Abstract
Every eukaryotic cell is covered with a thick layer of complex carbohydrates with essential roles in their social life. In Deuterostoma, sialic acids present at the outermost positions of glycans of glycoconjugates are known to be key players in cellular interactions including host-pathogen interactions. Their negative charge and hydrophilic properties enable their roles in various normal and pathological states and their expression is altered in many diseases including cancers. Sialylation of glycoproteins and glycolipids is orchestrated by the regulated expression of twenty sialyltransferases in human tissues with distinct enzymatic characteristics and preferences for substrates and linkages formed. However, still very little is known on the functional organization of sialyltransferases in the Golgi apparatus and how the sialylation machinery is finely regulated to provide the ad hoc sialome to the cell. This review summarizes current knowledge on sialyltransferases, their structure–function relationships, molecular evolution, and their implications in human biology.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
My scientific career in the sialobiology field began in 1986 as a PhD student under the supervision of Professor André Verbert at Lille University, France. The aim of my studies was to understand how charged molecules like the sugar-nucleotides could reach the site of glycosylation within the Golgi apparatus. At that time, I studied transport of sialic acids from the cytosol to the Golgi apparatus, where the sialyltransferases were known to be located using permeabilized cells [1] and microsomes preparations. Using radiolabeled CMP-Neu5Ac in these in situ models, I could show the existence in the Golgi membranes of an antiporter allowing CMP/CMP-Neu5Ac exchange. In 1989, I had the great opportunity as an Erasmus student to spend six weeks in Professor Roland Schauer’s laboratory in Kiel. R. Schauer was professor of Biochemistry and director of the Institute of Biochemistry at the Christian-Albrechts-Universität Kiel. He was studying the biosynthetic pathways leading to other natural sialic acids like Neu5Gc or O-acetylated derivatives. He and his co-workers had elucidated some aspects of CMP-Neu5Gc biosynthesis showing that the major mechanism was hydroxylation of CMP-Neu5Ac thanks to a cytosolic hydroxylase. In his lab, I conducted competition studies to show that CMP-Neu5Ac and CMP-Neu5Gc shared the same carrier molecule involving CMP in mouse Golgi vesicles [2]. In addition, we showed that the factor determining the higher amount of Neu5Gc in mouse liver glycoproteins (95%) compared to rat liver glycoproteins (5%) was not the antiporter nor the sialyltransferases, but the mouse hydroxylase activity present in the cytosol [3]. This first meeting with Pr R. Schauer and his wife Elfriede was decisive for the rest of my scientific carrier as it definitely oriented it in the field the sialic acid biology and more specifically on sialyltransferases and how this terminal sialylation step is regulated in vertebrates. Pr R. Schauer has been for me a major guide in the sialobiology field following my work with always a lot of enthusiasm and kindness, and most of this work would not have been possible without the fruitful supporting and stimulating interactions I have had with him over the years.
In this review dedicated to the late Pr. R. Schauer, I summarized the various research developments in vertebrate sialic acid biology and focused on the recent insights gained on the structure-function studies of sialyltransferases.
Structural diversity and distribution of Sialic acids in Metazoa
Sialic acid structures
Sialic acids (Sia) represent a highly diverse set of nine-carbon monosaccharides (Nonulosonic acids: NulOs), derivatives of neuraminic acid (Neu, 5-amino, 3,5-dideoxy-D-glycero-D-galacto-nonulosonicacid) all containing three functional groups: a carboxyl group at the C2 anomeric carbon, a glycerol-like three carbon side chain at the C6 carbon and an amino-acyl group or hydroxyl group attached to the C5 carbon (Fig. 1A) [4, 5]. Neu is almost not present in nature, but the derivatives of N-acetylneuraminic acid (Neu5Ac), N-glycolylneuraminic acid (Neu5Gc), and ketodeoxynonulosonic acid (Kdn, 3-deoxy-non-2-ulosonic acid) are the main Sia encountered. These Sia molecules can be substituted with glycolyl (Gc), acetyl (Ac), methyl (Me), lactyl, phosphate and sulfate groups generating a family over 50 structurally different members (Fig. 1B) [4, 6,7,8].
An additional level of structural diversity of these molecules results from the different glycosidic linkages formed between Sia (e.g. α-2,4, α-2,8, α-2,9 and α-2,5-O-glycolyl and the different degrees of polymerization (DP). DiSia (DP = 2), oligoSia (3 < DP < 7) or polySia (DP ≥ 8) that can reach 400 units [9, 10] have been described in vertebrates.
Distribution of sialylated molecules in Metazoa
Sia have been described mainly in Deuterostoma, i.e. vertebrates, echinoderms, hemichordates and cephalochordates [4, 11, 12]. Although it has long been controversial, Sia are also reported in ecdysozoa protostomians like arthropods as Drosophila melanogaster (Dme) [13, 14] or Galleria mellonella [15], and in lophotrochozoa protostomians mollusks like the cephalopods Octopus vulgaris [16, 17], the gastropod Arion lusitanicus [18], or in pathogenic fungi such as Candida albicans [4, 19]. However, Sia are not found in plants, in archeabacteria nor in the ecdysozoa protostomia Caenorhabditis elegans [4] and thus show discontinuous distribution across evolutionary lineages [20]. Neu5Ac is also found in Prokaryota associated to glycolipids known as lipopolysaccharides (LPS) and of capsular polysaccharides of Gram-negative bacteria like the pathogen Escherichia coli K1, and a number of other NulOs are described in proteobacteria among which the 5, 7-diamino-3, 5, 7,9-tetradeoxy-D-glycero-D-galacto-nonulosonic acid (Legionaminic acid (Leg)) and the 5, 7-diamino-3, 5, 7, 9-tetradeoxy-L-glycero-L-manno-nonulosonic (Pseudaminic acid (Pse)) [4, 21].
The major Sia encountered in Deuterostoma is Neu5Ac. Neu5Gc shows a very unusual distribution across tissues and animal species; although it is also found in most deuterostomes like echinoderms (sea urchin and star fish), it was lost independently in various vertebrate branches and lineages. It is found in most placental mammals like horses, pigs and cows [22] with notable exceptions like humans, ferrets and monotremes like platypus [23]. It is not found in birds and reptiles [23,24,25] although low levels of Neu5Gc were described in the eggs and adult tissues of the green basilisk lizard [23]. Apart from the polyNeu5Gc found in the polysialylglycoprotein (PSGP) from salmonid eggs [26], only low levels of Neu5Gc were found in most tissues of fish and frogs although Neu5Gc was not found in Rana esculata [27]. Of particular note, Neu5Gc is usually not detected in vertebrate brain and the biological relevance of this observation is still not well understood [28,29,30]. Kdn harboring a hydroxyl group at C5 is less abundant in mammals and most abundant in cold-blooded vertebrates like amphibians and fish [31, 32]. It is observed in salmonid and amphibian eggs [33,34,35]. Free and conjugated forms of Kdn have been reported in human cancers [36, 37] as a result of high Man-6P and Fru-6P levels [38]. Kdn-glycoconjugates have been reported in microalgae such as Emiliania huxleyi [39] and Prymnesium parvum [40].
Sias are found at the outermost ends of glycoproteins and glycolipids constituting the sialome of an organism. As illustrated in Fig. 2, Sia are glycosidically linked to either the 3- or 6-hydroxyl groups of β-D-galactopyranosyl (Gal) residues, or to the 6-hydroxyl group of β-D-N-acetylglucosaminyl (GlcNAc) or of β-D-N-acetylgalactosaminyl (GalNAc) residues and can even form di-, oligo-, or poly-Sia chains via their 8-hydroxyl group and terminate with a Sia linked via the 8-or 9-hydroxyl group. Sialylated molecules can be secreted or attached to cell membranes leading to a huge diversity of sialoglycoconjugates at the cell surface known as sialome [41]. The sialome is highly diverse and variable according to the organism studied and even closely related animals such as a mouse and a rat, which diverge 25 million years ago (MYA), show a different sialome. The simplest sialome profiles are found in human and the evolutionary changes observed in primates Sia biology are thought to have major implications for human biology and diseases [38, 42,43,44].
Sia implication in human physiology and pathologies
Due to the terminal position at the non-reducing end of glycans on cell-surface lipids and proteins, and the polar and charged nature of Sia, sialylated molecules play fundamental roles in many physiological processes and in the social life of vertebrate cells. They are pivotal molecules related to molecular and cellular recognition in most biological systems and processes like polySia-NCAM during embryonic development or polySia-PSGP during fertilization, and they serve as a molecular signal to modulate innate immunes responses [45]. Known intrinsic vertebrate sialic acid–binding proteins include factor H, selectins and sialic acid-binding immunoglobulin-like lectins known as Siglecs [5, 46,47,48,49,50,51]. Sia also serve as ligands for receptors mediated interactions in host–pathogen recognition involving bacteria and viruses like Helicobacter pylori [52] or influenza virus A [53] and coronavirus [54] reviewed recently [55]. The huge variety of biological functions of Sia reflect their structure diversity [56, 57]. In addition, their dynamic changes and aberrant expression are associated with several pathologies including neurological disorders like schizophrenia, and tumor metastasis [58, 59].
It has long been known that the cell surface of cancer cells is covered with Tumor Associated Carbohydrate Antigens (TACA) including sialylated molecules and hypersialylation of tumor cell surface glycoconjugates is a well-established hallmark of cancer with fundamental implication in tumor growth, metastasis, immune evasion and drug resistance [60, 61]. Among these sialylated TACA, the Thomsen Freidenreich antigens sialyl-Tn (CA72-4: sTn, Neu5Acα2,6GalNAc), sialyl-T (sT, Neu5Acα2,3Galβ1,3GalNAc) are truncated O-glycans frequently observed on proteins in breast cancer cell lines, and bladder cancer. Other sialylated structures that show increased levels in cancer include the serological cancer-biomarker sialyl-Lewis a (CA19.9; sLea: Neu5Ac α2,3Galβ1,3[Fuc α1,4]GlcNAc) and the selectin ligand sialyl-Lewis x (sLex: Neu5Ac α2,3Gal β1,4[Fuc α1,3]GlcNAc) which correlate with poor patient survival [62,63,64,65], the α2,3- or α2,6-linked sialic acid to N-acetyllactosamine (SLN) on N-glycosylproteins like cell receptors [66]. Solid tumor cells express hypersialylated neural cell adhesion molecule (NCAM), neuropilin-2 (NRP-2), or synaptic cell adhesion molecule 1 (SynCAM 1) to protect themselves from the immune effector cells [67]. Gangliosides like GM3, GM2, GD3 and GD2 are found in normal human tissues and are overexpressed in different cancer like lung cancer, melanoma, neuroblastoma, and breast cancer, in which they mediate cell proliferation, tumor growth and cancer cell migration [68]. In addition, cancer patients have been reported to express ‘Hanganutziu–Deicher’ antibodies that recognize gangliosides carrying the non-human Sia Neu5Gc, also detected in human tumors [69,70,71,72]. These sialylated TACA represent useful prognostic and diagnosis tools.
These sialylated TACA possess immunomodulatory properties and dendritic cells (DCs) are capable of sense them and stimulate naive T cells, thereby initiating the adaptive immune response [67, 73]. Siglecs are a family of 15 human cell surface receptors [74] that are primarily expressed by cells of the immune system, with the exception of most T cells. Siglecs recognize sialylated TACA expressed by tumor cells and mediate immunoregulatory signals both on myeloid and lymphoid immune cells [75, 76], suppressing T cell responses [77] and NK cytotoxicity [78], inducing the expression of transforming growth factor (TGF) by macrophages [79] modulating the immune response to cancer.
To explain these observations and gain a better understanding of these dynamic changes of the sialome, several questions remain to be answered like: how this diversity of the sialome is regulated? What is the sialylation machinery involved in the biosynthetic pathway of sialic acid molecules?
Human sialyltransferases: from genes to sialylated products
Human sialyltransferases represent a large set of inverting glycosyltransferases grouped in the glycosyltransferase GT-29 family of the CAZy database (CAZy, available at http://www.cazy.org/), which classifies all enzymes active on carbohydrates [80]. They are Leloir-type metal-independent enzymes catalyzing the transfer of Sia from the nucleotide-activated sugar donor cytidine 5’- monophosphate-β-Neu5Ac (CMP-β-Neu5Ac) to the non-reducing end of a growing carbohydrate chain linked to a protein or a lipid generating α-linkages. These enzymes exhibit a high fidelity of reaction and a high acceptor specificity with no side activity like ST3Gal V generating GM3 ganglioside only (Table 1).
On the other hand, they have a relatively more relaxed donor substrate specificity [81, 82], although their donor substrate specificities have been less explored. CMP-Neu5Gc, CMP-Neu5,9Ac2 [83], and CMP-Kdn [84] have shown to be acceptable donor substrates by some mammalian sialyltransferases like fish polysialyltransferase [85].
Human sialyltransferases genes
Twenty sialyltransferase genes have been identified in the human genome [82, 86,87,88]. Studies of the genomic organization and chromosomal assignment of the human genes have shown that the human sialyltransferase genes are polyexonic and widely dispersed in the genome on several chromosomes. Comparison of exon/intron boundaries and exons sizes of sialyltransferase genes have shown that they have a similar genomic structure delineating groups of genes likely originating from a common ancestor [82, 87]. Two ST6GAL genes named ST6GAL1 and ST6GAL2 according to the HUGO Gene Nomenclature Committee (HGNC), six ST6GALNAC genes (ST6GALNAC1-6), six ST8SIA genes (ST8SIA1-6) and six ST3GAL genes (ST3GAL1-6) were described in the human genome (https://www.genenames.org) [86, 88]. At least three pseudogenes were identified in ENSEMBL, ST3GAL1P1 on chromosome 4, ST6GALNAC2P1 on chromosome 2 and ST6GALNAC4P1 on chromosome 13 that could be retro-transposed or remnants of an ancestral gene.
Structure-function studies and biochemical characterization of human sialyltransferases
In the nineties, thanks to the molecular biology developments, most of the human sialyltransferases cDNA were cloned allowing the production of recombinant proteins and their functional characterization [82, 87, 89]. Biochemical characterization of a number of human sialyltransferases was achieved using soluble truncated protein restricted to their catalytic domains in vitro assays, radiolabeled CMP-[14C]Neu5Ac as a substrate donor and synthetic acceptors substrates either purified glycoproteins or glycolipids, shedding light on their substrate specificity. They were classified into four families depending on the type of linkage formed in α-2,3, α-2,6 or α-2,8 and on the nature of the monosaccharide acceptor namely ST6GAL, ST6GALNAC, ST3GAL and ST8SIA and each member was named accordingly [81, 90].
The six protein members of the ST3GAL family (ST3Gal I to ST3Gal VI) catalyze the formation of a α2,3-linkage between Neu5Ac and terminal galactose (Gal) residues found on glycoproteins (Galβ1,3GalNAc on O-glycosylproteins (O-GP) and Galβ1,3/4GlcNAc on N-glycosylproteins (N-GP)) and glycolipids as illustrated in Table 1. ST6Gal I and ST6Gal II in the ST6GAL family catalyze the transfer of Neu5Ac residues to the hydroxyl group in C6 of a terminal Gal residue of the type 2 disaccharide Galβ1-4GlcNAc, and potentially to the N-acetylgalactosamine (GalNAc) residue of LacdiNAc disaccharide (GalNAcβ1-4GlcNAc) [91]. The recombinant human ST6Gal I shows a broad substrate specificity towards these Gal(NAc)β1-4GlcNAc bearing substrates, whereas ST6Gal II exhibits in vitro a more restricted substrate specificity towards a few Galβ1-4GlcNAc and GalNAcβ1-4GlcNAc bearing glycoconjugates [91]. The ST6GALNAC family comprises six different members (ST6GalNAc I to ST6GalNAc VI) that catalyze similar reactions using a GalNAc residue found on mucin-type O-GP as an acceptor monosaccharide (ST6GalNAc I, ST6GalNAc II and ST6GalNAc IV) or on glycolipids (ST6GalNAc III, ST6GalNAc V and ST6GalNAc VI) to form gangliosides of the α-series. Interestingly, ST6GalNAc I and ST6GalNAc II show a narrow acceptor specificity requiring a GalNAc residue O-linked to a peptide acceptor substrate [92,93,94] whereas ST6GalNAc V and ST6GalNAc VI show a broader specificity also catalyzing the transfer of sialic acid on a GlcNAc residue leading to the formation of disialyl lactotetraosyl-ceramide (Lc4), a precursor of disialyl-Lewis a (disialyl-Lea) [95]. The six enzymes of the ST8SIA (ST8Sia I to ST8Sia VI) mediate the transfer of Neu5Ac to the hydroxyl group in C8 of another terminal Neu5Ac residue forming α2,8-linkages found on glycoproteins and glycolipids (Table 1). ST8Sia I, ST8Sia V and ST8Sia VI are mono-α2,8-sialyltransferases, ST8Sia III is an oligo-α2,8-sialyltransferase and ST8Sia II and ST8Sia IV are polysialyltransferases.
The human sialyltransferases adopt the same topology as other Golgi-glycosyltransferases in the trans-Golgi and trans-Golgi Network: they are type II transmembrane proteins showing a short cytoplasmic tail (~ 10–15 aa) a unique trans membrane domain, an intermediate stem region and a large catalytic domain (~ 250 aa) oriented within the Golgi lumen [86]. The functional organization of these enzymes within the Golgi membranes and the influence of the Golgi environment are still not understood; yet seminal studies of Kellokumpu’s group indicated the impact of Golgi pH, and ions and redox homeostasis [96, 97] as well as the formation of Golgi-glycosyltransferase complexes [98, 99] in the correct final sialylation status of glycoconjugates [100]. In addition, some sialyltransferases like ST6Gal I undergo proteolytic cleavage by proteases like the β-secretase BACE 1 or signal-peptide peptidase-like 3 (SPPL3) and are found in biological fluids [101, 102]. These enzymes undergo a series of post-translational modifications along their biosynthesis such as O- and N-glycosylation, disulfide-bond formation, which modulate their proper folding, dimer assembly and are essential to their enzymatic activity [103]. Therefore, these membrane-bound Golgi enzymes are very difficult to produce in high yield in a recombinant and active form and many challenges thus remain in understanding their function at the molecular level. The recent developments using eukaryotic HEK293 cells [104, 105] and progress in the biotechnology of glycosyltransferases afforded by structure-based rational design and directed evolution approaches [106, 107] led to the generation of suitable amounts of these stereoselective human sialyltransferases amenable to structural and biochemical studies for the refinement of their kinetic properties [104, 105, 108,109,110].
Despite very low sequence identity (< 30%) between the sialyltransferases subfamilies, comparative sequence-based analysis of the mammalian sialyltransferases have led to the discovery of conserved peptide motifs, the sialylmotifs Large (L), Small (S), III and Very Small (VS) [81] found in all the sialyltransferases of the CAZy GT-29 family (Fig. 3). Further site-directed mutagenesis strategies and structural approaches showed implication of the sialylmotifs in donor and acceptor binding and revealed a conserved histidine residue in the VS sialylmotif identified as the catalytic base [111,112,113,114] (Figs. 3 and 4). Highly conserved cysteines residues are found in sialylmotifs L and S forming intramolecular disulfide bounds [115, 116] that constrain sialyltransferase in a folded conformation. Further multiple sequence alignments of vertebrate sialyltransferase sequences led to the identification of family motifs named “a” to “e” characteristic of each vertebrate sialyltransferase family (Fig. 3), although their functional relevance still remain to be established [82, 117]. Also, specificity-determining positions (SDPs) i.e. the critical amino acids determining their functional specificity were determined for the ST3GAL and ST6GAL families [118, 119]. These amino acid positions often play critical roles as they are involved in the molecular mechanisms ensuring functional diversity. Finally, analysis of evolutionary co-mutations identified pairs of contacting and coevolving amino acid residues in the ST3GAL family likely important to maintain protein function [118].
Only three human sialyltransferases ST6Gal I [120, 121], ST6GalNAc II [105], ST8Sia III [122] and two additional vertebrate sialyltransferases rat ST6Gal I [123] and porcine ST3Gal I [114] were crystallized up to now with or without (apoenzyme form) their donor/acceptor substrates (Table 2). The GT-29 sialyltransferases are thought to use a single-displacement SN2-like mechanism (Fig. 4) and to adopt a modified GT-A fold structure called GT-A variant 2 comprised of the sialylmotifs L, S, III and VS, which lie in the core of the Rossmann-fold scaffold to assemble a metal-independent CMP-Neu5Ac binding site using adjoining proximal loop regions [82, 86, 111, 124, 125]. Interestingly, sialyltransferase structures show distinct binding-site architectures and significant differences in the amino acid residues predicted to interact with the glycan acceptor substrate [124].
Variable expression of sialyltransferases in cancer
Hypersialylation of cancer cells and increased sialylated TACA described above result from dysregulation mainly at the transcriptional level involving alternative splicing and promoter utilization leading to differential sialyltransferases expression in various types of malignancies as broadly reviewed this past decade [126,127,128,129,130]. The main cancer associated sialyltransferases include ST3Gal I and ST3Gal II driving the expression of sT antigen and GD1a and GT1b gangliosides, which are overexpressed in different types of malignancies [131,132,133], ST3Gal III, ST3Gal IV and ST3Gal VI involved in the synthesis of sLea and sLex antigens and overexpressed in gastric carcinoma [134, 135], ST6Gal I contributing to the formation of Sia6LacNAc (SLN) in colon, stomach and ovarian cancers [136, 137], ST6GalNAc I and ST6GalNAc II generating sTn and sialyl-6-T antigens in breast and colon cancer and gastrointestinal tissues [93, 138,139,140], ST8Sia II forming polySia chains in small cell lung cancer and neuroblastoma [141, 142]. As mentioned before, changes in the Golgi environment associated with tumorigenesis like hypoxia, redox homeostasis or pH also impact sialyltransferases expression, assembly and localization in the Golgi apparatus [96, 97, 100, 143]. These sialyltransferases represent potential biomarkers and treatment targets.
The development of cell-permeable, non-toxic sialyltransferase specific small-molecule inhibitors is much needed and represents a field of intense investigations largely reviewed these past years [61, 76, 127, 129, 144,145,146,147,148,149,150,151]. Natural products such as soyasaponin I, ginsenosides and lithocholic acid and derivatives were shown to reduce sialylation modifying invasive behavior of tumor cells [152,153,154,155]. So far, the only one known pan-sialyltransferase inhibitor is the peracetylated sialic acid glycomimetic P3Fax-Neu5Ac [156] and encapsulated into tumor-targeting nanoparticles, 3Fax-Neu5Ac-related drugs were shown to impair adhesion, migration and delays tumor growth in vivo [157, 158]. The most potent sialyltransferase inhibitors to date are those mimicking the transition state of the sialylation process based on activated form of CMP-Neu5Ac (Fig. 4) [159, 160] including carbamate or triazole linker as an isosteric replacement for the phosphodiester to improve pharmacokinetic properties [161, 162]. In addition, the development of new methodologies like high-throughput screening (HTS) and rapid and sensitive biochemical assays [108, 163] exploiting sialyltransferase promiscuity towards artificial Sia or electrochemical biosensing platform [164] also contributed to open new avenues of drug discovery. Although some advances in sialyltransferase inhibitors have been achieved these past years, the field still suffers from many limitations: i) only a handful 3D-structure of sialyltransferases exist hindering the structure-based design of inhibitors targeting other sialyltransferases; ii) assessment of the selectivity of inhibitors is limited to the most studied and frequently targeted sialyltransferases ST3Gal I and ST6Gal I; iii) cell-based assays are limited and almost nothing is known on the cytotoxicity, cell uptake and target specificity of the newly developed small-molecule inhibitors. Therefore, advances in new approaches and methodologies for specific sialyltransferase targeting and cancer-specific delivery are still much required.
Origin and evolution of GT-29 sialyltransferases and sialic acid pathway in Eukaryota
Evolutionary studies of the GT-29 sialyltransferases indicated a patchy distribution of these enzymes in eukaryotes [165]. In this recent study, GT-29 sialyltransferase-related sequences were search in the three domains of life including the five main eukaryotic branches. Nineteen were identified in protists, 30 in Archaeplastida, 106 in Opisthokonta, one in Amoebozoa, and one in Archaea and 23 in Alpha-, Gamma- and Epsilon-Proteobacteria. Although widespread among the three domains of life, no GT-29-related sequence could be identified in the eukaryotic branches of Excavata nor in Rhizaria, whereas an expansion of these sequences was noted in the prasinophyte Bathycoccus prasinos and in the sponge Oscarella carmela suggesting that the sialylation pathway was more ancient than anticipated. Comparative sequence-based analysis of these GT-29-related sequences in their informative region (92 aa in the catalytic domain) indicated the presence of conserved amino acid residues in the four sialylmotifs important to maintain structure and function of these enzymes. Molecular phylogenetic analyses and sequence similarity networks using Cytoscape led to the conclusion that the Last Eukaryotes Common Ancestor (LECA) already possessed two types of GT-29 sequences ST6Gal/ST6GalNAc III-VI and ST8Sia/ST6GalNAc I-II/ST3Gal likely inherited from a single sialyltransferase of proteobacteria [165], an horizontal gene transfer event that could be concomitant to the massive introduction of α-Proteobacterial genes in the first Eukaryotes that resulted in mitochondrial incorporation [165]. Along evolution, protists sialyltransferases likely conserved similar function to those of bacteria, whereas multicellular organisms have evolved new functions in cell–cell interaction through functional divergence in four distinct ancestral families described in invertebrates [88]. In addition, phylogenetic studies of key actors of the sialylation pathway were carried out [165]. Among the 60 glyco-genes known to be involved in sialic acid biology, some are endogenous to the cell and linked to Sia biosynthesis like the UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE), the Neu5Ac-9-phosphate synthetase NANS (known as Neub in Bacteria and Archaea), the Neu5Ac-9-phosphate phosphatase NANP, some are involved in Sia use like sialyltransferases, the CMP-sialic acid synthase known as CSS or CMAS, the CMP-Neu5Ac hydroxylase (CMAH) and the CMP-sialic acid transporter SLC35A1 and the other are implicated in the catabolic pathway like sialidases (Neu) and transport of sialic acid like SLC17A5 (sialin) and the bacterial sialic acid transporter NanT (Fig. 5). These studies led to the conclusion that LECA possessed the ability to use either exogenous sialic acid molecules (presence of sialidases and transporters of the SLC17A family) or an endogenous sialic acid biosynthetic pathway involving a Man-kinase, NANS, NANP and CMAS in the cytosol to produce CMP-sialic acid and supply Golgi GT-29 sialyltransferases via the SLC35A1 transporter with their activated sugar-donor [165]. During eukaryotes evolution, this sialylation pathway was partially maintained or totally lost as illustrated in Fig. 6.
Seminal evolutionary studies of the GT-29 sialyltransferases identified in Metazoa showed the presence of ancestral gene families in the invertebrates and a burst of novelties in vertebrates through gene and genome duplication events and a first model of divergent evolution was proposed [82, 88, 119] (Fig. 7). This model highlighted the existence of ancestral sialyltransferase families in invertebrates and their evolutionary relationships with the vertebrate sialyltransferase sequences were established through sequence-based analysis showing that they are orthologous to the genes found in the last common ancestor of vertebrate. A single copy gene st3gal1/2 was described in the tunicates Ciona intestinalis [88, 166] and Ciona savignyi [88, 167] and this gene was found to be ancestral to the vertebrate ST3Gal I and ST3Gal II subfamilies [88, 118]. Similarly, a single copy gene st6gal1/2 (DSIAT) was described in the insects Drosophila melanogaster [13, 14, 88] that regulates the nervous system function in Drosophila [168]. This gene is ancestral to the two vertebrate subfamilies ST6Gal I and ST6Gal II [88, 119, 169]. Four groups of multiple copy st8sia-related genes were identified in the cephalochordates Branchiostoma floridae, ancestral to the vertebrate mono-α-2,8-sialyltransferases, oligo-α-2,8-sialyltransferases and poly-α-2,8-sialyltransferases subfamilies and the last group of ancestral genes named st8siaex disappeared in vertebrates [88, 170]. Finally, a single copy gene st6galnac3/4/5/6 was identified in the sea urchin Strongylocentrotus purpuratus [88].
This model also highlighted the existence of several new vertebrate subfamilies. Comparative and functional genomics approaches were used to unravel the evolutionary relationships and fate of these newly described genes. Most of these new vertebrate subfamilies have arisen from the two whole genome duplication (WGD) events that took place at the base of vertebrate emergence, around 500 million years ago (MYA) for the WGD-R2 and ~ 555 MYA for WGD-R1, and after the teleost-specific WGD (TGD or Ts3R) that took place at the base of Actinopterygii ~ 320 MYA [118, 119, 169, 171,172,173]. These duplicated genes, paralogous to the one described in mammals were maintained or lost immediately after the WGD events or later on during vertebrate evolution, like st3gal6, st3gal9 and st8sia6, which were lost in teleosts or st3gal7 and st8sia8 lost in tetrapods and st3gal8 lost in mammals (Fig. 7). In addition, almost all the duplicated genes generated after the TGD were lost in the fish genomes with the exception of st6gal2-r and st3gal3-r genes conserved in the zebrafish genome [118, 119, 169]. Interestingly, several new ST8Sia subfamilies were identified resulting from fish specific WGD events beyond the Ts3R event like st8sia2-r1 and st8sia2-r2 resulting from the salmonid-specific 4R (Ss4R) ~ 100 MYA [174] or st8sia4-r1 and st8sia4-r2 resulting from the carp-specific 4R (Cs4R) [173, 175]. The recent enzymatic characterization of the salmonid polysialyltransferases ST8Sia IV, ST8Sia II-r1 and ST8Sia II-r2 pointed to a broader specificity towards CMP-sialic acid donors of the fish enzymes compared to their human orthologues (Decloquement et al. 2023, unpublished data).
Altogether, these studies of the functional diversification of vertebrate sialyltransferases provided a conceptual framework to understand sialylation evolution and explain why closely related species differ in their sialome. The evolutionary relationship of these sialyltransferase sequences could be established shedding light not only on their evolutionary history which was shaped mostly by the WGD and gene losses events, but also on the molecular function of newly described enzymes. Understanding how these proteins evolved will help addressing challenges of the future like those relating to the design and engineering of sialyltransferase with new molecular functions.
Availabity of data and materials
Data and materials sharing not applicable – no new data generated.
References
Lepers, A., Cacan, R., Verbert, A.: Permeabilized cells as a way of gaining access to intracellular organelles: an approach to glycosylation reactions. Biochimie 72(1), 1–5 (1990). https://doi.org/10.1016/0300-9084(90)90166-E
Lepers, A., Shaw, L., Cacan, R., Schauer, R., Montreuil, J., Verbert, A.: Transport of CMP-N-glycoloylneuraminic acid into mouse liver Golgi vesicles. FEBS Lett. 250(2), 245–250 (1989). https://doi.org/10.1016/0014-5793(89)80731-8
Lepers, A., Shaw, L., Schneckenburger, P., Cacan, R., Verbert, A., Schauer, R.: A study on the regulation of N-glycoloylneuraminic acid biosynthesis and utilization in rat and mouse liver. Eur. J. Biochem. 193(3), 715–723 (1990)
Angata, T., Varki, A.: Chemical diversity in the sialic acids and related alpha-keto acids: an evolutionary perspective. Chem. Rev. 102(2), 439–469 (2002)
Schauer, R., Kamerling, J.P.: Exploration of the Sialic Acid World. Adv. Carbohydr. Chem. Biochem. 75, 1–213 (2018). https://doi.org/10.1016/bs.accb.2018.09.001
Schauer, R.: Chemistry, metabolism, and biological functions of sialic acids. Adv. Carbohydr. Chem. Biochem. 40, 131–234 (1982). https://doi.org/10.1016/s0065-2318(08)60109-2
Schauer, R.: Sialic acids as regulators of molecular and cellular interactions. Curr. Opin. Struct. Biol. 19(5), 507–514 (2009)
Traving, C., Schauer, R.: Structure, function and metabolism of sialic acids. Cell. Mol. Life Sci. 54(12), 1330–1349 (1998)
Colley, K.J., Kitajima, K., Sato, C.: Polysialic acid: biosynthesis, novel functions and applications. Crit. Rev. Biochem. Mol. Biol. 49(6), 498–532 (2014). https://doi.org/10.3109/10409238.2014.976606
Sato, C.: Polysialic Acid. In: Tiralongo, J., Martinez-Duncker, I. (eds.) Sialobiology: Structure, Biosynthesis and Function. Sialic acid glycoconjugates in health and diseases, (vol. 5. pp. 33–75). Bentham Science, Schipol, The Netherlands (2013)
Corfield, A.P., Schauer, R.: Sialic Acids - Chemistry, Metabolism and Function, vol. 10. Cell Biology Monographs. Springer-Verlag, Vienna (1982)
Klein, A., Diaz, S., Ferreira, I., Lamblin, G., Roussel, P., Manzi, A.E.: New sialic acids from biological sources identified by a comprehensive and sensitive approach: liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) of SIA quinoxalinones. Glycobiology 7(3), 421–432 (1997). https://doi.org/10.1093/glycob/7.3.421
Koles, K., Irvine, K.D., Panin, V.M.: Functional characterization of Drosophila sialyltransferase. J. Biol. Chem. 279(6), 4346–4357 (2004)
Koles, K., Repnikova, E., Pavlova, G., Korochkin, L.I., Panin, V.M.: Sialylation in protostomes: a perspective from Drosophila genetics and biochemistry. Glycoconj. J. 26(3), 313–324 (2009)
Karacali, S., Kirmizigul, S., Deveci, R., Deveci, O., Onat, T., Gurcu, B.: Presence of sialic acid in prothoracic glands of Galleria mellonella (Lepidoptera). Tissue Cell 29(3), 315–321 (1997)
Saito, M., Kitamura, H., Sugiyama, K.: Occurrence of gangliosides in the common squid and pacific octopus among protostomia. Biochim. Biophys. Acta 1511(2), 271–280 (2001)
Saito, M., Kitamura, H., Sugiyama, K.: Occurrence and tissue distribution of c-series gangliosides in the common squid Todarodes pacificus. Comp. Biochem. Physiol. B Biochem. Mol. Biol. 131(3), 433–441 (2002)
Burgmayr, S., Grabher-Meier, H., Staudacher, E.: Sialic acids in gastropods. FEBS Lett. 508(1), 95–98 (2001)
Soares, R.M., de, A.S.R.M., Alviano, D.S., Angluster, J., Alviano, C.S., Travassos, L.R.: Identification of sialic acids on the cell surface of Candida albicans. Biochim. Biophys. Acta 1474(2), 262–268 (2000)
Bishop, J.R., Gagneux, P.: Evolution of carbohydrate antigens–microbial forces shaping host glycomes? Glycobiology 17(5), 23R-34R (2007)
Lewis, A.L., Chen, X., Schnaar, R.L., Varki, A.: Sialic Acids and Other Nonulosonic Acids. In: Varki, A., Cummings, R.D., Esko, J.D., Stanley, P., Hart, G.W., Aebi, M., Mohnen, D., Kinoshita, T., Packer, N.H., Prestegard, J.H., Schnaar, R.L., Seeberger, P.H. (eds.) Essentials of Glycobiology. pp. 185–204. Cold Spring Harbor (NY) (2022)
Davies, L.R., Pearce, O.M., Tessier, M.B., Assar, S., Smutova, V., Pajunen, M., Sumida, M., Sato, C., Kitajima, K., Finne, J., Gagneux, P., Pshezhetsky, A., Woods, R., Varki, A.: Metabolism of vertebrate amino sugars with N-glycolyl groups: resistance of alpha2-8-linked N-glycolylneuraminic acid to enzymatic cleavage. J. Biol. Chem. 287(34), 28917–28931 (2012). https://doi.org/10.1074/jbc.M112.365056
Schauer, R., Srinivasan, G.V., Coddeville, B., Zanetta, J.P., Guerardel, Y.: Low incidence of N-glycolylneuraminic acid in birds and reptiles and its absence in the platypus. Carbohydr. Res. 344(12), 1494–1500 (2009)
Peri, S., Kulkarni, A., Feyertag, F., Berninsone, P.M., Alvarez-Ponce, D.: Phylogenetic Distribution of CMP-Neu5Ac Hydroxylase (CMAH), the Enzyme Synthetizing the Proinflammatory Human Xenoantigen Neu5Gc. Genome. Biol. Evol. 10(1), 207–219 (2018). https://doi.org/10.1093/gbe/evx251
Schauer, R., Kamerling, J.: Chemistry,biochemistry and biology of sialic acids. In: Montreuil, J., Vliegenthart, J., Schachter, H. (eds.) Glycoproteins II. New comprehensive biochemistry, (vol. 29b, pp. 243–402). Elsevier, Amsterdam (1997)
Inoue, S., Iwasaki, M.: Isolation of a novel glycoprotein from the eggs of rainbow trout: occurrence of disialosyl groups on all carbohydrate chains. Biochem. Biophys. Res. Commun 83(3), 1018–1023 (1978)
Schauer, R., Haverkamp, J., Ehrlich, K.: Isolation and characterization of acylneuraminate cytidylyltransferase from frog liver. Hoppe Seylers Z. Physiol. Chem. 361(5), 641–648 (1980). https://doi.org/10.1515/bchm2.1980.361.1.641
Davies, L.R., Varki, A.: Why Is N-Glycolylneuraminic Acid Rare in the Vertebrate Brain? Top. Curr. Chem. 366, 31–54 (2015). https://doi.org/10.1007/128_2013_419
Naito-Matsui, Y., Davies, L.R., Takematsu, H., Chou, H.H., Tangvoranuntakul, P., Carlin, A.F., Verhagen, A., Heyser, C.J., Yoo, S.W., Choudhury, B., Paton, J.C., Paton, A.W., Varki, N.M., Schnaar, R.L., Varki, A.: Physiological Exploration of the Long Term Evolutionary Selection against Expression of N-Glycolylneuraminic Acid in the Brain. J. Biol. Chem. 292(7), 2557–2570 (2017). https://doi.org/10.1074/jbc.M116.768531
Yang, Y., Murai, R., Takahashi, Y., Mori, A., Hane, M., Kitajima, K., Sato, C.: Comparative Studies of Polysialic Acids Derived from Five Different Vertebrate Brains. Int. J. Mol. Sci. 21(22) (2020). https://doi.org/10.3390/ijms21228593
Nadano, D., Iwasaki, M., Endo, S., Kitajima, K., Inoue, S., Inoue, Y.: 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. Bio. Chem. 261(25), 11550–11557 (1986)
Saha, S., Coady, A., Sasmal, A., Kawanishi, K., Choudhury, B., Yu, H., Sorensen, R.U., Inostroza, J., Schoenhofen, I.C., Chen, X., Munster-Kuhnel, A., Sato, C., Kitajima, K., Ram, S., Nizet, V., Varki, A.: Exploring the Impact of Ketodeoxynonulosonic Acid in Host-Pathogen Interactions Using Uptake and Surface Display by Nontypeable Haemophilus influenzae. mBio 12(1) (2021). https://doi.org/10.1128/mBio.03226-20
Kimura, M., Hama, Y., Sumi, T., Asakawa, M., Rao, B.N., Horne, A.P., Li, S.C., Li, Y.T., Nakagawa, H.: Characterization of a deaminated neuraminic acid-containing glycoprotein from the skin mucus of the loach. Misgurnus anguillicaudatus. J. Biol. Chem. 269(51), 32138–32143 (1994)
Strecker, G., Wieruszeski, J.M., Michalski, J.C., Alonso, C., Boilly, B., Montreuil, J.: Characterization of Le(x), Le(y) and A Le(y) antigen determinants in KDN-containing O-linked glycan chains from Pleurodeles waltlii jelly coat eggs. FEBS Lett. 298(1), 39–43 (1992). https://doi.org/10.1016/0014-5793(92)80018-c
Strecker, G., Wieruszeski, J.M., Michalski, J.C., Alonso, C., Leroy, Y., Boilly, B., Montreuil, J.: Primary structure of neutral and acidic oligosaccharide-alditols derived from the jelly coat of the Mexican axolotl. Occurrence of oligosaccharides with fucosyl(alpha 1-3)fucosyl(alpha 1-4)-3-deoxy-D-glycero-D-galacto-nonulosonic acid and galactosyl(alpha 1-4)[fucosyl(alpha 1-2)]galactosyl(beta 1-4)-N-acetylglucosamine sequences. Eur. J. Biochem. 207(3), 995–1002 (1992). https://doi.org/10.1111/j.1432-1033.1992.tb17135.x
Inoue, J.G., Miya, M., Tsukamoto, K., Nishida, M.: Mitogenomic evidence for the monophyly of elopomorph fishes (Teleostei) and the evolutionary origin of the leptocephalus larva. Mol. Phylogenet. Evol. 32(1), 274–286 (2004). https://doi.org/10.1016/j.ympev.2003.11.009
Wang, F., Xie, B., Wang, B., Troy, F.A., 2nd.: LC-MS/MS glycomic analyses of free and conjugated forms of the sialic acids, Neu5Ac, Neu5Gc and KDN in human throat cancers. Glycobiology 25(12), 1362–1374 (2015). https://doi.org/10.1093/glycob/cwv051
Kawanishi, K., Saha, S., Diaz, S., Vaill, M., Sasmal, A., Siddiqui, S.S., Choudhury, B., Sharma, K., Chen, X., Schoenhofen, I.C., Sato, C., Kitajima, K., Freeze, H.H., Munster-Kuhnel, A., Varki, A.: Evolutionary conservation of human ketodeoxynonulosonic acid production is independent of sialoglycan biosynthesis. J. Clin. Invest. 131(5) (2021). https://doi.org/10.1172/JCI137681
Rose, S.L., Fulton, J.M., Brown, C.M., Natale, F., Van Mooy, B.A., Bidle, K.D.: Isolation and characterization of lipid rafts in Emiliania huxleyi: a role for membrane microdomains in host-virus interactions. Environ. Microbiol. 16(4), 1150–1166 (2014). https://doi.org/10.1111/1462-2920.12357
Wagstaff, B.A., Rejzek, M., Field, R.A.: Identification of a Kdn biosynthesis pathway in the haptophyte Prymnesium parvum suggests widespread sialic acid biosynthesis among microalgae. J. Biol. Chem. 293(42), 16277–16290 (2018). https://doi.org/10.1074/jbc.RA118.004921
Varki, A., Angata, T.: Siglecs–the major subfamily of I-type lectins. Glycobiology 16(1), 1R-27R (2006)
Paul, A., Padler-Karavani, V.: Evolution of sialic acids: Implications in xenotransplant biology. Xenotransplantation 25(6), e12424 (2018). https://doi.org/10.1111/xen.12424
Varki, A.: Loss of N-glycolylneuraminic acid in humans: Mechanisms, consequences, and implications for hominid evolution. Am. J. Phys. Anthropol. Suppl. 33, 54–69 (2001)
Varki, N.M., Varki, A.: Diversity in cell surface sialic acid presentations: implications for biology and disease. Lab. Invest. 87(9), 851–857 (2007)
Abeln, M., Albers, I., Peters-Bernard, U., Flachsig-Schulz, K., Kats, E., Kispert, A., Tomlinson, S., Gerardy-Schahn, R., Munster-Kuhnel, A., Weinhold, B.: Sialic acid is a critical fetal defense against maternal complement attack. J. Clin. Invest 129(1), 422–436 (2019). https://doi.org/10.1172/JCI99945
Bordron, A., Morel, M., Bagacean, C., Dueymes, M., Pochard, P., Harduin-Lepers, A., Jamin, C., Pers, J.-O.: Hyposialylation Must Be Considered to Develop Future Therapies in Autoimmune Diseases. Int. J. Mol. Sci. 22(7) (2021). https://doi.org/10.3390/ijms22073402
Fliniaux, I., Marchand, G., Molinaro, C., Decloquement, M., Martoriati, A., Marin, M., Bodart, J.F., Harduin-Lepers, A., Cailliau, K.: Diversity of sialic acids and sialoglycoproteins in gametes and at fertilization. Front. Cell Dev. Biol. 10, 982931 (2022). https://doi.org/10.3389/fcell.2022.982931
Miyata, S., Sato, C., Kitamura, S., Toriyama, M., Kitajima, K.: A major flagellum sialoglycoprotein in sea urchin sperm contains a novel polysialic acid, an a2,9-linked poly-N-acetylneuraminic acid chain, capped by an 8-O-sulfated sialic acid residue. Glycobiology 14(9), 827–840 (2004)
Schnaar, R.L.: Glycobiology simplified: diverse roles of glycan recognition in inflammation. J. Leukoc. Biol. 99(6), 825–838 (2016). https://doi.org/10.1189/jlb.3RI0116-021R
Varki, A., Gagneux, P.: Biological Functions of Glycans. In: Varki, A., Cummings, R.D., Esko, J.D., Stanley, P., Hart, G.W., Aebi, M., Darvill, A.G., Kinoshita, T., Packer, N.H., Prestegard, J.H., Schnaar, R.L., Seeberger, P.H. (eds.) Essentials of Glycobiology. pp. 77–88. Cold Spring Harbor (NY) (2015)
Villanueva-Cabello, T.M., Gutiérrez-Valenzuela, L.D., Salinas-Marín, R., López-Guerrero, D.V., Martínez-Duncker, I.: Polysialic Acid in the Immune System. Frontiers in Immunology, 5987 (2022).
Mahdavi, J., Sonden, B., Hurtig, M., Olfat, F.O., Forsberg, L., Roche, N., Angstrom, J., Larsson, T., Teneberg, S., Karlsson, K.A., Altraja, S., Wadstrom, T., Kersulyte, D., Berg, D.E., Dubois, A., Petersson, C., Magnusson, K.E., Norberg, T., Lindh, F., Lundskog, B.B., Arnqvist, A., Hammarstrom, L., Boren, T.: Helicobacter pylori SabA adhesin in persistent infection and chronic inflammation. Science 297(5581), 573–578 (2002). https://doi.org/10.1126/science.1069076
de Graaf, M., Fouchier, R.A.: Role of receptor binding specificity in influenza A virus transmission and pathogenesis. EMBO J. 33(8), 823–841 (2014). https://doi.org/10.1002/embj.201387442
Huang, X., Dong, W., Milewska, A., Golda, A., Qi, Y., Zhu, Q.K., Marasco, W.A., Baric, R.S., Sims, A.C., Pyrc, K., Li, W., Sui, J.: Human Coronavirus HKU1 Spike Protein Uses O-Acetylated Sialic Acid as an Attachment Receptor Determinant and Employs Hemagglutinin-Esterase Protein as a Receptor-Destroying Enzyme. J. Virol. 89(14), 7202–7213 (2015). https://doi.org/10.1128/JVI.00854-15
Burzynska, P., Sobala, L.F., Mikolajczyk, K., Jodlowska, M., Jaskiewicz, E.: Sialic Acids as Receptors for Pathogens. Biomolecules 11(6) (2021). https://doi.org/10.3390/biom11060831
Kelm, S., Schauer, R.: Sialic acids in molecular and cellular interactions. Int. Rev. Cytol. 175, 137–240 (1997)
Schauer, R., Kelm, S., Reuter, G., Roggentin, P., Shaw, L.: Biochemistry and role of sialic acids. Biol. Sialic Acid 7–67 (1995)
Pietrobono, S., Stecca, B.: Aberrant Sialylation in Cancer: Biomarker and Potential Target for Therapeutic Intervention? Cancers (Basel) 13(9) (2021). https://doi.org/10.3390/cancers13092014
Sato, C., Kitajima, K.: Polysialylation and disease. Mol. Aspects Med. 79, 100892 (2021). https://doi.org/10.1016/j.mam.2020.100892
Pearce, O.M., Läubli, H.: Sialic acids in cancer biology and immunity. Glycobiology 26(2), 111–128 (2016)
Rodrigues, E., Macauley, M.S.: Hypersialylation in Cancer: Modulation of Inflammation and Therapeutic Opportunities. Cancers (Basel) 10(6) (2018). https://doi.org/10.3390/cancers10060207
Magalhães, A., Duarte, H.O., Reis, C.A.: Aberrant Glycosylation in Cancer: A Novel Molecular Mechanism Controlling Metastasis. Cancer Cell 31(6), 733–735 (2017). https://doi.org/10.1016/j.ccell.2017.05.012
Magalhaes, A., Duarte, H.O., Reis, C.A.: The role of O-glycosylation in human disease. Mol. Aspects Med. 79, 100964 (2021). https://doi.org/10.1016/j.mam.2021.100964
Pinho, S., Marcos, N.T., Ferreira, B., Carvalho, A.S., Oliveira, M.J., Santos-Silva, F., Harduin-Lepers, A., Reis, C.A.: Biological significance of cancer-associated sialyl-Tn antigen: modulation of malignant phenotype in gastric carcinoma cells. Cancer Lett. 249(2), 157–170 (2007). https://doi.org/10.1016/j.canlet.2006.08.010
Pinho, S.S., Reis, C.A.: Glycosylation in cancer: mechanisms and clinical implications. Nat. Rev. Cancer 15(9), 540–555 (2015). https://doi.org/10.1038/nrc3982
Gc, S., Bellis, S.L., Hjelmeland, A.B.: ST6Gal1: Oncogenic signaling pathways and targets. Front. Mol. Biosci, 9, 962908 (2022). https://doi.org/10.3389/fmolb.2022.962908
Jarahian, M., Marofi, F., Maashi, M.S., Ghaebi, M., Khezri, A., Berger, M.R.: Re-Expression of Poly/Oligo-Sialylated Adhesion Molecules on the Surface of Tumor Cells Disrupts Their Interaction with Immune-Effector Cells and Contributes to Pathophysiological Immune Escape. Cancers 13(20), 5203 (2021)
Cazet, A., Julien, S., Bobowski, M., Krzewinski-Recchi, M.A., Harduin-Lepers, A., Groux-Degroote, S., Delannoy, P.: Consequences of the expression of sialylated antigens in breast cancer. Carbohydr. Res. 345(10), 1377–1383 (2010)
Altman, M.O., Gagneux, P.: Absence of Neu5Gc and Presence of Anti-Neu5Gc Antibodies in Humans-An Evolutionary Perspective. Front. Immunol. 10, 789 (2019). https://doi.org/10.3389/fimmu.2019.00789
Bellis, S.L., Reis, C.A., Varki, A., Kannagi, R., Stanley, P.: Glycosylation Changes in Cancer. Essential. Glycobiol. (2022)
Malykh, Y.N., Schauer, R., Shaw, L.: N-Glycolylneuraminic acid in human tumours. Biochimie 83(7), 623–634 (2001). https://doi.org/10.1016/s0300-9084(01)01303-7
Munkley, J.: The role of sialyl-Tn in cancer. Int. J. Mol. Sci. 17(3), 275 (2016)
da Costa, V., Freire, T.: Advances in the Immunomodulatory Properties of Glycoantigens in Cancer. Cancers 14(8), 1854 (2022)
Varki, A., Gagneux, P.: Multifarious roles of sialic acids in immunity. Ann. N. Y. Acad. Sci. 1253(1), 16–36 (2012)
RodrÍguez, E., Schetters, S.T., van Kooyk, Y.: The tumour glyco-code as a novel immune checkpoint for immunotherapy. Nat. Rev. Immunol. 18(3), 204–211 (2018)
Scott, E., Elliott, D.J., Munkley, J.: Tumour associated glycans: a route to boost immunotherapy? Clin. Chim. Acta 502, 167–173 (2020)
Wang, J., Sun, J., Liu, L.N., Flies, D.B., Nie, X., Toki, M., Zhang, J., Song, C., Zarr, M., Zhou, X.: Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy. Nat. Med. 25(4), 656–666 (2019)
Zheng, Y., Ma, X., Su, D., Zhang, Y., Yu, L., Jiang, F., Zhou, X., Feng, Y., Ma, F.: The roles of Siglec7 and Siglec9 on natural killer cells in virus infection and tumour progression. J. Immunol. Res. 2020 (2020)
Takamiya, R., Ohtsubo, K., Takamatsu, S., Taniguchi, N., Angata, T.: The interaction between Siglec-15 and tumor-associated sialyl-Tn antigen enhances TGF-β secretion from monocytes/macrophages through the DAP12–Syk pathway. Glycobiology 23(2), 178–187 (2013)
Drula, E., Garron, M.L., Dogan, S., Lombard, V., Henrissat, B., Terrapon, N.: The carbohydrate-active enzyme database: functions and literature. Nucleic Acids Res. 50(D1), D571–D577 (2022). https://doi.org/10.1093/nar/gkab1045
Datta, A.K.: Comparative sequence analysis in the sialyltransferase protein family: analysis of motifs. Curr. Drug Targets 10(6), 483–498 (2009)
Harduin-Lepers, A.: Comprehensive Analysis of Sialyltransferases in Vertebrate Genomes. Glycobiol Insight 2(1870-GBI-Comprehensive-Analysis-of-Sialyltransferases-in-Vertebrate-Genomes.pdf), 29–61 (2010). https://doi.org/10.4137/GBI.S3123
Higa, H.H., Paulson, J.C.: Sialylation of glycoprotein oligosaccharides with N-acetyl-, N-glycolyl-, and N-O-diacetylneuraminic acids. J. Biol. Chem. 260(15), 8838–8849 (1985)
Angata, T., Matsuda, T., Kitajima, K.: Synthesis of neoglycoconjugates containing deaminated neuraminic acid (KDN) using rat liver alpha2,6-sialyltransferase. Glycobiology 8(3), 277–284 (1998)
Li, Y., Chen, X.: Sialic acid metabolism and sialyltransferases: natural functions and applications. Appl. Microbiol. Biotechnol. 94(4), 887–905 (2012)
Harduin-Lepers, A.: Vertebrate sialyltransferases. In: Tiralongo, J., Martinez-Duncker, I. (eds.) Sialobiology: Structure, Biosynthesis and Function. Sialic acid glycoconjugates in health and diseases, (vol. 5. pp. 139–187). Bentham Science, Schipol, The Netherlands (2013)
Harduin-Lepers, A., Krzewinski-Recchi, M.A., Hebbar, M., Samyn-Petit, B., Vallejo-Ruiz, V., Julien, S., Peyrat, J.P., Delannoy, P.: Sialyltransferases and breast cancer. Recent Res. Devel. Cancer 3, 111–126 (2001)
Harduin-Lepers, A., Mollicone, R., Delannoy, P., Oriol, R.: The animal sialyltransferases and sialyltransferase-related genes: a phylogenetic approach. Glycobiology 15(8), 805–817 (2005). https://doi.org/10.1093/glycob/cwi063
Harduin-Lepers, A., Recchi, M.A., Delannoy, P.: 1994, the year of sialyltransferases. Glycobiology 5(8), 741–758 (1995). https://doi.org/10.1093/glycob/5.8.741
Tsuji, S., Datta, A.K., Paulson, J.C.: Systematic nomenclature for sialyltransferases. Glycobiology 6(7), v–vii (1996)
Rohfritsch, P.F., Joosten, J.A., Krzewinski-Recchi, M.A., Harduin-Lepers, A., Laporte, B., Juliant, S., Cerutti, M., Delannoy, P., Vliegenthart, J.F., Kamerling, J.P.: Probing the substrate specificity of four different sialyltransferases using synthetic beta-D-Galp-(1–>4)-beta-D-GlcpNAc-(1–>2)-alpha-D-Manp-(1–>O) (CH(2))7CH3 analogues general activating effect of replacing N-acetylglucosamine by N-propionylglucosamine. Biochim. Biophys. Acta 1760(4), 685–692 (2006). https://doi.org/10.1016/j.bbagen.2005.12.012
Ikehara, Y., Kojima, N., Kurosawa, N., Kudo, T., Kono, M., Nishihara, S., Issiki, S., Morozumi, K., Itzkowitz, S., Tsuda, T., Nishimura, S.I., Tsuji, S., Narimatsu, H.: Cloning and expression of a human gene encoding an N-acetylgalactosamine-alpha2,6-sialyltransferase (ST6GalNAc I): a candidate for synthesis of cancer-associated sialyl-Tn antigens. Glycobiology 9(11), 1213–1224 (1999)
Marcos, N.T., Pinho, S., Grandela, C., Cruz, A., Samyn-Petit, B., Harduin-Lepers, A., Almeida, R., Silva, F., Morais, V., Costa, J., Kihlberg, J., Clausen, H., Reis, C.A.: Role of the human ST6GalNAc-I and ST6GalNAc-II in the synthesis of the cancer-associated sialyl-Tn antigen. Cancer Res. 64(19), 7050–7057 (2004). https://doi.org/10.1158/0008-5472.CAN-04-1921
Samyn-Petit, B., Krzewinski-Recchi, M.A., Steelant, W.F., Delannoy, P., Harduin-Lepers, A.: Molecular cloning and functional expression of human ST6GalNAc II. Molecular expression in various human cultured cells. Biochim. Biophys. Acta 1474(2), 201–211 (2000). https://doi.org/10.1016/s0304-4165(00)00020-9
Tsuchida, A., Okajima, T., Furukawa, K., Ando, T., Ishida, H., Yoshida, A., Nakamura, Y., Kannagi, R., Kiso, M., Furukawa, K.: Synthesis of disialyl Lewis a (Le(a)) structure in colon cancer cell lines by a sialyltransferase, ST6GalNAc VI, responsible for the synthesis of alpha-series gangliosides. J. Biol. Chem. 278(25), 22787–22794 (2003)
Rivinoja, A., Hassinen, A., Kokkonen, N., Kauppila, A., Kellokumpu, S.: Elevated Golgi pH impairs terminal N-glycosylation by inducing mislocalization of Golgi glycosyltransferases. J. Cell Physiol. 220(1), 144–154 (2009)
Rivinoja, A., Pujol, F.M., Hassinen, A., Kellokumpu, S.: Golgi pH, its regulation and roles in human disease. Ann. Med. 44(6), 542–554 (2012). https://doi.org/10.3109/07853890.2011.579150
Hassinen, A., Rivinoja, A., Kauppila, A., Kellokumpu, S.: Golgi N-glycosyltransferases form both homo- and heterodimeric enzyme complexes in live cells. J. Biol. Chem. 285(23), 17771–17777 (2010). https://doi.org/10.1074/jbc.M110.103184
Khoder-Agha, F., Harrus, D., Brysbaert, G., Lensink, M.F., Harduin-Lepers, A., Glumoff, T., Kellokumpu, S.: Assembly of B4GALT1/ST6GAL1 heteromers in the Golgi membranes involves lateral interactions via highly charged surface domains. J. Biol. Chem. 294(39), 14383–14393 (2019). https://doi.org/10.1074/jbc.RA119.009539
Kellokumpu, S.: Golgi pH, Ion and Redox Homeostasis: How Much Do They Really Matter? Front. Cell. Dev. Biol. 7, 93 (2019). https://doi.org/10.3389/fcell.2019.00093
Kitazume, S., Kotani, N., Nakato, H., Saido, T., Hashimoto, Y.: Glycosyltransferases as substrates for Alzheimer’s beta-secretase. Tanpakushitsu. Kakusan. Koso. 49(15 Suppl), 2468–2472 (2004)
Voss, M., Künzel, U., Higel, F., Kuhn, P.H., Colombo, A., Fukumori, A., Haug-Kröper, M., Klier, B., Grammer, G., Seidl, A.: Shedding of glycan-modifying enzymes by signal peptide peptidase-like 3 (SPPL 3) regulates cellular N-glycosylation. EMBO J. 33(24), 2890–2905 (2014)
Mikolajczyk, K., Kaczmarek, R., Czerwinski, M.: How glycosylation affects glycosylation: the role of N-glycans in glycosyltransferase activity. Glycobiology 30(12), 941–969 (2020)
Jaroentomeechai, T., Kwon, Y.H., Liu, Y., Young, O., Bhawal, R., Wilson, J.D., Li, M., Chapla, D.G., Moremen, K.W., Jewett, M.C., Mizrachi, D., DeLisa, M.P.: A universal glycoenzyme biosynthesis pipeline that enables efficient cell-free remodeling of glycans. Nat. Commun. 13(1), 6325 (2022). https://doi.org/10.1038/s41467-022-34029-7
Moremen, K.W., Ramiah, A., Stuart, M., Steel, J., Meng, L., Forouhar, F., Moniz, H.A., Gahlay, G., Gao, Z., Chapla, D., Wang, S., Yang, J.Y., Prabhakar, P.K., Johnson, R., Rosa, M.D., Geisler, C., Nairn, A.V., Seetharaman, J., Wu, S.C., Tong, L., Gilbert, H.J., LaBaer, J., Jarvis, D.L.: Expression system for structural and functional studies of human glycosylation enzymes. Nat. Chem. Biol. 14(2), 156–162 (2018). https://doi.org/10.1038/nchembio.2539
Benkoulouche, M., Faure, R., Remaud-Simeon, M., Moulis, C., Andre, I.: Harnessing glycoenzyme engineering for synthesis of bioactive oligosaccharides. Interface Focus 9(2), 20180069 (2019). https://doi.org/10.1098/rsfs.2018.0069
Cui, T., Man, Y., Wang, F., Bi, S., Lin, L., Xie, R.: Glycoenzyme Tool Development: Principles, Screening Methods, and Recent Advances. Chin. J. Chem. 40(6), 746–758 (2022)
Noel, M., Gilormini, P.A., Cogez, V., Lion, C., Biot, C., Harduin-Lepers, A., Guerardel, Y.: MicroPlate Sialyltransferase Assay: A Rapid and Sensitive Assay Based on an Unnatural Sialic Acid Donor and Bioorthogonal Chemistry. Bioconjug. Chem. 29(10), 3377–3384 (2018). https://doi.org/10.1021/acs.bioconjchem.8b00529
Noel, M., Gilormini, P.A., Cogez, V., Yamakawa, N., Vicogne, D., Lion, C., Biot, C., Guerardel, Y., Harduin-Lepers, A.: Probing the CMP-Sialic Acid Donor Specificity of Two Human beta-d-Galactoside Sialyltransferases (ST3Gal I and ST6Gal I) Selectively Acting on O- and N-Glycosylproteins. ChemBioChem 18(13), 1251–1259 (2017). https://doi.org/10.1002/cbic.201700024
Vallejo-Ruiz, V., Haque, R., Mir, A.M., Schwientek, T., Mandel, U., Cacan, R., Delannoy, P., Harduin-Lepers, A.: Delineation of the minimal catalytic domain of human Galbeta1-3GalNAc alpha2,3-sialyltransferase (hST3Gal I). Biochim. Biophys. Acta 1549(2), 161–173 (2001). https://doi.org/10.1016/s0167-4838(01)00257-6
Audry, M., Jeanneau, C., Imberty, A., Harduin-Lepers, A., Delannoy, P., Breton, C.: Current trends in the structure-activity relationships of sialyltransferases. Glycobiology 21(6), 716–726 (2011). https://doi.org/10.1093/glycob/cwq189
Datta, A.K., Paulson, J.C.: The sialyltransferase “sialylmotif” participates in binding the donor substrate CMP-NeuAc. J. Biol. Chem. 270(4), 1497–1500 (1995)
Datta, A.K., Sinha, A., Paulson, J.C.: Mutation of the sialyltransferase S-sialylmotif alters the kinetics of the donor and acceptor substrates. J. Biol. Chem. 273(16), 9608–9614 (1998)
Rao, F.V., Rich, J.R., Rakic, B., Buddai, S., Schwartz, M.F., Johnson, K., Bowe, C., Wakarchuk, W.W., Defrees, S., Withers, S.G., Strynadka, N.C.: Structural insight into mammalian sialyltransferases. Nat. Struct. Mol. Biol. (2009)
Datta, A.K., Chammas, R., Paulson, J.C.: Conserved cysteines in the sialyltransferase sialylmotifs form an essential disulfide bond. J. Biol. Chem. 276(18), 15200–15207 (2001)
Qian, R., Chen, C., Colley, K.J.: Location and mechanism of alpha 2,6-sialyltransferase dimer formation. Role of cysteine residues in enzyme dimerization, localization, activity, and processing. J. Biol. Chem. 276(31), 28641–28649 (2001)
Patel, R.Y., Balaji, P.V.: Identification of linkage-specific sequence motifs in sialyltransferases. Glycobiology 16(2), 108–116 (2006)
Petit, D., Teppa, E., Mir, A.M., Vicogne, D., Thisse, C., Thisse, B., Filloux, C., Harduin-Lepers, A.: Integrative view of alpha2,3-sialyltransferases (ST3Gal) molecular and functional evolution in deuterostomes: significance of lineage-specific losses. Mol. Biol. Evol. 32(4), 906–927 (2015). https://doi.org/10.1093/molbev/msu395
Teppa, R.E., Petit, D., Plechakova, O., Cogez, V., Harduin-Lepers, A.: Phylogenetic-Derived Insights into the Evolution of Sialylation in Eukaryotes: Comprehensive Analysis of Vertebrate beta-Galactoside alpha2,3/6-Sialyltransferases (ST3Gal and ST6Gal). Int. J. Mol. Sci. 17(8) (2016). https://doi.org/10.3390/ijms17081286
Harrus, D., Harduin-Lepers, A., Glumoff, T.: Unliganded and CMP-Neu5Ac bound structures of human alpha-2,6-sialyltransferase ST6Gal I at high resolution. J. Struct. Biol. 212(2), 107628 (2020). https://doi.org/10.1016/j.jsb.2020.107628
Kuhn, B., Benz, J., Greif, M., Engel, A.M., Sobek, H., Rudolph, M.G.: The structure of human alpha-2,6-sialyltransferase reveals the binding mode of complex glycans. Acta Crystallogr. D Biol. Crystallogr. 69(Pt 9), 1826–1838 (2013)
Volkers, G., Worrall, L.J., Kwan, D.H., Yu, C.C., Baumann, L., Lameignere, E., Wasney, G.A., Scott, N.E., Wakarchuk, W., Foster, L.J., Withers, S.G., Strynadka, N.C.: Structure of human ST8SiaIII sialyltransferase provides insight into cell-surface polysialylation. Nat. Struct. Mol. Biol. 22(8), 627–635 (2015). https://doi.org/10.1038/nsmb.3060
Meng, L., Forouhar, F., Thieker, D., Gao, Z., Ramiah, A., Moniz, H., Xiang, Y., Seetharaman, J., Milaninia, S., Su, M., Bridger, R., Veillon, L., Azadi, P., Kornhaber, G., Wells, L., Montelione, G.T., Woods, R.J., Tong, L., Moremen, K.W.: Enzymatic Basis for N-Glycan Sialylation: STructure of rat α2,6-sialyltransferase (st6gal1) reveals conserved and unique features for glycan sialylation. J. Biol. Chem. 288(48), 34680–34698 (2013). https://doi.org/10.1074/jbc.M113.519041
Moremen, K.W., Haltiwanger, R.S.: Emerging structural insights into glycosyltransferase-mediated synthesis of glycans. Nat. Chem. Biol. 15(9), 853–864 (2019). https://doi.org/10.1038/s41589-019-0350-2
Tvaroška, I.: Glycosyltransferases as targets for therapeutic intervention in cancer and inflammation: molecular modeling insights. Chem. Paper 1–36 (2022)
Dall’Olio, F., Chiricolo, M.: Sialyltransferases in cancer. Glycoconj. J. 18(11–12), 841–850 (2001)
Harduin-Lepers, A., Krzewinski-Recchi, M.A., Colomb, F., Foulquier, F., Groux-Degroote, S., Delannoy, P.: Sialyltransferases functions in cancers. Front. Biosci. (Elite Ed) 4, 499–515 (2012). https://doi.org/10.2741/396
Hugonnet, M., Singh, P., Haas, Q., von Gunten, S.: The Distinct Roles of Sialyltransferases in Cancer Biology and Onco-Immunology. Front. Immunol. 12, 799861 (2021). https://doi.org/10.3389/fimmu.2021.799861
Munkley, J.: Aberrant Sialylation in Cancer: Therapeutic Opportunities. Cancers (Basel) 14(17) (2022). https://doi.org/10.3390/cancers14174248
Recchi, M.A., Hebbar, M., Hornez, L., Harduin-Lepers, A., Peyrat, J.P., Delannoy, P.: Multiplex reverse transcription polymerase chain reaction assessment of sialyltransferase expression in human breast cancer. Cancer. Res. 58(18), 4066–4070 (1998)
Burchell, J., Poulsom, R., Hanby, A., Whitehouse, C., Cooper, L., Clausen, H., Miles, D., Taylor-Papadimitriou, J.: An alpha2,3 sialyltransferase (ST3Gal I) is elevated in primary breast carcinomas. Glycobiology 9(12), 1307–1311 (1999). https://doi.org/10.1093/glycob/9.12.1307
Dalziel, M., Huang, R.Y., Dall’Olio, F., Morris, J.R., Taylor-Papadimitriou, J., Lau, J.T.: Mouse ST6Gal sialyltransferase gene expression during mammary gland lactation. Glycobiology 11(5), 407–412 (2001)
Picco, G., Julien, S., Brockhausen, I., Beatson, R., Antonopoulos, A., Haslam, S., Mandel, U., Dell, A., Pinder, S., Taylor-Papadimitriou, J., Burchell, J.: Over-expression of ST3Gal-I promotes mammary tumorigenesis. Glycobiology 20(10), 1241–1250 (2010). https://doi.org/10.1093/glycob/cwq085
Carvalho, A.S., Harduin-Lepers, A., Magalhaes, A., Machado, E., Mendes, N., Costa, L.T., Matthiesen, R., Almeida, R., Costa, J., Reis, C.A.: Differential expression of alpha-2,3-sialyltransferases and alpha-1,3/4-fucosyltransferases regulates the levels of sialyl Lewis a and sialyl Lewis x in gastrointestinal carcinoma cells. In. J. Biochem. Cell Biol. 42(1), 80–89 (2010). https://doi.org/10.1016/j.biocel.2009.09.010
Gomes, J., Reis, C.A.: Immunodetection of glycosyltransferases in gastrointestinal tissues. Methods Mol. Biol. 1022, 349–356 (2013)
Dorsett, K.A., Marciel, M.P., Hwang, J., Ankenbauer, K.E., Bhalerao, N., Bellis, S.L.: Regulation of ST6GAL1 sialyltransferase expression in cancer cells. Glycobiology 31(5), 530–539 (2021). https://doi.org/10.1093/glycob/cwaa110
Garnham, R., Scott, E., Livermore, K.E., Munkley, J.: ST6GAL1: A key player in cancer. Oncol. Lett. 18(2), 983–989 (2019). https://doi.org/10.3892/ol.2019.10458
Julien, S., Adriaenssens, E., Ottenberg, K., Furlan, A., Courtand, G., Vercoutter-Edouart, A.S., Hanisch, F.G., Delannoy, P., Le Bourhis, X.: ST6GalNAc I expression in MDA-MB-231 breast cancer cells greatly modifies their O-glycosylation pattern and enhances their tumourigenicity. Glycobiology 16(1), 54–64 (2006). https://doi.org/10.1093/glycob/cwj033
Marcos, N.T., Bennett, E.P., Gomes, J., Magalhaes, A., Gomes, C., David, L., Dar, I., Jeanneau, C., DeFrees, S., Krustrup, D., Vogel, L.K., Kure, E.H., Burchell, J., Taylor-Papadimitriou, J., Clausen, H., Mandel, U., Reis, C.A.: ST6GalNAc-I controls expression of sialyl-Tn antigen in gastrointestinal tissues. Front. Biosci. (Elite Ed) 3(4), 1443–1455 (2011). https://doi.org/10.2741/e345
Sewell, R., Backstrom, M., Dalziel, M., Gschmeissner, S., Karlsson, H., Noll, T., Gatgens, J., Clausen, H., Hansson, G.C., Burchell, J., Taylor-Papadimitriou, J.: The ST6GalNAc-I sialyltransferase localizes throughout the Golgi and is responsible for the synthesis of the tumor-associated sialyl-Tn O-glycan in human breast cancer. J. Biol. Chem. 281(6), 3586–3594 (2006). https://doi.org/10.1074/jbc.M511826200
Falconer, R.A., Errington, R.J., Shnyder, S.D., Smith, P.J., Patterson, L.H.: Polysialyltransferase: a new target in metastatic cancer. Curr. Cancer Drug Target. 12(8), 925–939 (2012). https://doi.org/10.2174/156800912803251225
Guo, X., Elkashef, S.M., Patel, A., Ribeiro Morais, G., Shnyder, S.D., Loadman, P.M., Patterson, L.H., Falconer, R.A.: An assay for quantitative analysis of polysialic acid expression in cancer cells. Carbohydr. Polym. 259, 117741 (2021). https://doi.org/10.1016/j.carbpol.2021.117741
Hassinen, A., Khoder-Agha, F., Khosrowabadi, E., Mennerich, D., Harrus, D., Noel, M., Dimova, E.Y., Glumoff, T., Harduin-Lepers, A., Kietzmann, T., Kellokumpu, S.: A Golgi-associated redox switch regulates catalytic activation and cooperative functioning of ST6Gal-I with B4GalT-I. Redox. Biol. 24, 101182 (2019). https://doi.org/10.1016/j.redox.2019.101182
Heise, T., Pijnenborg, J.F., Büll, C., van Hilten, N., Kers-Rebel, E.D., Balneger, N., Elferink, H., Adema, G.J., Boltje, T.J.: Potent metabolic sialylation inhibitors based on C-5-modified fluorinated sialic acids. J. Med. Chem. 62(2), 1014–1021 (2018)
Perez, S.J.L.P., Fu, C.-W., Li, W.-S.: Sialyltransferase inhibitors for the treatment of cancer metastasis: current challenges and future perspectives. Molecules 26(18), 5673 (2021)
Skropeta, D., Dobie, C., Montgomery, A.P., Steele, H., Szabo, R., Yu, H.: Sialyltransferase Inhibitors as Potential Anti-Cancer Agents. Aust. J. Chem. 74(11), 758–766 (2021)
Szabo, R., Skropeta, D.: Advancement of sialyltransferase inhibitors: therapeutic challenges and opportunities. Med. Res. Rev. 37(2), 219–270 (2017)
Wang, L., Liu, Y., Wu, L., Sun, X.-L.: Sialyltransferase inhibition and recent advances. Biochim. Biophys. Acta Proteins Proteom. 1864(1), 143–153 (2016)
Bowles, W.H.D., Gloster, T.M.: Sialidase and Sialyltransferase Inhibitors: Targeting Pathogenicity and Disease. Front. Mol. Biosci. 8 (2021). https://doi.org/10.3389/fmolb.2021.705133
Costa, A.F., Campos, D., Reis, C.A., Gomes, C.: Targeting glycosylation: a new road for cancer drug discovery. Trend. Cancer 6(9), 757–766 (2020)
Dobie, C., Skropeta, D.: Insights into the role of sialylation in cancer progression and metastasis. Br. J. Cancer 124(1), 76–90 (2021)
Chang, W.-W., Yu, C.-Y., Lin, T.-W., Wang, P.-H., Tsai, Y.-C.: Soyasaponin I decreases the expression of α2, 3-linked sialic acid on the cell surface and suppresses the metastatic potential of B16F10 melanoma cells. Biochem. Biophys. Res. Commun. 341(2), 614–619 (2006)
Hsu, C.-C., Lin, T.-W., Chang, W.-W., Wu, C.-Y., Lo, W.-H., Wang, P.-H., Tsai, Y.-C.: Soyasaponin-I-modified invasive behavior of cancer by changing cell surface sialic acids. Gynecol. Oncol. 96(2), 415–422 (2005)
Huang, W., Sun, L., Wang, B., Ma, Y., Yao, D., Han, W., Wang, L.: Ginsenosides, potent inhibitors of sialyltransferase. Z. Naturforsch. C 75(1–2), 41–49 (2020)
Chen, J.-Y., Tang, Y.-A., Huang, S.-M., Juan, H.-F., Wu, L.-W., Sun, Y.-C., Wang, S.-C., Wu, K.-W., Balraj, G., Chang, T.-T.: A novel sialyltransferase inhibitor suppresses FAK/paxillin signaling and cancer angiogenesis and metastasis pathways. Can. Res. 71(2), 473–483 (2011)
Rillahan, C.D., Antonopoulos, A., Lefort, C.T., Sonon, R., Azadi, P., Ley, K., Dell, A., Haslam, S.M., Paulson, J.C.: Global metabolic inhibitors of sialyl- and fucosyltransferases remodel the glycome. Nat. Chem. Biol. 8(7), 661–668 (2012). https://doi.org/10.1038/nchembio.999
Büll, C., Boltje, T.J., van Dinther, E.A., Peters, T., de Graaf, A.M., Leusen, J.H., Kreutz, M., Figdor, C.G., den Brok, M.H., Adema, G.J.: Targeted delivery of a sialic acid-blocking glycomimetic to cancer cells inhibits metastatic spread. ACS Nano 9(1), 733–745 (2015). https://doi.org/10.1021/nn5061964
Büll, C., Boltje, T.J., Wassink, M., de Graaf, A.M., van Delft, F.L., den Brok, M.H., Adema, G.J.: Targeting aberrant sialylation in cancer cells using a fluorinated sialic acid analog impairs adhesion, migration, and in vivo tumor growth. Mol. Cancer. The. 12(10), 1935–1946 (2013). https://doi.org/10.1158/1535-7163.Mct-13-0279
Müller, B., Schaub, C., Schmidt, R.R.: Efficient sialyltransferase inhibitors based on transition-state analogues of the sialyl donor. Angew. Chem. In. Ed. 37(20), 2893–2897 (1998)
Skropeta, D., Schwörer, R., Haag, T., Schmidt, R.R.: Asymmetric synthesis and affinity of potent sialyltransferase inhibitors based on transition-state analogues. Glycoconj. J. 21(5), 205–219 (2004)
Montgomery, A., Szabo, R., Skropeta, D., Yu, H.: Computational characterisation of the interactions between human ST6Gal I and transition-state analogue inhibitors: insights for inhibitor design. J. Mol. Recog. 29(5), 210–222 (2016). https://doi.org/10.1002/jmr.2520
Montgomery, A.P., Skropeta, D., Yu, H.: Transition state-based ST6Gal I inhibitors: Mimicking the phosphodiester linkage with a triazole or carbamate through an enthalpy-entropy compensation. Sci. Rep. 7(1), 14428 (2017). https://doi.org/10.1038/s41598-017-14560-0
Rillahan, C.D., Brown, S.J., Register, A.C., Rosen, H., Paulson, J.C.: High-throughput screening for inhibitors of sialyl-and fucosyltransferases. Angew. Chem. 123(52), 12742–12745 (2011)
Alshanski, I., Sukhran, Y., Mervinetsky, E., Unverzagt, C., Yitzchaik, S., Hurevich, M.: Electrochemical biosensing platform based on complex biantennary N-glycan for detecting enzymatic sialylation processes. Biosens. Bioelectron. 172, 112762 (2021)
Petit, D., Teppa, E., Cenci, U., Ball, S., Harduin-Lepers, A.: Reconstruction of the sialylation pathway in the ancestor of eukaryotes. Sci. Rep. 8(1), 2946 (2018). https://doi.org/10.1038/s41598-018-20920-1
Lehmann, F., Kelm, S., Dietz, F., von Itzstein, M., Tiralongo, J.: The evolution of galactose alpha2,3-sialyltransferase: Ciona intestinalis ST3GAL I/II and Takifugu rubripes ST3GAL II sialylate Galbeta 1,3GalNAc structures on glycoproteins but not glycolipids. Glycoconj. J. 25(4), 323–334 (2008)
Kim, S., Lee, J., Oh, D.B., Kwon, O.: Marine invertebrate sialyltransferase of the sea squirt Ciona savignyi sialylated core 1 O-linked glycans. Int. J. Biol. Macromol. 194, 366–376 (2022). https://doi.org/10.1016/j.ijbiomac.2021.11.078
Repnikova, E., Koles, K., Nakamura, M., Pitts, J., Li, H., Ambavane, A., Zoran, M.J., Panin, V.M.: Sialyltransferase regulates nervous system function in Drosophila. J. Neurosci. 30(18), 6466–6476 (2010). https://doi.org/10.1523/JNEUROSCI.5253-09.2010
Petit, D., Mir, A.M., Petit, J.M., Thisse, C., Delannoy, P., Oriol, R., Thisse, B., Harduin-Lepers, A.: Molecular phylogeny and functional genomics of beta-galactoside alpha2,6-sialyltransferases that explain ubiquitous expression of st6gal1 gene in amniotes. J. Biol. Chem. 285(49), 38399–38414 (2010). https://doi.org/10.1074/jbc.M110.163931
Harduin-Lepers, A., Petit, D., Mollicone, R., Delannoy, P., Petit, J.M., Oriol, R.: Evolutionary history of the alpha2,8-sialyltransferase (ST8Sia) gene family: tandem duplications in early deuterostomes explain most of the diversity found in the vertebrate ST8Sia genes. BMC Evol. Biol. 8, 258 (2008). https://doi.org/10.1186/1471-2148-8-258
Amores, A., Force, A., Yan, Y.L., Joly, L., Amemiya, C., Fritz, A., Ho, R.K., Langeland, J., Prince, V., Wang, Y.L., Westerfield, M., Ekker, M., Postlethwait, J.H.: Zebrafish hox clusters and vertebrate genome evolution. Science 282(5394), 1711–1714 (1998)
Chang, L.Y., Teppa, E., Noel, M., Gilormini, P.A., Decloquement, M., Lion, C., Biot, C., Mir, A.M., Cogez, V., Delannoy, P., Khoo, K.H., Petit, D., Guerardel, Y., Harduin-Lepers, A.: Novel Zebrafish Mono-alpha2,8-sialyltransferase (ST8Sia VIII): An Evolutionary Perspective of alpha2,8-Sialylation. Int. J. Mol. Sci. 20(3) (2019). https://doi.org/10.3390/ijms20030622
Venuto, M.T., Decloquement, M., Martorell Ribera, J., Noel, M., Rebl, A., Cogez, V., Petit, D., Galuska, S.P., Harduin-Lepers, A.: Vertebrate Alpha2,8-Sialyltransferases (ST8Sia): A Teleost Perspective. Int. J. Mol. Sci. 21(2) (2020). https://doi.org/10.3390/ijms21020513
Macqueen, D.J., Johnston, I.A.: A well-constrained estimate for the timing of the salmonid whole genome duplication reveals major decoupling from species diversification. Proc. Biol. Sci. 281(1778), 20132881 (2014). https://doi.org/10.1098/rspb.2013.2881
Xu, P., Zhang, X., Wang, X., Li, J., Liu, G., Kuang, Y., Xu, J., Zheng, X., Ren, L., Wang, G., Zhang, Y., Huo, L., Zhao, Z., Cao, D., Lu, C., Li, C., Zhou, Y., Liu, Z., Fan, Z., Shan, G., Li, X., Wu, S., Song, L., Hou, G., Jiang, Y., Jeney, Z., Yu, D., Wang, L., Shao, C., Song, L., Sun, J., Ji, P., Wang, J., Li, Q., Xu, L., Sun, F., Feng, J., Wang, C., Wang, S., Wang, B., Li, Y., Zhu, Y., Xue, W., Zhao, L., Wang, J., Gu, Y., Lv, W., Wu, K., Xiao, J., Wu, J., Zhang, Z., Yu, J., Sun, X.: Genome sequence and genetic diversity of the common carp. Cyprinus carpio. Nat. Genet. 46(11), 1212–1219 (2014). https://doi.org/10.1038/ng.3098
Varki, A., Cummings, R.D., Aebi, M., Packer, N.H., Seeberger, P.H., Esko, J.D., Stanley, P., Hart, G., Darvill, A., Kinoshita, T., Prestegard, J.J., Schnaar, R.L., Freeze, H.H., Marth, J.D., Bertozzi, C.R., Etzler, M.E., Frank, M., Vliegenthart, J.F., Lutteke, T., Perez, S., Bolton, E., Rudd, P., Paulson, J., Kanehisa, M., Toukach, P., Aoki-Kinoshita, K.F., Dell, A., Narimatsu, H., York, W., Taniguchi, N., Kornfeld, S.: Symbol Nomenclature for Graphical Representations of Glycans. Glycobiology 25(12), 1323–1324 (2015). https://doi.org/10.1093/glycob/cwv091
Neelamegham, S., Aoki-Kinoshita, K., Bolton, E., Frank, M., Lisacek, F., Lutteke, T., O’Boyle, N., Packer, N.H., Stanley, P., Toukach, P., Varki, A., Woods, R.J., Group, S.D.: Updates to the Symbol Nomenclature for Glycans guidelines. Glycobiology 29(9), 620–624 (2019). https://doi.org/10.1093/glycob/cwz045
Gonzalez-Gil, A., Porell, R.N., Fernandes, S.M., Wei, Y., Yu, H., Carroll, D.J., McBride, R., Paulson, J.C., Tiemeyer, M., Aoki, K., Bochner, B.S., Schnaar, R.L.: Sialylated keratan sulfate proteoglycans are Siglec-8 ligands in human airways. Glycobiology 28(10), 786–801 (2018). https://doi.org/10.1093/glycob/cwy057
Haltiwanger, R.S., Wells, L., Freeze, H.H., Jafar-Nejad, H., Okajima, T., Stanley, P.: Other Classes of Eukaryotic Glycans. In: Varki, A., Cummings, R.D., Esko, J.D., Stanley, P., Hart, G.W., Aebi, M., Mohnen, D., Kinoshita, T., Packer, N.H., Prestegard, J.H., Schnaar, R.L., Seeberger, P.H. (eds.) Essentials of Glycobiology. pp. 155–164. Cold Spring Harbor Laboratory Press Copyright © 2022. The Consortium of Glycobiology Editors, La Jolla, California; published by Cold Spring Harbor Laboratory Press. https://doi.org/10.1101/glycobiology.4e.13. All rights reserved., Cold Spring Harbor (NY) (2022)
Kitajima, K.: Identification of KDN-Gangliosides. Method. Mol. Biol. 1804, 429–435 (2018). https://doi.org/10.1007/978-1-4939-8552-4_22
Crooks, G.E., Hon, G., Chandonia, J.M., Brenner, S.E.: WebLogo: a sequence logo generator. Genome. Res. 14(6), 1188–1190 (2004)
Funding
The contribution of the COST Action CA18103-INNOGLY supported by the European Cooperation in Science and Technology (COST) is greatly acknowledged. This work was supported by the CNRS, Ligue de la recherche contre le cancer 2022; the ANR-21-CE44-0032 (project PsaMar), the University of Lille (France).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The author declares no conflict of interest.
Ethical approval
This non-research work is original and was not published elsewhere. It does not contain any studies with human participants or animals. Appropriate and relevant literature in support of the claims made were cited.
Additional information
Tribute to Professor Roland Schauer.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Harduin-Lepers, A. The vertebrate sialylation machinery: structure-function and molecular evolution of GT-29 sialyltransferases. Glycoconj J 40, 473–492 (2023). https://doi.org/10.1007/s10719-023-10123-w
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10719-023-10123-w