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. 2013 Jan 15:2013:816713.
doi: 10.1155/2013/816713. Print 2013.

Unified theory of bacterial sialometabolism: how and why bacteria metabolize host sialic acids

Eric R Vimr  1
Affiliations

Unified theory of bacterial sialometabolism: how and why bacteria metabolize host sialic acids

Eric R Vimr. ISRN Microbiol. .

Abstract

Sialic acids are structurally diverse nine-carbon ketosugars found mostly in humans and other animals as the terminal units on carbohydrate chains linked to proteins or lipids. The sialic acids function in cell-cell and cell-molecule interactions necessary for organismic development and homeostasis. They not only pose a barrier to microorganisms inhabiting or invading an animal mucosal surface, but also present a source of potential carbon, nitrogen, and cell wall metabolites necessary for bacterial colonization, persistence, growth, and, occasionally, disease. The explosion of microbial genomic sequencing projects reveals remarkable diversity in bacterial sialic acid metabolic potential. How bacteria exploit host sialic acids includes a surprisingly complex array of metabolic and regulatory capabilities that is just now entering a mature research stage. This paper attempts to describe the variety of bacterial sialometabolic systems by focusing on recent advances at the molecular and host-microbe-interaction levels. The hope is that this focus will provide a framework for further research that holds promise for better understanding of the metabolic interplay between bacterial growth and the host environment. An ability to modify or block this interplay has already yielded important new insights into potentially new therapeutic approaches for modifying or blocking bacterial colonization or infection.

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Figures

Figure 1
Figure 1
Human gastrointestinal tract. Note that the large intestine (colon with appendix) is permanently colonized by enteric bacteria, Streptococcus faecalis, bacteroides, bifidobacteria, eubacteria, peptococci, peptostreptococci, ruminococci, clostridia, and lactobacilli.
Figure 2
Figure 2
Intestinal structures reflecting different animal dietary types. Examples of monogastric herbivores are horse, rabbit, rat, and pig; carnivore or omnivores are cats, dogs, and man; ruminant examples are cow and sheep while granivorous bird examples are chickens or turkeys. The diagram is modified from reference [6].
Figure 3
Figure 3
Sialic acid structural diversity. (a) Neu5Ac, the most common sialic acid. The 4 and 7–9 hydroxyls may all be substituted with acetyl groups or less commonly methy, lactyl, succinyl, or phosphate groups. A hydroxyl group on the C-5 acetamido yields Neu5Gc, which is common in all higher animals but humans. (b) Oxidized sialic acid. (c) Lactone detected in high amounts in humans. (d) Anhydro sialic acid and transition state analog of sialidases. Neu5Ac and its derivatives and Neu5Ac1,7L exist bound to other sugars on oligosaccharides of mucin and other glycoconjugates, while ADOA and Neu5Ac2en are free in solution and thus missed by most structural analyses.
Figure 4
Figure 4
Relative distribution of sialic acids in the human and murine gut. Sialic acid abundances were determined for the human GIT compartments highlighted in rectangles [14]. Mouse values are for the small and large intestine [15].
Figure 5
Figure 5
Canonical N-acylneuraminate (nan) dissimilatory pathway for metabolism of Neu5Ac by E. coli. Colored arrows indicate relative transcriptional directions and functions of genes involved in converting Neu5Ac to GlcNAc-6-P after transport of exogenous sialic acid by the permease, NanT (yellow): aldolase or lyase (blue), epimerase (green), kinase (purple), yhcH (orange). Expression of the structural genes of this operon are regulated by the repressor, NanR (red) located immediately upstream of the nanA start site. Depending on the bacterial species, NagA or NagB may be part of the canonical operon or, as in the case of E. coli, located in a separate operon.
Figure 6
Figure 6
Proposed organization of nan gene clusters in selected streptococci. Canonical nan genes in S. pneumoniae strains D39, ATCC700669 and TIGR4, and GBS S. agalactiae have the same color designations as given in the legend to Figure 5, with the addition of Axe (magenta), YjhC (grey), and YjhB (gold) based on orthologs of E. coli genes described in the text. The known or proposed functions of other genes in the various clusters are listed above the open arrows. The numbers below at left or right of the first or last gene in the cluster gives the beginning and ending nucleotide positions of each gene segment.
Figure 7
Figure 7
Modes of acquisition of host sialic acids by typical Gram-negative bacterial species. (a) Bacteria with a scavenger mode of sialic acid acquisition depend on either their own or another source of sialidase (bold arrows) to release free sialic acid (diamond) from carbohydrate chains linked to host substrates (jagged lines). Released sialic acids diffuse into the periplasm between the outer and inner membranes (OM and IM, resp.,) for transport by specific permease(s) into the cytoplasm. (b) The spitter mode of acquisition involves sialidase release but inability to further metabolize sialic acid. These bacteria then sequentially release GlcNAc (open squares), galactose (Gal, open circles), and N-acetylgalactosamine (GalNAc, bold circles) from the idealized oligosaccharide for subsequent dissimilatory pathways. Note that the entire oligosaccharide chain may be degraded within the periplasm. (c) The swallower mode is identical to that of the spitter, except that swallowers catabolize the released sialic acid(s). Note that the scavenger and spitter modes are available to Gram-positive bacteria that lack a periplasmic space.
Figure 8
Figure 8
The E. coli sialoregulon. In addition to the canonical nan operon (with colored arrows having the same designations as given in Figure 6), other genes regulated by NanR include nanC (pink), nanM (teal), and nanS (magenta), which is homologous to the axe genes shown for streptococci in Figure 6. Another coregulated operon is composed of a putative permease, YjhB (gold) and oxidoreductase, YjhC (grey).
Figure 9
Figure 9
Bacteria with putative nan genes coregulated by NanR. Colored and open arrows have their same designations as given in Figures 6 and 8.
Figure 10
Figure 10
Auxanographic analysis of Neu5Ac utilization by S. typhimurium nanT and nanV mutants. The indicated strains were grown in minimal medium with glycerol as sole carbon source and plated in top agar with no carbon source and with or without 100 mM sodium chloride. Black rectangles indicate areas where Neu5Ac was added, with growth shown by the hazy zones or individual colonies.
Figure 11
Figure 11
Proposed pathway for utilization of Neu5Gc by E. coli. After transport by NanT, Neu5Gc is degraded to pyruvate and N-glycolylmannosamine (ManNGc) by NanA. It is proposed that the combined actions of NanK and NanE convert ManNGc to N-glycolylglucosamine-6-phosphate (GclNGc-6-P). The rest of the pathway combines the actions of NagAB with the glyoxylate shunt to complete catabolism of Neu5Gc. This pathway implies that the hydroxyl group of Neu5Gc does not impede already known enzymatic activities as described in the text.
Figure 12
Figure 12
Known or proposed functions of the E. coli sialoregulon. Wavy lines indicate mucin peptide backbones with idealized O-linked (serine/threonine) oligosaccharides composed of GalNAc (bold circle); GlcNAc (open squares); Gal (open circles); Neu5Ac (open diamonds, indicating the alpha anomer while hatched diamonds represent the thermodynamically favored beta anomer). Neu5Ac derivatives: acetyl (Ac) groups indicated by their linkages to different Neu5Ac carbon position (numbers in diamonds); Neu5,9Ac2, Neu5,7Ac2, Neu5,8Ac2, Neu4,5Ac2, Neu5,7,9Ac3, Neu5,8,9Ac3, and Neu5Gc (diamond with OH) is Neu5Ac with hydroxyl at position 5 (see Figure 1), Lt (lactyl), Me (methy). Bold diamond is neuraminic acid (Neu, which lacks the carbon-5 acetamido group). Triangle represents ADOA while diamond with horizontal line represents Neu5Ac1,7L (see Figures 3(b) and 3(c)). Diamond with cross lines represents Neu5Ac2en (see Figure 3(d)). Other abbreviations are as given in the legend to Figure 7.
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