| Structural highlights
Function
FUT9_HUMAN Catalyzes alpha(1->3) linkage of fucosyl moiety transferred from GDP-beta-L-fucose to N-acetyl glucosamine (GlcNAc) within type 2 lactosamine (LacNAc, beta-D-Gal-(1->4)-beta-D-GlcNAc-) glycan attached to glycolipids and N- or O-linked glycoproteins. Fucosylates distal type 2 LacNAc and its fucosylated (H-type 2 LacNAc) and sialylated (sialyl-type 2 LacNAc) derivatives to form Lewis x (Lex) (CD15) and Lewis y (Ley) antigenic epitopes involved in cell adhesion and differentiation (PubMed:10386598, PubMed:10622713, PubMed:11278338, PubMed:12107078, PubMed:16282604, PubMed:17335083, PubMed:18395013, PubMed:23192350, PubMed:23263199, PubMed:29593094, PubMed:37202521). Generates Lex epitopes in the brain, presumably playing a role in the maintenance of neuronal stemness and neurite outgrowth in progenitor neural cells (By similarity) (PubMed:17335083, PubMed:23000574). Fucosylates the internal type 2 LacNAc unit of the polylactosamine chain to form VIM-2 antigen that serves as recognition epitope for SELE (PubMed:23192350). Can also modify milk oligosaccharides, in particular type 2 tetrasaccharide LNnT (PubMed:37202521).[UniProtKB:O88819][1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]
Publication Abstract from PubMed
Mammalian cell surface and secreted glycoproteins exhibit remarkable glycan structural diversity that contributes to numerous physiological and pathogenic interactions. Terminal glycan structures include Lewis antigens synthesized by a collection of alpha1,3/4-fucosyltransferases (CAZy GT10 family). At present, the only available crystallographic structure of a GT10 member is that of the Helicobacter pylori alpha1,3-fucosyltransferase, but mammalian GT10 fucosyltransferases are distinct in sequence and substrate specificity compared with the bacterial enzyme. Here, we determined crystal structures of human FUT9, an alpha1,3-fucosyltransferase that generates Lewis(x) and Lewis(y) antigens, in complex with GDP, acceptor glycans, and as a FUT9-donor analog-acceptor Michaelis complex. The structures reveal substrate specificity determinants and allow prediction of a catalytic model supported by kinetic analyses of numerous active site mutants. Comparisons with other GT10 fucosyltransferases and GT-B fold glycosyltransferases provide evidence for modular evolution of donor- and acceptor-binding sites and specificity for Lewis antigen synthesis among mammalian GT10 fucosyltransferases.
Structural basis for Lewis antigen synthesis by the alpha1,3-fucosyltransferase FUT9.,Kadirvelraj R, Boruah BM, Wang S, Chapla D, Huang C, Ramiah A, Hudson KL, Prudden AR, Boons GJ, Withers SG, Wood ZA, Moremen KW Nat Chem Biol. 2023 Aug;19(8):1022-1030. doi: 10.1038/s41589-023-01345-y. Epub , 2023 May 18. PMID:37202521[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kaneko M, Kudo T, Iwasaki H, Ikehara Y, Nishihara S, Nakagawa S, Sasaki K, Shiina T, Inoko H, Saitou N, Narimatsu H. Alpha1,3-fucosyltransferase IX (Fuc-TIX) is very highly conserved between human and mouse; molecular cloning, characterization and tissue distribution of human Fuc-TIX. FEBS Lett. 1999 Jun 11;452(3):237-42. PMID:10386598 doi:10.1016/s0014-5793(99)00640-7
- ↑ Nishihara S, Iwasaki H, Kaneko M, Tawada A, Ito M, Narimatsu H. Alpha1,3-fucosyltransferase 9 (FUT9; Fuc-TIX) preferentially fucosylates the distal GlcNAc residue of polylactosamine chain while the other four alpha1,3FUT members preferentially fucosylate the inner GlcNAc residue. FEBS Lett. 1999 Dec 3;462(3):289-94. PMID:10622713 doi:10.1016/s0014-5793(99)01549-5
- ↑ Nakayama F, Nishihara S, Iwasaki H, Kudo T, Okubo R, Kaneko M, Nakamura M, Karube M, Sasaki K, Narimatsu H. CD15 expression in mature granulocytes is determined by alpha 1,3-fucosyltransferase IX, but in promyelocytes and monocytes by alpha 1,3-fucosyltransferase IV. J Biol Chem. 2001 May 11;276(19):16100-6. PMID:11278338 doi:10.1074/jbc.M007272200
- ↑ Toivonen S, Nishihara S, Narimatsu H, Renkonen O, Renkonen R. Fuc-TIX: a versatile alpha1,3-fucosyltransferase with a distinct acceptor site-specificity profile. Glycobiology. 2002 Jun;12(6):361-8. PMID:12107078 doi:10.1093/glycob/12.6.361
- ↑ Bogoevska V, Horst A, Klampe B, Lucka L, Wagener C, Nollau P. CEACAM1, an adhesion molecule of human granulocytes, is fucosylated by fucosyltransferase IX and interacts with DC-SIGN of dendritic cells via Lewis x residues. Glycobiology. 2006 Mar;16(3):197-209. PMID:16282604 doi:10.1093/glycob/cwj057
- ↑ Brito C, Escrevente C, Reis CA, Lee VM, Trojanowski JQ, Costa J. Increased levels of fucosyltransferase IX and carbohydrate Lewis(x) adhesion determinant in human NT2N neurons. J Neurosci Res. 2007 May 1;85(6):1260-70. PMID:17335083 doi:10.1002/jnr.21230
- ↑ Brito C, Kandzia S, Graça T, Conradt HS, Costa J. Human fucosyltransferase IX: specificity towards N-linked glycoproteins and relevance of the cytoplasmic domain in intra-Golgi localization. Biochimie. 2008 Sep;90(9):1279-90. PMID:18395013 doi:10.1016/j.biochi.2008.03.002
- ↑ Gouveia R, Schaffer L, Papp S, Grammel N, Kandzia S, Head SR, Kleene R, Schachner M, Conradt HS, Costa J. Expression of glycogenes in differentiating human NT2N neurons. Downregulation of fucosyltransferase 9 leads to decreased Lewis(x) levels and impaired neurite outgrowth. Biochim Biophys Acta. 2012 Dec;1820(12):2007-19. PMID:23000574 doi:10.1016/j.bbagen.2012.09.004
- ↑ Buffone A Jr, Mondal N, Gupta R, McHugh KP, Lau JT, Neelamegham S. Silencing α1,3-fucosyltransferases in human leukocytes reveals a role for FUT9 enzyme during E-selectin-mediated cell adhesion. J Biol Chem. 2013 Jan 18;288(3):1620-33. PMID:23192350 doi:10.1074/jbc.M112.400929
- ↑ Seelhorst K, Stacke C, Ziegelmüller P, Hahn U. N-glycosylations of human α1,3-fucosyltransferase IX are required for full enzyme activity. Glycobiology. 2013 May;23(5):559-67. PMID:23263199 doi:10.1093/glycob/cws219
- ↑ Mondal N, Dykstra B, Lee J, Ashline DJ, Reinhold VN, Rossi DJ, Sackstein R. Distinct human α(1,3)-fucosyltransferases drive Lewis-X/sialyl Lewis-X assembly in human cells. J Biol Chem. 2018 May 11;293(19):7300-7314. PMID:29593094 doi:10.1074/jbc.RA117.000775
- ↑ Kadirvelraj R, Boruah BM, Wang S, Chapla D, Huang C, Ramiah A, Hudson KL, Prudden AR, Boons GJ, Withers SG, Wood ZA, Moremen KW. Structural basis for Lewis antigen synthesis by the α1,3-fucosyltransferase FUT9. Nat Chem Biol. 2023 May 18. PMID:37202521 doi:10.1038/s41589-023-01345-y
- ↑ Kadirvelraj R, Boruah BM, Wang S, Chapla D, Huang C, Ramiah A, Hudson KL, Prudden AR, Boons GJ, Withers SG, Wood ZA, Moremen KW. Structural basis for Lewis antigen synthesis by the α1,3-fucosyltransferase FUT9. Nat Chem Biol. 2023 May 18. PMID:37202521 doi:10.1038/s41589-023-01345-y
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