2 Zentrum Biochemie, Abteilung Zelluläre Chemie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany; 3 Institute for Glycomics, Griffith University, PMB 50 Gold Coast Mail Centre, QLD 9726, Australia; 4 Proteros Biostructures GmbH, Am Klopferspitz 19, D-82152 Martinsried, Germany; and 5 Max-Planck-Institut für Biochemie, Abteilung Strukturforschung, Am Klopferspitz 18a, D-82152 Martinsried, Germany
Received on September 22, 2003; revised on May 18, 2004; accepted on June 10, 2004
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: CMP-sialic acid synthetase / nuclear localization / sialic acids / structure-function aspects
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
Neu5Ac and KDN are believed to be the biosynthetic precursors for other members of the sialic acid family (for reviews see Schauer, 2000; Varki, 1992
). The biosynthetic pathways providing Neu5Ac are well known in bacteria and vertebrates (for review see Bliss and Silver, 1996
; Roseman, 1968
). Even though the biosynthetic pathway leading to KDN seems to be very similar to that leading to Neu5Ac (Angata et al., 1999a
,b
), the primary structures of many of the enzymes involved in the biosynthesis and catabolism of KDN remain to be resolved. However, the activation of Neu5Ac, as well as KDN to its CMP diester (CMP-Neu5Ac and CMP-KDN, respectively), which is a prerequisite for the incorporation into glycoconjugates, is conserved from bacteria through humans. CMPsialic acid is synthesized by the following reaction:
![]() |
This reaction is catalyzed by the CMPsialic acid synthetases (EC 2.7.7.43, CMP-Neu5Ac synthetase and CMP-KDN synthetase, respectively). The product of this reaction, CMPsialic acid, is, in eukaryotic cells, specifically transported into the Golgi apparatus, where it acts as a substrate for sialyltransferases.
The activation of sialic acids is unique in the following ways. (1) The majority of sugars are activated by GDP or UDP. Apart from sialic acids, activation by CMP only occurs in the case of 3-deoxy-D-manno-octulosonate (KDO), generating CMP-KDO (Ghalambor and Heath, 1966). KDO is an eight-carbon sugar and an essential component of gram-negative bacterial cell wall oligo- and some capsular polysaccharides. In addition KDO is found in plants and some green algae (for review see Royo et al., 2000
). (2) Free sialic acids, not the phosphorylated forms, are used as substrates (Comb et al., 1966
). (3) In contrast to all other eukaryotic nucleotide sugar synthetases, which are cytoplasmic enzymes, CMPsialic acid synthetases are localized in the nucleus. The nuclear localization has been documented in a number of sophisticated studies, the earliest of which probably provides the most impressive example. Studying the expression of the sialic acid activating enzyme in ocular tissue E. L. Kean (1969)
realized that only the nucleated cells in the lens epithelial layer and not the enucleated fiber cells derived from these cells express CMP-Neu5Ac synthetase activity. The multitude of biochemical studies addressing the issue of nuclear localization of the sialic acidactivating enzymes has been intensively reviewed (Kean, 1991
; Kean et al., 2004
; Vionnet et al., 1999
).
Several hypotheses have been advocated to explain the unusual subcellular localization of the CMPsialic acid synthetase, including the following. (1) The nuclear environment may be a prerequisite for enzymatic activity. (2) The CTP concentration may be higher in the nuclear compartment. (3) Activated sialic acids may be required for sialyltransferases localized in the nucleus (Richard et al., 1975). (4) Activation of Neu5Ac in the nucleus may protect the nucleotide sugar from subsequent modifications by cytoplasmic enzymes, such as the CMP-Neu5Ac hydroxylase that generates Neu5Gc (Malykh et al., 2001b
; Shaw and Schauer, 1988
) or (5) from degradation by the CMP-Neu5Ac hydrolase (Kean and Bighouse, 1974
; van Dijk et al., 1976
). (6) Because CMP-Neu5Ac has been shown to be an allosteric inhibitor of UDP-GlcNAc 2-epimerase/kinase, the enzyme that controls Neu5Ac synthesis (Hinderlich et al., 1997
; Kornfeld et al., 1964
; Stäsche et al., 1997
), sequestration of CMP-Neu5Ac in the nucleus may be necessary to prevent early inactivation of cytoplasmic UDP-GlcNAc 2-epimerase/kinase (Kornfeld et al., 1964
). (7) The CMP-Neu5Ac synthetase may have a second, as yet unidentified function within the nucleus.
![]() |
Cloning and characterization of vertebrate CMPsialic acid synthetases |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The isolated murine enzyme is a protein of 432 amino acids with a calculated molecular mass of 48.1 kDa. The overall sequence identity between the murine and bacterial CMPsialic acid synthetases ranges between 41% and 47% and, as shown in Figure 2A, is concentrated to five conserved amino acid stretches (Münster et al., 1998). This finding, which provides strong evidence for a common ancestral gene, received support through the cloning of the human CMP-Neu5Ac synthetase (Lawrence et al., 2001
) and the CMP-KDN synthetase from rainbow trout (Nakata et al., 2001
). Both enzymes also contain the five conserved motifs (Figure 2A). Thus the CMPsialic acid synthetases provide the first identified sialic acidmetabolizing enzymes, which conserve specific sequence motifs from bacteria through humans. Therefore it was not surprising to see that the murine CMP-Neu5Ac synthetase cDNA complements Escherichia coli EV5, a polySia-capsule negative mutant of the neuroinvasive E. coli K1 (Vimr and Troy, 1985
). The capsular defect in E. coli EV5 results from a genetic defect in the endogenous CMP-Neu5Ac synthetase (Vimr et al., 1989
). Expression of the murine CMP-Neu5Ac synthetase reconstituted the K1 phenotype (Münster et al., 1998
, 2002
).
|
In Figure 3 a phylogenetic tree is shown, which includes the confirmed CMPsialic acid and CMP-KDO synthetase sequences. The tree indicates a common ancestor for CMPsialic acid and CMP-KDO synthetases. Within the family of CMPsialic acid synthetases, the vertebrate genes cluster into a separate branch, but the tree clearly demonstrates phylogenetic connection with the bacterial enzymes. These data confirm an earlier extended phylogenetic study by Angata and Varki (2002), which includes two enzymes of the sialylation pathway (Neu5Ac[-9-phosphate] synthase and CMPsialic acid synthetase). Based on their data, the authors suggested that genes involved in the biosynthesis of sialic acids predate the split of deuterostomes (vertebrates, ascidians, and echinoderms) and protostomes (arthropods and mollusks), possibly even the split of the three domains of life (Angata and Varki, 2002
).
|
The human CMPsialic acid synthetase (94% identity to the murine enzyme) was isolated by Lawrence and co-workers (2001) and has been shown to be transported to the nucleus if expressed in insect cells. In vitro testing of activity demonstrated that Neu5Ac and Neu5Gc are the preferred substrates also of the human enzyme (Lawrence et al., 2001
).
![]() |
Nuclear transport of vertebrate sialic acid synthetases |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Sequence analysis revealed one putative NLS in the human (Lawrence et al., 2001), two in the fish (Nakata et al., 2001
), and three in the murine CMPsialic acid synthetase (Münster et al., 2002
). With the help of deletion mutants, the NLS responsible for nuclear import of the murine CMP-Neu5Ac synthetase could be narrowed down to BC2 (Münster et al., 2002
). The sequence in BC2: K198RPRR fits well with the four-residue NLS motif suggested by Chelsky (K-R/K-X-R/K, Chelsky et al., 1989
) and is strictly conserved in the human enzyme and highly conserved in the rainbow trout CMP-KDN synthetase (Figure 4A). In fact, K200RPR has been suggested to be the human NLS (Lawrence et al., 2001
). A detailed study carried out by site-directed mutagenesis demonstrated that each basic amino acid residue in BC2 is of importance for the correct nuclear import of the murine enzyme (Münster et al., 2002
). In contrast, no information is available to date on the factors that mediate the nuclear transport of CMP-Neu5Ac synthetases.
|
![]() |
Structurefunction relationships in CMPsialic acid synthetases |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
The crystal structure of the catalytic domain of the murine CMP-Neu5Ac synthetase has been obtained in its closed conformation with the product CMP-Neu5Ac bound, making visible the contacts formed between the nucleotide sugar and the protein (Figure 5B). The active site is located at the interface of the core domain of monomer A (ochre) and the dimerization domain of monomer B (blue). The two crucial residues for enzymatic activity, Arg-199 and -202, are part of the substrate loop (monomer B) and make polar contacts to the sugar moiety. Arg-199 interacts with the carbonyl oxygen of the N-acetyl group, and the side chain of the highly conserved Arg-202 coordinates the carboxylate group at position one of the sugar. Similarly, Arg-165 in the NmB enzyme, corresponding to Arg-202 in the murine enzyme (Figure 4), has been demonstrated to be essential for Neu5Ac binding and stabilization of the transition state in the NmB enzyme (Mosimann et al., 2001).
Crystal structure data about the binding of the sugar moiety have been obtained only in the case of the murine enzyme (Figure 5B, Krapp et al., 2003). The NmB crystal structure was resolved with CDP bound and information concerning Neu5Ac binding is restricted to modeling data (Mosimann et al., 2001
). In Figure 5C the information obtained from crystal structure analyses, sugar docking experiments, and mutational approaches are summarized for the murine and NmB CMPsialic acid as well as the E. coli CMP-KDO synthetase (Jelakovic and Schulz, 2002
). Amino acid residues involved in nucleotide binding can be superimposed in the different crystal structures and in the case of the ß- and
-phosphate coordinating residues provide highly conserved positions at primary sequence level (motif I; see also Figure 2). The same is true for the coordination of the carboxylate group at C1 of the sialic acid. The polar contact made by Arg-202 in the murine enzyme is substituted by Arg-165 in the NmB synthetase and by Arg-155 in the E. coli CMP-KDO synthetase. In contrast, trials to overlay the residues involved in the binding of the sugar moiety (shaded residues in Figure 5C) demonstrate that this part of the proteins is less conserved not only in terms of primary sequence but also with respect to the 3D structure. Although the highly conserved Gln-residue of motif III (Gln-141 in Mus musculus; Gln-104 in NmB) has been demonstrated to be involved in the coordination of the O8 and N5 atoms by either modeling (NmB) or structural (murine enzyme) data, the trial to overlay this position in the crystal structures failed (this study). Similarly, imperfect overlay was obtained for the residues involved in the formation of the hydrophobic pocket that accommodates the methyl-group of the 5N-acetyl group. The partial failure of positional identity in this area correlates with the rather low conservation at primary sequence level and may explain differences in the substrate specificities between the murine and the NmB enzyme. Molecular reasons for differences in the substrate specificities observed between the murine (mainly active with Neu5Ac) and the closely related rainbow trout enzyme (active with both Neu5Ac and KDN) are presently not available. However, also in this case the dissimilarity at the dimer interface may be responsible for the changes in the substrate recognition.
In the subfamily of CMP-KDO synthetases, the highly conserved arginine (Arg-202 in mouse) corresponds to Arg-155 in E. coli (KSU5) and is part of a conserved motif (open box in Figure 4B), known from crystal structure data to be involved in the dimerization of the enzyme and in the formation of the active site (Jelakovic et al., 1996; Jelakovic and Schulz, 2001
, 2002
). Significant similarities in the overall structure and in the nucleotide binding pocket (see Figure 5C) support an evolutionary relationship. However, the dimerization interfaces and therefore the sugar-binding pockets in CMPsialic acid and CMP-KDO synthetases are different and explain the strict substrate specificities of the two enzyme classes.
![]() |
Conclusions and perspectives |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The generation of transgenic mouse models is necessary to finally reveal the systemic relevance of the nuclear localization of CMPsialic acid synthetases in animals. Moreover, the identification of potential interaction partners of the CMP-Neu5Ac synthetase in the cell nucleus may give a hint toward a possible second function. Last but not least, the bulk of genetic information and the associated ease in obtaining additional structurefunction information for these enzymes should provide an efficient path toward answering the open questions with respect to substrate specificity and phylogenetic occurrence.
![]() |
Footnotes |
---|
![]() |
Abbreviations |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Angata, T. and Varki, A. (2002) Chemical diversity in the sialic acids and related alpha-keto acids: an evolutionary perspective. Chem. Rev., 102, 439469.[CrossRef][ISI][Medline]
Angata, T., Matsuda, T., and Kitajima, K. (1998) Synthesis of neoglycoconjugates containing deaminated neuraminic acid (KDN) using rat liver alpha2,6-sialyltransferase. Glycobiology, 8, 277284.
Angata,T., Nakata,D., Matsuda,T., and Kitajima,K. (1999a) Elevated expression of free deaminoneuraminic acid in mammalian cells cultured in mannose-rich media. Biochem. Biophys Res. Commun., 261, 326331.[CrossRef][ISI][Medline]
Angata,T., Nakata,D., Matsuda,T., Kitajima,K., and Troy,F.A. (1999b) Biosynthesis of KDN (2-keto-3-deoxy-D-glycero-D-galacto-nononic acid). Identification and characterization of a KDN-9-phosphate synthetase activity from trout testis. J. Biol. Chem., 274, 2294922956.
Bailey, T.L. and Elkan, C. (1994) Fitting a mixture model by expectation maximization to discover motifs in biopolymers. Ismb., 2, 2836.[Medline]
Bailey, T.L. and Gribskov, M. (1998) Combining evidence using p-values: application to sequence homology searches. Bioinformatics, 14, 4854.[Abstract]
Barry, D.M. and Wente, S.R. (2000) Nuclear transport: never-ending cycles of signals and receptors. Essays Biochem., 36, 89103.[Medline]
Bliss, J.M. and Silver, R.P. (1996) Coating the surface: a model for expression of capsular polysialic acid in Escherichia coli K1. Mol. Microbiol., 21, 221231.[ISI][Medline]
Chelsky, D., Ralph, R., and Jonak, G. (1989) Sequence requirements for synthetic peptide-mediated translocation to the nucleus. Mol. Cell Biol., 9, 24872492.[ISI][Medline]
Chook, Y.M. and Blobel, G. (2001) Karyopherins and nuclear import. Curr. Opin. Struct. Biol., 11, 703715.[CrossRef][ISI][Medline]
Comb, D.G., Watson, D.R., and Roseman, S. (1966) The sialic acids. IX. Isolation of cytidine 5'-monophospho-N-acetylneuraminic acid from Escherichia coli K-235. J. Biol. Chem., 241, 56375642.
Corpet, F. (1988) Multiple sequence alignment with hierarchical clustering. Nucleic Acids Res., 16, 1088110890.[Abstract]
Crocker, P.R. and Varki, A. (2001) Siglecs in the immune system. Immunology, 103, 137145.[CrossRef][ISI][Medline]
Daniel, L., Trouillas, J., Renaud, W., Chevallier, P., Gouvernet, J., Rougon, G., and Figarella-Branger, D. (2000) Polysialylated-neural cell adhesion molecule expression in rat pituitary transplantable tumors (spontaneous mammotropic transplantable tumor in Wistar-Furth rats) is related to growth rate and malignancy. Cancer Res., 60, 8085.
Deutscher, S.L., Nuwayhid, N., Stanley, P., Briles, E.I., and Hirschberg, C.B. (1984) Translocation across Golgi vesicle membranes: a CHO glycosylation mutant deficient in CMP-sialic acid transport. Cell, 39, 295299.[ISI][Medline]
Eckhardt, M., Gotza, B., and Gerardy-Schahn, R. (1998) Mutants of the CMP-sialic acid transporter causing the Lec2 phenotype. J. Biol. Chem., 273, 2018920195.
Edwards, U. and Frosch, M. (1992) Sequence and functional analysis of the cloned Neisseria meningitidis CMP-NeuNAc synthetase. FEMS Microbiol. Lett., 75, 161166.[Medline]
Fleischmann, R.D., Adams, M.D., White, O., Clayton, R.A., Kirkness, E.F., Kerlavage, A.R., Bult, C.J., Tomb, J.F., Dougherty, B.A., and Merrick, J.M. (1995) Whole-genome random sequencing and assembly of Haemophilus influenzae Rd. Science, 269, 496512.[ISI][Medline]
Garcia-Bustos, J., Heitman, J., and Hall, M.N. (1991) Nuclear protein localization. Biochim. Biophys Acta, 1071, 83101.[ISI][Medline]
Ghalambor, M.A. and Heath, E.C. (1966) The biosynthesis of cell wall lipopolysaccharide in Escherichia coli. IV. Purification and properties of cytidine monophosphate 3-deoxy-d-manno-octulosonate synthetase. J. Biol. Chem., 241, 32163221.
Gilbert, M., Karwaski, M.F., Bernatchez, S., Young, N.M., Taboada, E., Michniewicz, J., Cunningham, A.M., and Wakarchuk, W.W. (2002) The genetic bases for the variation in the lipo-oligosaccharide of the mucosal pathogen, Campylobacter jejuni. Biosynthesis of sialylated ganglioside mimics in the core oligosaccharide. J. Biol. Chem., 277, 327337.
Glüer, S., Wunder, M.A., Schelp, C., Radtke, E., and Gerardy-Schahn, R. (1998) Polysialylated neural cell adhesion molecule serum levels in normal children. Pediatr. Res., 44, 915919.[Abstract]
Goldman, R.C. and Kohlbrenner, W.E. (1985) Molecular cloning of the structural gene coding for CTP:CMP-3-deoxy-manno-octulosonate cytidylyltransferase from Escherichia coli K-12. J. Bacteriol., 163, 256261.[ISI][Medline]
Görlich, D. and Kutay, U. (1999) Transport between the cell nucleus and the cytoplasm. Annu. Rev. Cell Dev. Biol., 15, 607660.[CrossRef][ISI][Medline]
Görlich, D. and Mattaj, I.W. (1996) Nucleocytoplasmic transport. Science, 271, 15131518.[Abstract]
Guerry, P., Doig, P., Alm, R.A., Burr, D.H., Kinsella, N., and Trust, T.J. (1996) Identification and characterization of genes required for post-translational modification of Campylobacter coli VC167 flagellin. Mol. Microbiol., 19, 369378.[CrossRef][ISI][Medline]
Haft, R.F. and Wessels, M.R. (1994) Characterization of CMP-N-acetylneuraminic acid synthetase of group B streptococci. J. Bacteriol., 176, 73727374.[Abstract]
Higa, H.H. and Paulson, J.C. (1985) Sialylation of glycoprotein oligosaccharides with N-acetyl-, N-glycolyl-, and N-O-diacetylneuraminic acids. J. Biol. Chem., 260, 88388849.
Hinderlich, S., Stasche, R., Zeitler, R., and Reutter, W. (1997) A bifunctional enzyme catalyzes the first two steps in N-acetylneuraminic acid biosynthesis of rat liver. Purification and characterization of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase. J. Biol. Chem., 272, 2431324318.
Hood, D.W., Makepeace, K., Deadman, M.E., Rest, R.F., Thibault, P., Martin, A., Richards, J.C., and Moxon, E.R. (1999) Sialic acid in the lipopolysaccharide of Haemophilus influenzae: strain distribution, influence on serum resistance and structural characterization 4. Mol. Microbiol., 33, 679692.[CrossRef][ISI][Medline]
Inoue, S., Lin, S.L., Chang, T., Wu, S.H., Yao, C.W., Chu, T.Y., Troy, F.A., and Inoue, Y. (1998) Identification of free deaminated sialic acid (2-keto-3-deoxy-D-glycero-D-galacto-nononic acid) in human red blood cells and its elevated expression in fetal cord red blood cells and ovarian cancer cells. J. Biol. Chem., 273, 2719927204.
Jann, B. and Jann, K. (1990) Structure and biosynthesis of the capsular antigens of Escherichia coli. Curr. Top. Microbiol. Immunol., 150, 1942.[ISI][Medline]
Jelakovic, S. and Schulz, G.E. (2001) The structure of CMP:2-keto-3-deoxy-manno-octonic acid synthetase and of its complexes with substrates and substrate analogs. J. Mol. Biol., 312, 143155.[CrossRef][ISI][Medline]
Jelakovic, S. and Schulz, G.E. (2002) Catalytic mechanism of CMP: 2-keto-3-deoxy-manno-octonic acid synthetase as derived from complexes with reaction educt and product. Biochemistry, 41, 11741181.[CrossRef][ISI][Medline]
Jelakovic, S., Jann, K., and Schulz, G.E. (1996) The three-dimensional structure of capsule-specific CMP: 2-keto-3-deoxy-manno-octonic acid synthetase from Escherichia coli. FEBS Lett., 391, 157161.[CrossRef][ISI][Medline]
Kean, E.L. (1969) Sialic acid activating enzymes in ocular tissue. Exp. Eye Res., 8, 4454.[ISI][Medline]
Kean, E.L. (1991) Sialic acid activation. Glycobiology, 1, 441447.[Abstract]
Kean, E.L. and Bighouse, K.J. (1974) Cytidine 5'-monophosphosialic acid hydrolase. Subcellular location and properties. J. Biol. Chem., 249, 78137823.
Kean, E.L. and Roseman, S. (1966) The sialic acids. X. Purification and properties of cytidine 5'-monophosphosialic acid synthetase. J. Biol. Chem., 241, 56435650.
Kean, E.L., Münster-Kühnel, A.K. and Gerardy-Schahn, R. (2004) CMP-sialic acid synthetase of the nucleus. Biochim. Biophys. Acta, forthcoming.
Kohlbrenner, W.E., Nuss, M.M., and Fesik, S.W. (1987) 31P and 13C NMR studies of oxygen transfer during catalysis by 3-deoxy-D-manno-octulosonate cytidylyltransferase from Escherichia coli. J. Biol. Chem., 262, 45344537.
Kornfeld, S., Kornfeld, R., Neufeld, E.F., and O'Brien, P.J. (1964) The seedback control of sugar nucleotide biosynthesis in liver. Proc. Natl Acad. Sci. USA, 52, 371379.[ISI][Medline]
Krapp, S., Münster-Kühnel, A.K., Kaiser, J.T., Huber, R., Tiralongo, J., Gerardy-Schahn, R., and Jacob, U. (2003) The crystal structure of murine CMP-5-N-acetylneuraminic acid synthetase. J. Mol. Biol., 334, 625637.[CrossRef][ISI][Medline]
Lawrence, S.M., Huddleston, K.A., Tomiya, N., Nguyen, N., Lee, Y.C., Vann, W.F., Coleman, T.A., and Betenbaugh, M.J. (2001) Cloning and expression of human sialic acid pathway genes to generate CMP-sialic acids in insect cells. Glycoconj. J., 18, 205213.[CrossRef][ISI][Medline]
Lüneberg, E., Zetzmann, N., Alber, D., Knirel, Y.A., Kooistra, O., Zahringer, U., and Frosch, M. (2000) Cloning and functional characterization of a 30 kb gene locus required for lipopolysaccharide biosynthesis in Legionella pneumophila. Int. J. Med. Microbiol., 290, 3749.[ISI][Medline]
Malykh, Y.N., Schauer, R., and Shaw, L. (2001a) N-glycolylneuraminic acid in human tumours*(*). Biochimie, 83, 623634.[CrossRef][ISI][Medline]
Malykh, Y.N., Krisch, B., Shaw, L., Warner, T.G., Sinicropi, D., Smith, R., Chang, J., and Schauer, R. (2001b) Distribution and localization of CMP-N-acetylneuraminic acid hydroxylase and N-glycolylneuraminic acid-containing glycoconjugates in porcine lymph node and peripheral blood lymphocytes. Eur. J. Cell Biol., 80, 4858.[ISI][Medline]
Moran, A.P., Prendergast, M.M., and Appelmelk, B.J. (1996) Molecular mimicry of host structures by bacterial lipopolysaccharides and its contribution to disease. FEMS Immunol. Med. Microbiol., 16, 105115.[CrossRef][ISI][Medline]
Mosimann, S.C., Gilbert, M., Dombroswki, D., To, R., Wakarchuk, W., and Strynadka, N.C. (2001) Structure of a sialic acid-activating synthetase, CMP-acylneuraminate synthetase in the presence and absence of CDP. J. Biol. Chem., 276, 81908196.
Mühlenhoff, M., Eckhardt, M., and Gerardy-Schahn, R. (1998) Polysialic acid: three-dimensional structure, biosynthesis and function. Curr. Opin. Struct. Biol., 8, 558564.[CrossRef][ISI][Medline]
Munday, J., Floyd, H., and Crocker, P.R. (1999) Sialic acid binding receptors (siglecs) expressed by macrophages. J. Leukoc. Biol., 66, 705711.[Abstract]
Münster, A.K., Eckhardt, M., Potvin, B., Mühlenhoff, M., Stanley, P., and Gerardy-Schahn, R. (1998) Mammalian cytidine 5'-monophosphate N-acetylneuraminic acid synthetase: a nuclear protein with evolutionarily conserved structural motifs. Proc. Natl Acad. Sci. USA, 95, 91409145.
Münster, A.K., Weinhold, B., Gotza, B., Mühlenhoff, M., Frosch, M., and Gerardy-Schahn, R. (2002) Nuclear localization signal of murine CMP-Neu5Ac synthetase includes residues required for both nuclear targeting and enzymatic activity. J. Biol. Chem., 277, 1968819696.
Nadano, D., Iwasaki, M., Endo, S., Kitajima, K., Inoue, S., and Inoue, Y. (1986) A naturally occurring deaminated neuraminic acid, 3-deoxy-D-glycero-D-galacto-nonulosonic acid (KDN). Its unique occurrence at the nonreducing ends of oligosialyl chains in polysialoglycoprotein of rainbow trout eggs. J. Biol. Chem., 261, 1155011557.
Nakata, D., Münster, A.K., Gerardy-Schahn, R., Aoki, N., Matsuda, T., and Kitajima, K. (2001) Molecular cloning of a unique CMP-sialic acid synthetase that effectively utilizes both deaminoneuraminic acid (KDN) and N-acetylneuraminic acid (Neu5Ac) as substrates. Glycobiology, 11, 685692.
Potvin, B., Raju, T.S., and Stanley, P. (1995) Lec32 is a new mutation in Chinese hamster ovary cells that essentially abrogates CMP-N-acetylneuraminic acid synthetase activity. J. Biol. Chem., 270, 3041530421.
Richard, M., Martin, A., and Louisot, P. (1975) Evidence for glycosyl-transferases in rat liver nuclei. Biochem. Biophys Res. Commun., 64, 109114.[Medline]
Roseman, S. (1968) Studies on the biosynthesis of sialic acid, sialoglycoproteins, and gangliosides. Univ Mich. Med. Cent. J., 252254.
Royo, J., Gomez, E., and Hueros, G. (2000) A maize homologue of the bacterial CMP-3-deoxy-D-manno-2-octulosonate (KDO) synthetases. Similar pathways operate in plants and bacteria for the activation of KDO prior to its incorporation into outer cellular envelopes. J. Biol. Chem., 275, 2499324999.
Saitou, N. and Nei, M. (1987) The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol. Biol. Evol., 4, 40625.[Abstract]
Scanlin, T.F. and Glick, M.C. (2000) Terminal glycosylation and disease: influence on cancer and cystic fibrosis. Glycoconj. J., 17, 617626.[CrossRef][ISI][Medline]
Schauer, R. (2000) Achievements and challenges of sialic acid research. Glycoconj. J., 17, 485499.[CrossRef][ISI][Medline]
Schauer, R. and Kamerling, J.P. (1997) Chemistry, biochemistry and biology of sialic acids. In Montreuil, J., Vliegenthart, F.G., and Schachter, H. (Eds.), Glycoproteins II. Elsevier, Amsterdam, Netherlands, pp. 243402.
Schwarzkopf, M., Knobeloch, K.P., Rohde, E., Hinderlich, S., Wiechens, N., Lucka, L., Horak, I., Reutter, W., and Horstkorte, R. (2002) Sialylation is essential for early development in mice. Proc. Natl Acad. Sci. USA, 99, 52675270.
Shaw, L. and Schauer, R. (1988) The biosynthesis of N-glycoloylneuraminic acid occurs by hydroxylation of the CMP-glycoside of N-acetylneuraminic acid. Biol. Chem. Hoppe Seyler, 369, 477486.[ISI][Medline]
Stäsche, R., Hinderlich, S., Weise, C., Effertz, K., Lucka, L., Moormann, P., and Reutter, W. (1997) A bifunctional enzyme catalyzes the first two steps in N-acetylneuraminic acid biosynthesis of rat liver. Molecular cloning and functional expression of UDP-N-acetyl-glucosamine 2-epimerase/N-acetylmannosamine kinase. J. Biol. Chem., 272, 2431924324.
Terada, T., Kitazume, S., Kitajima, K., Inoue, S., Ito, F., Troy, F.A., and Inoue, Y. (1993) Synthesis of CMP-deaminoneuraminic acid (CMP-KDN) using the CTP:CMP-3-deoxynonulosonate cytidylyltransferase from rainbow trout testis. Identification and characterization of a CMP-KDN synthetase. J. Biol. Chem., 268, 26402648.
Tettelin, H., Saunders, N.J., Heidelberg, J., Jeffries, A.C., Nelson, K.E., Eisen, J.A., Ketchum, K.A., Hood, D.W., Peden, J.F., Dodson, R.J., and others. (2000) Complete genome sequence of Neisseria meningitidis serogroup B strain MC58. Science, 287, 18091815.
Thompson, J.D., Gibson, T.J., Plewniak, F., Jeanmougin, F., and Higgins, D.G. (1997) The ClustalX windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res., 24, 48764882.[CrossRef]
Tullius, M.V., Munson, R.S.J., Wang, J., and Gibson, B.W. (1996) Purification, cloning, and expression of a cytidine 5'-monophosphate N-acetylneuraminic acid synthetase from Haemophilus ducreyi. J. Biol. Chem., 271, 1537315380.
van Dijk, W., Maier, H., and Van den Eijnden, D.H. (1976) Properties and subcellular localization of CMP-N-acetylneuraminic acid hydrolase of calf kidney. Biochim. Biophys. Acta, 444, 816834.[ISI][Medline]
Varki, A. (1992) Diversity in the sialic acids. Glycobiology, 2, 2540.[ISI][Medline]
Vimr, E.R. and Troy, F.A. (1985) Regulation of sialic acid metabolism in Escherichia coli: role of N-acylneuraminate pyruvate-lyase. J. Bacteriol., 164, 854860.[ISI][Medline]
Vimr, E.R., Aaronson, W., and Silver, R.P. (1989) Genetic analysis of chromosomal mutations in the polysialic acid gene cluster of Escherichia coli K1. J. Bacteriol., 171, 11061117.[ISI][Medline]
Vionnet, J., Concepcion, N., Warner, T., Zapata, G., Hanover, J., and Vann, W.F. (1999) Purification of CMP-N-acetylneuraminic acid synthetase from bovine anterior pituitary glands. Glycobiology, 9, 481487.
Wente, S.R. (2000) Gatekeepers of the nucleus. Science, 288, 13741377.
Wylie, J.L., Iliffe, E.R., Wang, L.L., and McClarty, G. (1997) Identification, characterization, and developmental regulation of Chlamydia trachomatis 3-deoxy-D-manno-octulosonate (KDO)-8-phosphate synthetase and CMP-KDO synthetase. Infect. Immun., 65, 15271530.[Abstract]
Yoneda, Y. (2000) Nucleocytoplasmic protein traffic and its significance to cell function. Genes Cells, 5, 777787.
Zapata, G., Vann, W.F., Aaronson, W., Lewis, M.S., and Moos, M. (1989) Sequence of the cloned Escherichia coli K1 CMP-N-acetylneuraminic acid synthetase gene. J. Biol. Chem., 264, 1476914774.
Ziak, M., Qu, B., Zuo, X., Zuber, C., Kanamori, A., Kitajima, K., Inoue, S., Inoue, Y., and Roth, J. (1996) Occurrence of poly(alpha2,8-deaminoneuraminic acid) in mammalian tissues: widespread and developmentally regulated but highly selective expression on glycoproteins. Proc. Natl Acad. Sci. USA, 93, 27592763.
|