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Lipoteichoic Acid Synthesis
and Function in Gram-Positive
Bacteria
Matthew G. Percy and Angelika Gründling
Section of Microbiology and MRC Centre for Molecular Bacteriology and Infection,
Imperial College London, London, SW7 2AZ UK; email: [email protected],
[email protected]
Annu. Rev. Microbiol. 2014. 68:81–100
Keywords
The Annual Review of Microbiology is online at
micro.annualreviews.org
bacterial cell wall, D-alanylation, glycosylation, cholination, lipid turnover,
osmoregulated periplasmic glucans
This article’s doi:
10.1146/annurev-micro-091213-112949
c 2014 by Annual Reviews.
Copyright All rights reserved
Abstract
Lipoteichoic acid (LTA) is an important cell wall polymer found in grampositive bacteria. Although the exact role of LTA is unknown, mutants display significant growth and physiological defects. Additionally, modification
of the LTA backbone structure can provide protection against cationic antimicrobial peptides. This review provides an overview of the different LTA
types and their chemical structures and synthesis pathways. The occurrence
and mechanisms of LTA modifications with D-alanyl, glycosyl, and phosphocholine residues will be discussed along with their functions. Similarities
between the production of type I LTA and osmoregulated periplasmic glucans in gram-negative bacteria are highlighted, indicating that LTA should
perhaps be compared to these polymers rather than lipopolysaccharide, as is
presently the case. Lastly, current efforts to use LTAs as vaccine candidates,
synthesis proteins as novel antimicrobial targets, and LTA mutant strains as
improved probiotics are highlighted.
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Contents
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
LTA STRUCTURES AND THEIR SYNTHESIS AND FUNCTION . . . . . . . . . . . . .
Polyglycerolphosphate (Type I) LTA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Type I LTA Synthesis and Lipid Turnover . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Complex LTA Structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Streptococcus Pneumoniae (Type IV) LTA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
MODIFICATIONS OF LTAS AND THEIR FUNCTIONS . . . . . . . . . . . . . . . . . . . . . . .
D-Alanylation of LTA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Glycosylation of LTA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Phosphocholine Modification of Type IV LTA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
APPLICATIONS OF LTA AND MUTANT STRAINS . . . . . . . . . . . . . . . . . . . . . . . . . . .
COMPARISON OF TYPE I LTA AND OSMOREGULATED
PERIPLASMIC GLUCAN SYNTHESIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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91
92
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INTRODUCTION
TA: teichoic acid
GroP:
glycerolphosphate
RboP:
ribitolphosphate
WTA: wall teichoic
acid
LTA: lipoteichoic
acid
OPG: osmoregulated
periplasmic glucans
Teichoic acids (TAs) were first detected by Baddiley and coworkers in 1958 (6, 7). A structural
diversity was soon recognized, and the term TA, derived from the Greek word teichos, for “wall,”
was subsequently used to describe all bacterial cell wall, membrane, and capsular polymers containing glycerolphosphate (GroP) or ribitolphosphate (RboP) residues (8). Currently the term
TA describes two bacterial cell wall polymers found in gram-positive bacteria: wall teichoic acid
(WTA) and lipoteichoic acid (LTA). WTA synthesis has recently been reviewed (17), and here
we focus only on LTA synthesis. LTA is now defined as an alditolphosphate-containing polymer
that is linked via a lipid anchor to the membrane in gram-positive bacteria. However, this definition may need to be revised to include recently described complex glycosyl-phosphate-containing
polymers (107). LTAs have been grouped into different types based on their chemical structures
(Figure 1). This review focuses on the synthesis, modifications, and functions of type I and type
IV LTAs, as these have been studied in the greatest detail. Furthermore, we summarize recent attempts to utilize LTAs as vaccine candidates, LTA mutant strains as improved probiotic strains, and
biosynthetic enzymes as antimicrobial targets. Lastly, we highlight similarities between the synthesis pathways of LTA and osmoregulated periplasmic glucans (OPGs) of gram-negative bacteria.
LTA STRUCTURES AND THEIR SYNTHESIS AND FUNCTION
Polyglycerolphosphate (Type I) LTA
Polyglycerolphosphate, or type I LTA, is the best-characterized LTA. It is found in a large range of
gram-positive bacteria belonging to the phylum Firmicutes, such as Bacillus subtilis, Staphylococcus
aureus, and Listeria monocytogenes. Type I LTA has an unbranched 1–3 linked GroP backbone
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−→
Figure 1
Different LTA types. Chemical structures of (a) type I LTA as found in Bacillus subtilis, (b) type II LTA from Lactococcus garvieae, (c) type
III LTA from Clostridium innocuum, (d ) type IV LTA from Streptococcus pneumoniae, and (e) type V LTA from Clostridium difficile.
Glycolipid anchors are shaded; R indicates a fatty acid, and R1 denotes backbone substitutions.
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a Type I LTA
O
HO
OR1
O
P
O O– O
OR1
P
O O– O
OR1
O
P O
O O–
O
HO
HO
OH
b Type II LTA
HO OH
O
O
HO
OH
HO
O
HO
HO
O
OH O
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HO
O
O
O
O
HO
HO
H3N+
R1=
R
O
O
OH
OH
O
R
O
O
HO
HO
H3C
D-Ala
AcHN
GlcNAc
O
OH
O
HO OH
O
O P
O–
O
HO
O
HO
O
OH
HO
OH
O
HO
O
HO
O
O
OH O
OH
O P O
O–
HO
HO
O
O
HO
O HO
O
O
OH O
R
O
c Type III LTA
O
P O
O O–
HO
OR1
HO
O
O
O
OH
O
P O
O O–
HO
OR1
HO
O
HO
O
OH
OH
O
OH
O
O
O
R
HO
HO
HO
H3N+
O
NH3
OH
O
R1= HO
O R
R
O
O
AcHN
GlcNAc
Gln
d Type IV LTA
N+
N+
O– O
P
O
O– O
O
P
O
O
O O
O
HO
O
O
O
NHAc
O
NHAc
HO
N+
N+
OR1
OR1
OR1
O
O– P O
O
HO
HO
H3
O
N+
O
OH
O
P O
O
O
O– P
O
O O
O
OR1
O
HO
O
O O
NHAc OR1
O
O
OR1
NHAc
NHAc
O
HO
O– P O
O–
O
O
O
HO
H3N+
O O
O
H3N+
R1=
H3 C
e Type V LTA
HO
HO
H3C
O
O
R
O
NHAc
OH
HO
HO
R
O
OH O
HO
O O
D-Ala
O
O P
O
NH
O– HO
O
HO
C
O
HO
O O
H
C
OH
O
3
H3C
NH
NH
C O HO
O
C
O
HO
O
H3C
O
O P O
O– HO
HO
O
O OH
NH
C
O
O
HO
O
OH
O
HO
HO
O
OH
O
O
HO
HO
O
O
O
R
O
OH
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R
O
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O
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Polyglycerolphosphate
chain
Glc2-DAG
25x
+ DAG
P
LtaA
LtaS
PgsA
P
YpfP
2x
UDP
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OH OH
OH
O
UDP
OH
?
P
P
CdsA
CDP
P
DgkB
P
CMP GroP
PPi
CTP ADP ATP
Figure 2
Type I LTA synthesis machinery and lipid turnover in Staphylococcus aureus. The glycolipid anchor
Glc2 -DAG is produced by YpfP and moved to the outside of the membrane, likely by LtaA. The LtaS
enzyme produces the polyglycerolphosphate chain by the repeated addition of GroP residues to the tip of
the growing chain using the lipid phosphatidylglycerol (PG) as substrate. The concomitantly formed DAG is
recycled in the cytoplasm to PG in reactions catalyzed by DgkB, CdsA, PgsA, and as of yet unknown
enzyme(s) with phosphatidylglycerol phosphate phosphatase activity. The scissors indicate the processing
step of LtaS by the type I signal peptidase SpsB. This figure was adapted with permission from Reichmann &
Gründling (106). The publisher for this copyrighted material is John Wiley and Sons. Abbreviations: DAG,
diacylglycerol; Glc2 , diglucosyl; GroP, glycerolphosphate; LTA, lipoteichoic acid.
PG:
phosphatidylglycerol
DAG: diacylglycerol
84
structure and is usually linked to the bacterial membrane via a glycolipid anchor (33, 106). The
hydroxyl groups at the C2 position of the GroP repeating units are, to varying degrees, modified
with D-alanyl or glycosyl groups. The key enzymes involved in type I LTA synthesis have been
identified and are depicted in Figure 2 for S. aureus. The glycolipid anchor is produced in the
cytoplasm of the cell by the glycosyltransferase YpfP, which uses a nucleotide-activated sugar
as substrate, and this lipid is then moved to the outside of the membrane, presumably by the
flippase LtaA (43, 59, 60, 66). The GroP chain is then extended on the glycolipid anchor by
the repeated addition of GroP subunits derived from the head group of the membrane lipid
phosphatidylglycerol (PG) (69, 116) by the action of the LTA synthase (LtaS) enzyme (44). The
crystal structures of the enzymatic domain of the LTA synthases YflE from B. subtilis and LtaS from
S. aureus have been determined, including a cocrystal structure with GroP, providing insight into
the binding of the lipid head group to the enzyme (77, 110). LtaS enzymes are processed between
the membrane and the extracellular enzymatic domain, likely by type I signal peptidases (132).
Whereas the soluble extracellular domain of LtaS can hydrolyze PG to diacylglycerol (DAG) in
vitro (61, 108, 131), expression of this domain alone is insufficient for LTA synthesis (132): Only
the full-length enzyme can produce LTA in vivo. A model has been proposed in which the signal
peptidase–dependent cleavage of LtaS serves to inactivate the enzyme under conditions where
LTA production is no longer required (132).
Even though all type I LTAs contain the same GroP backbone, the number of LtaS-type enzymes involved in its synthesis differ between bacterial species. In S. aureus, LtaS initiates and
extends the GroP chain, whereas in L. monocytogenes LtaP links the first GroP to the glycolipid
anchor, after which LtaS extends the chain (44, 128). Many other bacteria contain multiple LtaS
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enzymes; however, the two-enzyme system found in Listeria spp. appears to be unique, as LtaP
has significantly diverged from the LtaS enzyme. In Bacillus spp., which contain four LTA synthase enzymes, these proteins are more closely related to each other and the LtaS protein of L.
monocytogenes than to LtaP.
Disaccharide-containing glycolipids are often the predominant glycolipids and are present
both as free membrane lipids and as LTA anchors such as β-glycosyl(1–6)-β-glucosyl(1–3)diacylglycerol (Glc2 -DAG) in S. aureus and B. subtilis or α-galactosyl(1–2)-α-glucosyl(1–3)-DAG
in L. monocytogenes (34, 59, 60, 66, 69, 123, 128). However, glycolipids with mono-, tri-, or tetrasaccharides are also found in bacterial membranes and are used as LTA anchors, and they can be
further substituted with acyl chains or fatty acids (33). A growth temperature–dependent variation
in the LTA lipid anchor has recently been observed for L. monocytogenes (28). The anchor contained a second DAG lipid when the bacteria were grown at 37◦ C, and this LTA polymer showed
reduced binding to the eukaryotic pattern-recognition protein L-ficolin (28). A comprehensive
review covering the diversity of glycolipids and phosphoglycolipids and their interrelationship
with LTA synthesis was published some years ago but is still relevant (33). Enzymes involved in
glycolipid synthesis were covered in a recent review and are not further discussed here (106).
Mutations in ltaS have now been generated in S. aureus, B. subtilis, Bacillus anthracis, L. monocytogenes, and Lactobacillus acidophilus (39, 44, 91, 97, 110, 128, 131). With the exception of L.
acidophilus, strains either lacking LTA or with defects in LTA backbone synthesis have severe
growth defects. L. monocytogenes, B. subtilis, and B. anthracis ltaS mutants display a filamentation
phenotype, which in B. subtilis was attributed to the inability of the key cell division protein FtsZ
to assemble at the division site (39, 110, 128, 131). In addition, evidence of a direct interaction
between cell division proteins and LTA synthesis proteins was recently provided for S. aureus
(105). An S. aureus ltaS mutant can only be maintained under osmotically stabilizing conditions
in medium with a high concentration of NaCl or sucrose, after acquisition of compensatory
mutations, or, for some strains, by lowering the growth temperature (22, 44, 97). The observation that an S. aureus ltaS mutant can be rescued in high-osmolality medium or by an increase
in the cellular concentration of cyclic-diadenosine-monophosphate (c-di-AMP), a nucleotidesignaling molecule that has been implicated in the control of potassium and/or other ion transport (9, 22–24, 94, 97), might indicate a crucial function of LTA in the osmoprotection of the
cell.
Type I LTA Synthesis and Lipid Turnover
Type I LTA synthesis is intimately linked with lipid biosynthesis and turnover, as has been described in detail for S. aureus (69). In this organism, every ninth lipid on the outer leaflet of the
membrane is an LTA molecule with an average length of 25 GroP units (69). It has been estimated
that the PG pool is turned over more than twice per generation time to support LTA synthesis
(69). For each PG molecule that is hydrolyzed to extend the LTA chain by one repeating unit, one
molecule of DAG is produced. DAG then reenters the cell, where it is recycled to PG or used for
the synthesis of glycolipids (Figure 2). In the first step of the recycling process, the cytoplasmic
enzyme DgkB converts DAG to phosphatidic acid (57, 58, 90) (Figure 2). Phosphatidic acid is
subsequently converted to PG via the conventional PG synthesis pathway by the successive actions
of the phosphatidate cytidyltransferase CdsA, the phosphatidylglycerol phosphate synthase PgsA,
and one or more enzymes with phosphatidylglycerol phosphate phosphatase activity that convert
phosphatidylglycerol phosphate to PG (Figure 2). Although three enzymes, PgpA, PgpB, and
PgpC (52, 53, 78), with this activity have been characterized in E. coli, the enzyme(s) with such
activity has not yet been identified in gram-positive bacteria.
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Gal: galactose
GlcNAc:
N-acetylglucosamine
Forssman antigen:
An antigen that has the
ability to induce
rabbits to form
hemolytic antibodies
to sheep red blood
cells
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D-Ala: D-alanine
15:26
DgkB activity is essential for the growth of B. subtilis; in a conditional dgkB mutant strain, LTA
synthesis ceased and DAG accumulated rapidly (57). However, the lethality was prevented by
the disruption of either of the two main LTA synthase enzymes, YflE or YfnI (87). Thus, DgkB
activity and the DAG recycling pathway are only essential in cells with a high PG turnover caused
by LTA synthesis, potentially indicating that the accumulation of DAG is not tolerated by the
cell. However, inactivation of YfnI does not result in a decrease in DAG levels, and therefore the
accumulation of DAG alone cannot explain the growth arrest seen in the dgkB mutant (87).
Complex LTA Structures
Several gram-positive bacteria produce more complex LTA polymers, here referred to as type
II–V LTAs (Figure 1). Significant progress has been made toward understanding the structure,
synthesis, and function of type IV LTA found in Streptococcus pneumoniae (see the following section).
As with type IV LTA, the chemical structures of type II, III, and V LTAs may undergo further
revisions once they are subjected to additional analysis. It is also likely that additional complex
LTAs will be discovered. Type II LTA, found in Lactococcus garvieae strain Kiel 4217, has a proposed
backbone of α-Gal(1–6)-α-Gal(1–3)-GroP repeating units in which the GroP units can be further
substituted with α-Gal residues (68). The polymer is linked via an α-Glc(1–2)-α-Glc(1–3)-DAG
anchor to the membrane, and the first glucose (Glc) molecule can carry an additional acyl chain
(68) (Figure 1). Type III LTA, found in Clostridium innocuum, has a proposed structure of αGal(1–3)-GroP–repeating units linked via a β-glucosamine(1–3)-α-Glc(1–3)-DAG lipid anchor
to the membrane. The GroP residues are substituted with either N-acetylglucosamine (25%)
or glucosamine (50%) residues (35). An LTA polymer with yet another structure, type V LTA,
has been observed in Peptostreptococcus anaerobius and C. difficile (107, 114). Type V LTA has a
proposed structure of α-D-GlcNAc(1–3)-α-D-GlcNAc repeating units linked through C-6 -C-6
phosphodiester bridges. The second N-acetylglucosamine (GlcNAc) residue is further decorated
with D–glyceric acid, and the polymer is retained in the membrane via a β-1-6-linked triglucosylDAG glycolipid anchor (107) (Figure 1). The enzymes involved in type II, III, and V LTA synthesis
are unknown. When and if the structures are confirmed, the definition of LTA as alditolphosphatecontaining polymers might need to be revised to include glycosyl-phosphate-containing polymers
such as type V LTA.
Streptococcus Pneumoniae (Type IV) LTA
Type IV LTA is found in S. pneumoniae and some other Streptococcus spp. Pneumococcal LTA
(pnLTA) was described in 1930 as pneumococcal C-polysaccharide (119) and was later shown to
possess Forssman antigenicity (41). This observation was only explained in 2008, when a revised
structure with two terminal GlcNAc residues was proposed; these represent the minimal Forssman
antigen (111). In 2013, additional revisions were proposed (40), and it is now assumed that the
backbone consists of pseudopentasaccharide repeating units made up of 2-acetamido-4-amino2,4,6-trideoxy-D-galactose (AATGal), Glc, RboP, and two GlcNAc residues (Figure 1). The
repeating units are α-1-4-linked to each other and β-1-4-linked to the glycolipid anchor αGlc-(1–3)-DAG (40, 111). It was further suggested that pnLTA contains only D-alanine (D-Ala)
modifications on the RboP residues and is not glycosylated, as originally proposed (40, 71).
Most bacteria containing LTA also synthesize WTA. On the one hand, in organisms with type I
LTA, the two polymers have different structures and are synthesized by different enzymes. pnLTA
and pnWTA, on the other hand, have identical structures and are produced by the same enzyme
machinery. A detailed model for their synthesis has been proposed (Figure 3) (29); however, many
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P
Spr
1222
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Spr
P
1655 PP
Spr
0091
P
P
UDP- UMP UDP- UDP
AATGal
Glc
LicD3
P
P
Spr
1223
P
P
LicD1
Spr
1224
LicD2
2x
2x
CDP- CMP UDP- UDP
RboP
GalNAc
P
P
P
P
LCP
LCP
TacF
P
P
CDP- CMP
Cho
Figure 3
Type IV LTA synthesis machinery in Streptococcus pneumoniae. The enzymes Spr1655, Spr0091, LicD3 and
Spr1123, and Spr1124 use the indicated nucleotide-activated sugars or ribitolphosphate (RboP) as substrate
for the synthesis of the C55 -P-linked pseudopentasaccharide intermediate. The N-acetylglucosamine
(GlcNAc) residues are decorated with phosphocholine (P-Cho) residues by LicD1 and LicD2. The chain is
polymerized by Spr1222, transported across the membrane by TacF, and transferred onto either the
glycolipid Glc-DAG (LTA) or peptidoglycan (WTA) by LCP family enzymes. This figure was adapted with
permission from Denapaite et al. (29) The publisher for this copyrighted material is Mary Ann Liebert, Inc.,
publishers. Abbreviations: Glc-DAG, glucosyl-diacylglycerol; LCP, LytR-CpsA-Psr; LTA, lipoteichoic acid.
enzymes have not been verified experimentally. The pseudopentasaccharide repeating units are
produced on undecaprenyl phosphate (C55 -P), and the GlcNAc residues are further decorated
with phosphocholine (P-Cho) residues. The chain is polymerized and then transported across the
membrane by TacF, where it is either transferred onto the glycolipid Glc-(1–3)-DAG (LTA) or
onto peptidoglycan (WTA), likely by enzymes belonging to the LytR-CpsA-Psr (LCP) family
(29, 62). Streptococcus mitis also produces type IV LTA (12). Interestingly, bioinformatics analysis
indicated the presence of an LtaS homolog (29), and further investigation is needed to determine
whether this species produces both type I and IV LTAs.
MODIFICATIONS OF LTAS AND THEIR FUNCTIONS
D-Alanylation
of LTA
Type I and IV LTAs (and WTAs) are modified with D-Ala residues, and the enzymes required
for this process are encoded by the dltABCD operon (46, 95). The D-alanylation process starts
in the cytoplasm of the cell, where the D-alanine-D-alanyl carrier protein ligase DltA activates
D-Ala using ATP to form a high-energy D-alanyl-AMP intermediate and subsequently transfers
it to the phosphopantheinyl prostetic group of the D-Ala carrier protein DltC (Figure 4a) (30,
98, 134). DltC shows sequence and structural homology to acyl carrier proteins (ACPs) (124),
and structural studies on DltA have shown that this protein belongs to the adenylate-forming
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C55 -P: undecaprenylphosphate
P-Cho:
phosphocholine
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enzyme family (30, 98, 134). DltA is assumed to undergo major structural rearrangements during
the reaction cycle that are driven by small changes in electrostatic interactions introduced by
substrate binding and product formation. The function of the remaining proteins, DltB and DltD,
is not completely understood, and different models have been proposed (27, 95, 100). Recent
work has provided experimental support for a model originally proposed by Werner Fischer and
colleagues (34, 100, 104). In this model, the multiple-membrane-spanning protein DltB transfers
a
P
DltD
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P
DltB
P
DltC
O
D-Ala
DltA
NH3+
NH3+
O
H
HO
ADP
H
HO
ATP
b
P
?
GT-A
P
GT-C
GlcNAc
OH OH
UDP
OH
O
UDP
NHAc
c
OH
N+
P
P
LicB
LicA
OH
N+
N+
CDP
LicC
P
P
LicD1
P
P
N+
LicD2
Choline
ATP ADP
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P-Cho
CTP PP
CDP-Cho
CMP
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the D-Ala from DltC to C55 -P and subsequently transports the D-Ala-P-C55 intermediate across
the membrane (Figure 4a). DltB has been grouped among membrane-bound O-acyltransferase
(MBOAT) proteins, where other members are known to transfer organic acids onto hydroxyl
groups of membrane-embedded components or reacylate lysophospholipids (50, 112). DltD has,
as recently shown, an N-in C-out membrane topology placing the functional part of the protein
on the outside of the cell (104). In a previous study, thioesterase activity was ascribed to DltD on
a cytoplasmic substrate and was unrelated to this pathway (27). The new findings and the location
of DltD on the outside of the cell, however, might suggest that this protein is the enzyme that
aids in the final step and transfers the D-Ala onto LTA (Figure 4a).
A number of environmental factors have been shown to influence the amount of D-alanines on
LTA. An increase in pH (79), temperature (51), or NaCl (37) leads to a decrease in D-alanylation.
At high pH the ester linkage is labile. The half-life of D-alanines on LTA is 3.9 h at pH 8, whereas it
is >10,000 h at pH 6 (20). Two-component systems play a crucial role in regulating the expression
of the dlt operon. In S. aureus, the expression of the dlt operon is repressed by ArlSR, in response
to an increase in the concentration of Mg2+ (70). The response is, however, species specific: An
increase in Mg2+ or K+ has no effect on dlt gene expression in Streptococcus gondii (89). The LiaSR
two-component system, which responds to cell membrane damage (115), induces the expression
of the dlt operon in response to polymyxin B as well as low pH in S. gondii (89), and in Streptococcus
agalactiae, dlt expression is controlled by the DltRS system (103).
Analysis of dlt mutants in diverse bacteria revealed that this modification plays an important
role in the regulation of autolysis (99, 113), cation homeostasis through the binding of Mg2+ ions
(5), host cell adhesion and invasion (1, 72), and biofilm formation (32) and is essential for the
virulence of pathogens such as L. monocytogenes and S. aureus (1, 21). In addition, D-alanylation of
TAs provides resistance to cationic antimicrobial peptides (CAMPs) (1, 102). It has been presumed
that the presence of D-alanines raises the overall net negative charge of the membrane, thereby
reducing the affinity for CAMPs. However a recent study on Streptococcus pyogenes questioned the
link between charge and the ability of CAMPs to cross the membrane, suggesting instead that the
D-alanines alter the conformation of LTA, leading to an increase in the density of the cell wall (109)
(see also sidebar, Amino Acid Modifications of Lipopolysaccharides in Gram-Negative Bacteria).
Glycosylation of LTA
A mechanism for the incorporation of glycosyl residues into type I LTA has been proposed based
on work performed in the 1980s (34, 55, 81, 133). Some but not all type I LTAs are glycosylated,
and variations are also observed in the type of sugar used for this modification. This has been
←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−
Figure 4
LTA modifications. (a) D-Ala modification mechanism of type I and IV LTAs based on the Fischer model
(100). DltA ligates D-alanines onto DltC. The D-alanines are transferred onto undecaprenyl phosphate
(C55 -P) and subsequently transported across the membrane by DltB. DltD then aids in the transfer of the
D-alanines to glycerolphosphate (GroP) of type I or ribitolphosphate (RboP) of type IV LTA. (b) Proposed
glycosylation mechanism of type I LTA. A cytoplasmic glycosyltransferase (likely a GT-A member) uses a
nucleotide-activated sugar such as UDP-GlcNAc and links it onto C55 -P. The intermediate is transported
across the membrane and an extracellular glycosyltransferase (likely a GT-C member) then transfers the
sugar onto LTA. (c) Phosphocholine (P-Cho) modification mechanism of type IV LTA. Choline is
transported into the cell by LicB and converted to P-Cho and CDP-Cho by the action of LicA and LicC.
The enzymes LicD1 and LicD2 then use CDP-Cho to substitute the N-acetylglucosamine (GlcNAc)
residues of the TA precursors with P-Cho residues. Abbreviation: LTA, lipoteichoic acid.
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AMINO ACID MODIFICATIONS OF LIPOPOLYSACCHARIDES IN GRAM-NEGATIVE
BACTERIA
Proteins with homology to DltA–D have been detected in some gram-negative bacteria belonging to the genera
Erwinia, Photorhabdus, and Bordetella (2). The genes were likely acquired by horizontal gene transfer, as their CG
content differs from that of the rest of the genome. A Bordetella pertussis strain with a deletion of this D-alanine
incorporation and resistance to AMPs, or dra, operon has been produced (2). Reminiscent of phenotypes observed
for dlt mutants in gram-positive bacteria, the dra mutant showed increased susceptibility to antimicrobial peptides
and was killed more readily by human phagocytes. Initial experiments suggest that outer membrane proteins might
be the targets of this modification (2). Another amino acid modification has been observed on the lipid A anchor of
lipopolysaccharide in Vibrio cholerae and compared to the Dlt system in gram-positive bacteria (45). Three proteins,
AlmE–G, are required for the introduction of these glycine and diglycine modifications. AlmE shows sequence
homology to DltA, and it activates and transfers the glycines onto the small carrier protein AlmF (45). AlmF does
not show sequence homology to DltC but has been suggested to possess a similar fold. The glycine residues are
then transferred from AlmF onto the lipid A anchor by AlmG (45).
best characterized for Bacillus strains, where some strains lack glycosyl groups and some contain
GlcNAc, whereas others have α-Gal residues on their LTA (54, 55). The LTA of all Listeria
strains investigated to date is glycosylated with α-Gal, although the degree of glycosylation can
vary between strains (48, 123). There is also some evidence that the LTA of S. aureus strain H is
glycosylated with GlcNAc (4); however, other strains lack this modification.
Early biochemical studies have shown that the glycosylation process of LTA involves two
separate glycosyltransferases and proceeds through the formation of a sugar-linked C55 -P lipid
intermediate (Figure 4b) (81, 133). These studies led to the following model: First a cytoplasmic
glycosyltransferase uses a nucleotide-activated sugar to form the sugar-P-C55 intermediate. After
the transport of this intermediate across the membrane, a second glycosyltransferase links the
sugar onto LTA (34, 133) (Figure 4b). The enzymes involved have not yet been identified,
however the types of glycosyltransferases required for this process can be speculated upon based
on similarities to the modification of lipopolysaccharide (LPS) in Escherichia coli with 4-amino-4deoxy-L-arabinose (L-Ara4N) or the glycosylation of complex cell wall polymers in Mycobacterium
tuberculosis (3, 11, 16). The GT-A-type glycosyltransferase ArnC of E. coli uses a UDP-activated
sugar to produce a sugar-P-C55 membrane intermediate (16). A GT-A-type glycosyltransferase is
therefore a good candidate enzyme that could act as the cytoplasmic glycosyltransferase in the LTA
glycosylation process, and proteins homologous to ArnC can be found in a range of gram-positive
bacteria. On the outside of the cell, the E. coli ArnT protein, a glycosyltransferase of the GT-C
type, transfers the sugar from the C55 -P membrane intermediate onto the lipid A moiety of LPS.
GT-C fold glycosyltransferases have not been characterized in much detail; proteins belonging to
this family usually contain 8–13 transmembrane helices but share only limited homology (73, 76).
However, GT-C enzymes use C55 -P-linked sugars as a substrate, and therefore we suggest that
the extracellular glycosyltransferase involved in LTA glycosylation likely belongs to this enzyme
family.
Phosphocholine Modification of Type IV LTA
LPS:
lipopolysaccharide
Type IV LTA in S. pneumoniae is modified with P-Cho residues (29, 120). In contrast to Dalanylation, this modification is essential for bacterial growth. The P-Cho residues are introduced
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into the TA precursors within the cytoplasm of the cell, and it is assumed that the polymer is
only exported once it is modified with P-Cho (26). Choline is transported into the cell by LicB
and converted into P-Cho and subsequently CDP-Cho by LicA and LicC, respectively, and then
attached to the O-6 position of one or both GalNAc residues by the enzymes LicD1 and LicD2
(Figure 4c) (10, 31, 36, 135). Once the modified polymer is exported, the P-Cho content can be
reduced by the phosphorylcholine esterase Pce (47, 125). Because of the structure of its active site,
this enzyme is only capable of removing the terminal choline residues, and it has been suggested
that the reduction in choline residues exposed on the bacterial surface is important to prevent the
interaction with host immune proteins (47).
The growth requirement of S. pneumoniae for choline can be counteracted by the addition
of other amino-alcohols such as ethanolamine, although cells grown under these conditions have
various morphological defects and are attenuated in virulence (121). The amino-alcohol physically
replaces the P-Cho residues on the TAs, but it cannot replace them functionally. Several cell
wall proteins, collectively referred to as choline-binding proteins (CBPs), require P-Cho for their
retention in the cell wall or even activity, as in the case of LytA (38, 122). CBPs are modular enzymes
that in several cases contain a peptidoglycan hydrolase domain and a variable number of cholinebinding domains (38). These enzymes are required for the remodeling of the peptidoglycan,
autolysis, and natural competence (122). Structural analyses of CBPs have provided insight into
the binding and substrate specificity of this class of enzymes (47, 92, 101). CBPs also play a
significant role in the virulence of S. pneumoniae, as some CBPs, including PspA, PspC, and
CbpG, mediate interactions with host cells (64, 82, 96, 126). PspA has an additional function: It
also prevents complement deposition on the pneumococcal surface by inhibiting the binding of
the C-reactive host immune protein (CRP) to bacteria by competing for P-Cho-binding sites (93).
Taken together, these findings make it clear that the P-Cho modifications on TAs play a key role
in bacterial physiology and the virulence of S. pneumoniae; however, it should be noted that one
cannot distinguish between the requirement of this modification on LTA versus WTA.
APPLICATIONS OF LTA AND MUTANT STRAINS
Several lines of research that are currently being pursued could be of direct clinical relevance. LTA
polymers and specific antibodies against these polymers have been tested as vaccine candidates.
Immunization of mice with gram-positive bacteria or purified LTA has been shown to elicit
the production of opsonic antibodies (67, 117). To increase the immunogenicity of LTAs, the
production of conjugate vaccines is currently being pursued. Recent studies have reported on
the synthesis of a conjugate between synthetic type I LTA and the immunogenic tetanus toxin
protein or between type V LTA of C. difficile with E. coli enterotoxin or a Pseudomonas exotoxin
(13, 18, 25). Much effort has gone into the use of type I LTA–specific antibodies in passive
immunization studies (118, 129, 130). A humanized antibody has been used in human trials in
very-low-weight neonates, and the vaccine appeared safe and well tolerated; however, no clear
protection was observed against staphylococcal sepsis in this study (129, 130). Enzymes involved in
LTA synthesis and their modifications can also be exploited as antimicrobial targets. For instance,
choline analogues have been shown to bind to and inhibit the activity of pneumococcal CBPs (80,
83). A d-Ala analog that blocks the activity of DltA in vitro has been shown to synergize with
the peptidoglycan synthesis inhibitor vancomycin and lead to growth inhibition when used in
combination (88). Recently, an LtaS enzyme inhibitor was identified (108). This small molecule
was shown to prevent the growth of S. aureus and several other antibiotic-resistant gram-positive
bacteria (108). Mice challenged with a lethal dose of S. aureus showed increased survival in the
presence of this compound (108). The identification of the genetic determinants required for
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LTA production made it possible to compare the interaction of wild-type and LTA-deficient
bacteria with immune cells. Recent work using an LTA-negative L. acidophilus strain highlighted
the potential use of such a mutant as a probiotic strain with improved properties (75). In contrast
to wild-type L. acidophilus, the ltaS mutant strain was shown to downregulate the production of the
inflammatory cytokines IL-12 and TNFα and enhance the production of the anti-inflammatory
cytokine IL-10 (91). Colonization of mice with the LTA-deficient L. acidophilus strain also showed
promising results: This treatment mitigated the effects of induced colitis, highlighting the potential
use of such a strain for the treatment of inflammatory intestinal disorders (91). More recently, its
application in preventing colon cancer is also being pursued (65).
COMPARISON OF TYPE I LTA AND OSMOREGULATED
PERIPLASMIC GLUCAN SYNTHESIS
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LTA is often compared to LPS of gram-negative bacteria. In particular for type I LTA, it might be
more appropriate to compare this polymer to OPGs of gram-negative bacteria, based on similarities between enzymes involved in their synthesis, their cellular location within the periplasm [they
are not surface-exposed molecules (105)], and their function in osmoprotection. OPGs, formerly
referred to as membrane-derived oligosaccharides (MDOs), are oligosaccharides that accumulate
under low osmolarity conditions in the periplasm of gram-negative bacteria (63). In E. coli, linear
β(1–2)-linked glucose units are produced as lipid-linked intermediates by the glycosyltransferase
OpgH. Similar to the LTA glycolipid anchor–producing enzyme YpfP of S. aureus (or UgtP of B.
subtilis), this enzyme uses UDP-glucose as a substrate. OpgH has also been shown to play a key role
in nutrient-dependent and UDP-glucose-concentration-dependent cell size control in E. coli (49).
A similar function has been previously reported for the B. subtilis UgtP enzyme through regulating the polymerization of the cell division protein FtsZ (19, 127). The linear lipid-linked glucose
chains are then transported to the outer leaflet of the inner membrane where the periplasmically
located glycosyltransferase OpgG adds β(1–6)-linked glucose branches. The oligosaccharides are
then decorated with succinyl, phosphoethanolamine, and GroP residues by the action of OpgC,
OpgE, and OpgB, respectively (15, 63). OpgB, also referred to as MdoB, shares many features
with LtaS-type enzymes. Both enzymes consist of an N-terminal transmembrane and a C-terminal
extracellular enzymatic domain (74). Similar to LtaS, OpgB is processed during bacterial growth
by a protease speculated to be the signal peptidase, and the enzymatic domain is released into the
periplasmic space (74). Both enzymes are Mn2+ -dependent metal enzymes that use the lipid PG
as substrate to add the GroP units onto the periplasmic oligosaccharides or onto the glycolipid
anchor, respectively (42, 56). In both instances, this leads to a rapid PG lipid turnover and the
requirement of a functional lipid-recycling pathway. Based on cryoelectron microscopy images,
LTA has been suggested to be an important constituent of the inner cell wall zone also referred
to as the gram-positive periplasm (84–86). OPGs accumulate in the gram-negative periplasm in
low-osmolarity medium and are thought to protect bacteria under these conditions, although only
modest growth defects have been observed in their absence (14, 63). The observation that an S.
aureus strain lacking LTA can be rescued in high-osmolality medium or by an increase in the
cellular c-di-AMP concentration, implicated in the control of ion transport (22, 23, 97), might
indicate a similar function for LTA in the osmoprotection of the cell.
CONCLUSIONS
LTA represents a significant proportion of the cell membrane and inner cell wall zone in grampositive bacteria. It plays an important role in bacterial growth and physiology and contributes to
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membrane homeostasis and virulence. Although we now have a good understanding of type I and
IV LTA synthesis and their modifications with D-Ala and P-Cho residues, more work is needed
on the glycosylation mechanism and the synthesis pathways of other complex LTAs. Recent
advances in the field have allowed the investigation of these polymers as vaccine candidates, LTA
mutant strains as probiotics with improved characteristics, and LTA synthesis enzymes as novel
antimicrobial targets.
SUMMARY POINTS
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1. LTA is defined as an alditolphosphate-containing polymer that is linked via a lipid anchor
to the outside of the membrane in gram-positive bacteria. However, this definition may
need to be revised to include recently described complex glycosyl-phosphate containing
polymers.
2. LTAs have been grouped into different types based on their chemical structures. Type I
LTA has a simple unbranched polyglycerolphosphate backbone structure whereas type
II–V LTAs have more complex structures.
3. Type I polyglycerolphosphate LTA production is intimately linked with membrane lipid
turnover, and its synthesis shows striking similarities to the production of osmoregulated
periplasmic glucans in gram-negative bacteria.
4. LTA plays an important role for bacterial growth and physiology and contributes to
membrane homeostasis and virulence.
5. The essential nature of LTA makes it an attractive target for vaccines and novel antimicrobials.
FUTURE ISSUES
1. Based on bioinformatics analysis, several enzymes have been predicted to be involved in
type IV LTA synthesis; however, these need to be confirmed experimentally.
2. Further analysis is needed to confirm the chemical structures of other complex LTA
types, and the enzymes required for their synthesis need to be identified.
3. DltB is thought to produce a D-Ala-P-C55 membrane intermediate, and DltD is thought
to transfer D-Ala onto LTA; however, these activities need to be confirmed experimentally.
4. The genetic determinants required for the glycosylation process of LTA need to be
identified and a function for this modification elucidated.
5. Further work is needed to validate LTA synthesis enzymes as a therapeutic target, LTA
polymers as vaccine candidates, and LTA mutant strains as probiotics with improved
characteristics.
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.
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ACKNOWLEDGMENTS
Work in the A.G. laboratory is currently supported by the European Research Council grant
260371 and the Wellcome Trust grant 100289.
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