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Chapter 4 : Integration of Capsular Polysaccharide Biosynthesis with Metabolic and Virulence Pathways in

Author: Janet Yother1
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Affiliations: 1: Department of Microbiology, University of Alabama at Birmingham, BBRB 661, 845 19th St. S., Birmingham, AL 35242
Content Type: Monograph
Publication Year: 2007

Category: Bacterial Pathogenesis

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Integration of Capsular Polysaccharide Biosynthesis with Metabolic and Virulence Pathways in , Page 1 of 2

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Abstract:

In the developing world, is a major cause of pneumonia in young children, and the total worldwide mortality due to pneumococcal infections is approximately 1 to 2 million per year. The capsule is an integral part of the pneumococcal cell surface. The type 3 polysaccharide, as discussed, is not linked to the peptidoglycan but remains cell associated via a membrane lipid linkage or interactions with a membrane protein involved in its synthesis. The synthesis of all polysaccharides begins with the synthesis of nucleotide precursor sugars in the cytoplasm. Global control pathways affecting carbon metabolism may also be involved in the regulation of capsule synthesis. In particular, catabolite control protein A (CcpA) is an important regulator of the phosphoenolpyruvate-dependent phosphotransferase system that is the major system for sugar uptake in many bacteria. A mechanism for cleaving the chain has not been demonstrated but is predicted to be enzymatic based on the inability to introduce mechanical breaks without using sonication. The release of capsular polysaccharide may be important in pathogenesis, and the identification of an enzyme involved in this process will be an important step in understanding this role. Analyses of the genetics and biosynthesis of capsule production have yielded many important insights into one of the most important bacterial virulence factors. Understanding the regulatory mechanisms involved in capsule synthesis and release, and their integration with the synthesis of other surface structures, will thus be an important step in understanding the overall metabolism and virulence of the cell.

Citation: Yother J. 2007. Integration of Capsular Polysaccharide Biosynthesis with Metabolic and Virulence Pathways in , p 51-66. In Brogden K, Minion F, Cornick N, Stanton T, Zhang Q, Nolan L, Wannemuehler M (ed), Virulence Mechanisms of Bacterial Pathogens, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815851.ch4

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Integration of Capsular Polysaccharide Biosynthesis with Metabolic and Virulence Pathways in Streptococcus pneumoniae
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Citation: Yother J. 2007. Integration of Capsular Polysaccharide Biosynthesis with Metabolic and Virulence Pathways in , p 51-66. In Brogden K, Minion F, Cornick N, Stanton T, Zhang Q, Nolan L, Wannemuehler M (ed), Virulence Mechanisms of Bacterial Pathogens, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815851.ch4
/content/10.1128/9781555815851.ch04.ch04fig01
FIGURE 1
Linkage of the capsule and teichoic acid to peptidoglycan. The phosphodiester linkage of the capsule to GlcNAc is inferred by analogy to the linkage in ( ). The teichoic acid structure and linkage are based on data from references and . Sites of cleavage by mutanolysin and autolysin (LytA) are indicated by down and right arrows, respectively. AATGal, 2-acetamido-4-amino-2,4,6-trideoxy--Gal.
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Image of FIGURE 1
FIGURE 1

Linkage of the capsule and teichoic acid to peptidoglycan. The phosphodiester linkage of the capsule to GlcNAc is inferred by analogy to the linkage in ( ). The teichoic acid structure and linkage are based on data from references and . Sites of cleavage by mutanolysin and autolysin (LytA) are indicated by down and right arrows, respectively. AATGal, 2-acetamido-4-amino-2,4,6-trideoxy--Gal.

Citation: Yother J. 2007. Integration of Capsular Polysaccharide Biosynthesis with Metabolic and Virulence Pathways in , p 51-66. In Brogden K, Minion F, Cornick N, Stanton T, Zhang Q, Nolan L, Wannemuehler M (ed), Virulence Mechanisms of Bacterial Pathogens, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815851.ch4
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FIGURE 2
Common pathways in the synthesis of cellular structures. Sugars common to the pathways of the type 2 and type 3 capsules, and other pathways, are shown. UDP-GlcNAc and AATGal (2-acetamido-4-amino-2,4,6-trideoxy--Gal) are used in the synthesis of capsules of other serotypes as well as peptidoglycan and teichoic acid, respectively. α--Glc is transported from the extracellular environment to the cytoplasm; lipid II is transported to the outer face of the cytoplasmic membrane for the polymerization of peptidoglycan. Choline-binding proteins are linked to the lipoteichoic acids ( ). Lipoteichoic acid exhibits the same repeat unit as teichoic acid ( Fig. 1 ) but is linked to the membrane via a Glc-AAT-Glc linkage to diacylglycerol ( ). Teichoic acid, the type 2 capsule, and other Wzy-dependent capsules are covalently linked to the peptidoglycan.
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Image of FIGURE 2
FIGURE 2

Common pathways in the synthesis of cellular structures. Sugars common to the pathways of the type 2 and type 3 capsules, and other pathways, are shown. UDP-GlcNAc and AATGal (2-acetamido-4-amino-2,4,6-trideoxy--Gal) are used in the synthesis of capsules of other serotypes as well as peptidoglycan and teichoic acid, respectively. α--Glc is transported from the extracellular environment to the cytoplasm; lipid II is transported to the outer face of the cytoplasmic membrane for the polymerization of peptidoglycan. Choline-binding proteins are linked to the lipoteichoic acids ( ). Lipoteichoic acid exhibits the same repeat unit as teichoic acid ( Fig. 1 ) but is linked to the membrane via a Glc-AAT-Glc linkage to diacylglycerol ( ). Teichoic acid, the type 2 capsule, and other Wzy-dependent capsules are covalently linked to the peptidoglycan.

Citation: Yother J. 2007. Integration of Capsular Polysaccharide Biosynthesis with Metabolic and Virulence Pathways in , p 51-66. In Brogden K, Minion F, Cornick N, Stanton T, Zhang Q, Nolan L, Wannemuehler M (ed), Virulence Mechanisms of Bacterial Pathogens, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815851.ch4
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FIGURE 3
Type 2 capsule structure (top) and genetic locus (bottom). The polymer is linked to Und-P in the membrane via the Glc residue in the backbone ( ). The type 2 genetic locus is flanked by the noncapsular genes and (also referred to as ) ( ). The common region contains genes found in all serotypes; the type-specific region contains genes unique to a given serotype. The genes predicted to encode the Wzy polymerase and the Wzx flippase (transporter) are indicated. The arrow indicates the predicted capsule operon. NDP, nucleotide diphosphate.
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Image of FIGURE 3
FIGURE 3

Type 2 capsule structure (top) and genetic locus (bottom). The polymer is linked to Und-P in the membrane via the Glc residue in the backbone ( ). The type 2 genetic locus is flanked by the noncapsular genes and (also referred to as ) ( ). The common region contains genes found in all serotypes; the type-specific region contains genes unique to a given serotype. The genes predicted to encode the Wzy polymerase and the Wzx flippase (transporter) are indicated. The arrow indicates the predicted capsule operon. NDP, nucleotide diphosphate.

Citation: Yother J. 2007. Integration of Capsular Polysaccharide Biosynthesis with Metabolic and Virulence Pathways in , p 51-66. In Brogden K, Minion F, Cornick N, Stanton T, Zhang Q, Nolan L, Wannemuehler M (ed), Virulence Mechanisms of Bacterial Pathogens, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815851.ch4
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FIGURE 4
The Wzy-dependent pathway for type 2 capsule synthesis. Synthesis begins with nucleotide precursor synthesis, shown in the lower right corner of the figure. The functions of enzymes in boxes and the order of action of the putative glycosyltransferases Cps2T, Cps2F, Cps2G, and Cps2I have not been experimentally demonstrated. Cps2J and Cps2H are the putative Wzx flippase and Wzy polymerase, respectively ( ). The functions of the type 19F homologues of the enzymes involved in TDP-Rha synthesis have been demonstrated previously ( ). After the transfer of a subunit or polymer, the C-P-P acceptor is expected to be cleaved to C-P and recycled to the inner face of the cytoplasmic membrane. It is not known whether the cleavage occurs on the inner or outer face of the membrane.
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Image of FIGURE 4
FIGURE 4

The Wzy-dependent pathway for type 2 capsule synthesis. Synthesis begins with nucleotide precursor synthesis, shown in the lower right corner of the figure. The functions of enzymes in boxes and the order of action of the putative glycosyltransferases Cps2T, Cps2F, Cps2G, and Cps2I have not been experimentally demonstrated. Cps2J and Cps2H are the putative Wzx flippase and Wzy polymerase, respectively ( ). The functions of the type 19F homologues of the enzymes involved in TDP-Rha synthesis have been demonstrated previously ( ). After the transfer of a subunit or polymer, the C-P-P acceptor is expected to be cleaved to C-P and recycled to the inner face of the cytoplasmic membrane. It is not known whether the cleavage occurs on the inner or outer face of the membrane.

Citation: Yother J. 2007. Integration of Capsular Polysaccharide Biosynthesis with Metabolic and Virulence Pathways in , p 51-66. In Brogden K, Minion F, Cornick N, Stanton T, Zhang Q, Nolan L, Wannemuehler M (ed), Virulence Mechanisms of Bacterial Pathogens, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815851.ch4
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FIGURE 5
Detection of capsule (CPS) and teichoic acid (TA) on immunoblots. The anti-capsule (α-CPS) blot was reacted with type 2 capsule-specific antiserum; the anti-teichoic acid blot was reacted with teichoic acid-specific antiserum. The protein molecular mass standards are for comparison between blots and do not represent polymer sizes. P, protoplast fraction; CW, cell wall fraction; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Methods and results are as described in reference .
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Image of FIGURE 5
FIGURE 5

Detection of capsule (CPS) and teichoic acid (TA) on immunoblots. The anti-capsule (α-CPS) blot was reacted with type 2 capsule-specific antiserum; the anti-teichoic acid blot was reacted with teichoic acid-specific antiserum. The protein molecular mass standards are for comparison between blots and do not represent polymer sizes. P, protoplast fraction; CW, cell wall fraction; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Methods and results are as described in reference .

Citation: Yother J. 2007. Integration of Capsular Polysaccharide Biosynthesis with Metabolic and Virulence Pathways in , p 51-66. In Brogden K, Minion F, Cornick N, Stanton T, Zhang Q, Nolan L, Wannemuehler M (ed), Virulence Mechanisms of Bacterial Pathogens, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815851.ch4
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FIGURE 6
Type 3 capsule biosynthetic pathway and genetic locus. The type 3 capsule genes are flanked by and (also referred to as ), as in the type 2 locus ( ). The 5′ end of is truncated (enclosure in parentheses indicates that the gene is mutated). The upstream common genes are not transcribed, and most are mutated ( ). is the homologue. is not homologous to but encodes the UDP-Glc dehydrogenase ( ). The boxed and (type 3 synthase) genes are the only genes in the locus that are necessary for type 3 capsule synthesis ( ). The locus is transcribed as an operon from through ( ). PGM and GalU are encoded outside the capsule locus ( ). is truncated and exhibits homology to IS ( ). , variable number.
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Image of FIGURE 6
FIGURE 6

Type 3 capsule biosynthetic pathway and genetic locus. The type 3 capsule genes are flanked by and (also referred to as ), as in the type 2 locus ( ). The 5′ end of is truncated (enclosure in parentheses indicates that the gene is mutated). The upstream common genes are not transcribed, and most are mutated ( ). is the homologue. is not homologous to but encodes the UDP-Glc dehydrogenase ( ). The boxed and (type 3 synthase) genes are the only genes in the locus that are necessary for type 3 capsule synthesis ( ). The locus is transcribed as an operon from through ( ). PGM and GalU are encoded outside the capsule locus ( ). is truncated and exhibits homology to IS ( ). , variable number.

Citation: Yother J. 2007. Integration of Capsular Polysaccharide Biosynthesis with Metabolic and Virulence Pathways in , p 51-66. In Brogden K, Minion F, Cornick N, Stanton T, Zhang Q, Nolan L, Wannemuehler M (ed), Virulence Mechanisms of Bacterial Pathogens, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815851.ch4
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FIGURE 7
Model for type 3 capsule synthesis catalyzed by the type 3 synthase (Cps3S). Synthesis initiates on the cytoplasmic face of the membrane by the addition of Glc (ovals) to phosphatidylglycerol (triangles) and proceeds by the alternate addition of GlcUA (squares) and Glc.
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Image of FIGURE 7
FIGURE 7

Model for type 3 capsule synthesis catalyzed by the type 3 synthase (Cps3S). Synthesis initiates on the cytoplasmic face of the membrane by the addition of Glc (ovals) to phosphatidylglycerol (triangles) and proceeds by the alternate addition of GlcUA (squares) and Glc.

Citation: Yother J. 2007. Integration of Capsular Polysaccharide Biosynthesis with Metabolic and Virulence Pathways in , p 51-66. In Brogden K, Minion F, Cornick N, Stanton T, Zhang Q, Nolan L, Wannemuehler M (ed), Virulence Mechanisms of Bacterial Pathogens, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815851.ch4
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FIGURE 8
Model for retention and release of the type 3 capsule. Release may occur following two breaks in the chain or the combination of a single break and ejection from the synthase, as shown in the right panel. Zipper-like symbols, phosphatidylglycerol; squares, Glc; circles, GlcUA.
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Image of FIGURE 8
FIGURE 8

Model for retention and release of the type 3 capsule. Release may occur following two breaks in the chain or the combination of a single break and ejection from the synthase, as shown in the right panel. Zipper-like symbols, phosphatidylglycerol; squares, Glc; circles, GlcUA.

Citation: Yother J. 2007. Integration of Capsular Polysaccharide Biosynthesis with Metabolic and Virulence Pathways in , p 51-66. In Brogden K, Minion F, Cornick N, Stanton T, Zhang Q, Nolan L, Wannemuehler M (ed), Virulence Mechanisms of Bacterial Pathogens, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815851.ch4
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References

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