino sugars, such as glucosamine and N-acetylglucosamine. After entering the cytoplasm, the sugars are mainly allocated to the glycolysis pathway (energy production) and to various bacterial component biosynthesis pathways, including the cell wall, nucleic acids and amino acids. Sugars are also utilized to produce several virulence factors, such as capsule and lipoteichoic acid. Glutamine-fructose-6-phosphate aminotransferase (GlmS) and glucosamine-6-phosphate deaminase (NagB) have crucial roles in sugar distribution to the glycolysis pathway and to cell wall biosynthesis. In Streptococcus mutans, a cariogenic pathogen, the expression levels of glmS and nagB are coordinately regulated in response to the presence or absence of amino sugars. In addition, the disruption of this regulation affects the virulence of S. mutans. The expression of nagB and glmS is regulated by NagR in S. mutans, but the precise mechanism underlying glmS regulation is not clear. In Staphylococcus aureus and Bacillus subtilis, the mRNA of glmS has ribozyme activity and undergoes self-degradation at the mRNA level. However, there is no ribozyme activity region on glmS mRNA in S. mutans. In this review article, we summarize the sugar distribution, particularly the coordinated regulation of GlmS and NagB expression, and its relationship with the virulence of S. mutans.

Keywords: GlmS; NagB; Streptococcus mutans; sugar distribution; virulence.

Figure 1

Streptococcus mutans virulence is related to sugars. GTF: glucosyltransferase; IPS: intercellular polysaccharide; EPS: extracellular polysaccharide.

Figure 2

Phosphotransferase (PTS) and non-PTS system in S. mutans. Bacteria can take up carbohydrates by specific sugar incorporation systems. In S. mutans, two major incorporation systems, the PTS and non-PTS systems, have been reported. After sugars are incorporated into cytoplasm, the sugar molecule is processed and finally metabolized to fructose 6-phosphate (Fru-6P). Fru-6P is distributed to glycolysis and the cell wall synthesis system. EI: Enzyme I; EII: Enzyme II; MSM: multiple sugar metabolism; msmEFGK: multiple sugar metabolism transporter; Glc-6P: glucose 6-phosphate; GlcN-6P: glucosamine 6-phosphate; HPr: histidine phosphocarrier protein.

Figure 3

Proposed sugar distribution mediated by glutamine-fructose-6-phosphate aminotransferase (GlmS) and glucosamine-6-phosphate deaminase (NagB). (A) In the presence of sugar (glucose) and amino sugar (GlcNAc), both sugars are incorporated into the cytoplasm and are distributed to cell wall synthesis and glycolysis by GlmS and NagB; (B) In the presence of glucose as a sole carbohydrate source, NagB expression is significantly suppressed to generate enough GlcN-6P for the cell wall biosynthesis pathway; (C) In the presence of GlcNAc as a sole carbohydrate source, GlmS expression is significantly suppressed to generate enough Fru-6P for glycolysis pathway. GlcNAc: N-acetylglucosamine; GlcNAc-6P: N-acetylglucosamine 6-phosphate; GlcN-6P: glucosamine-6-phosphate; Fru-6P: fructose 6-phosphate; glucose-6P: glucose 6-phosphate; NagA: N-acetylglucosamine 6-phosphate deacetylase; Pgi: glucose 6-phosphate isomerase.

Figure 4

Regulation of glmS and nagAB expression in Bacillus subtilis and S. mutans. (A) The regulation of glmS in B. subtilis (upper) and S. mutans (lower) is shown. B. subtilis glmS transcript has ribozyme activity, which causes self-cleavage in the presence of excess glucosamine-6-phosphate, a product of the GlmS reaction. GlmS of S. mutans is negatively regulated by NagR. NagR binds to the DasR responsive element (dre) sequence upstream of the glmS coding region, leading to inhibition of the glmS transcript; (B) Regulation of nagAB in B. subtilis (upper) and S. mutans (lower) is shown. In B. subtilis, nagA and nagB are tandemly located to form an operon, while nagA and nagB are independently located in S. mutans. NagR binds to the dre sequence upstream of nagAB in B. subtilis, leading to inhibition of the nagAB expression (upper right). However, NagR bound with GlcN-6P has no ability to bind to the dre sequence (upper left). The same regulation system is observed in nagA and nagB in S. mutans (lower left and right).