Human Gb3/CD77 synthase reveals specificity toward two or four different acceptors depending on amino acid at position 211, creating Pk, P1 and NOR blood group antigens

Kaczmarek, Radosław; Duk, Maria; Szymczak, Katarzyna; Korchagina, Elena; Tyborowska, Jolanta; Mikołajczyk, Krzysztof; Bovin, Nicolai V.; Szewczyk, Bogusław; Jaśkiewicz, Ewa; Czerwiński, Marcin

doi:10.1016/j.bbrc.2016.01.017

Cited by 23 publications

(21 citation statements)

References 26 publications

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“…S2 ). Interestingly, α1-4 GALT, also known as Gb3 synthase, is the only known GT enzyme that changes acceptor specificity because of point mutations, and therefore is considered to be a highly promiscuous enzyme 31 , 32 . In addition, a β1-4 GALT gene from Neisseria meningitidis , pglA , catalyses both β1-4 and α1-3 linkages between the galactose and deoxyhexose in a trisaccharide structure 14 .…”

Section: Resultsmentioning

confidence: 99%

Tick galactosyltransferases are involved in α-Gal synthesis and play a role during Anaplasma phagocytophilum infection and Ixodes scapularis tick vector development

Cabezas-Cruz

Espinosa

Alberdi

et al. 2018

Sci Rep

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The carbohydrate Galα1-3Galβ1-(3)4GlcNAc-R (α-Gal) is produced in all mammals except for humans, apes and old world monkeys that lost the ability to synthetize this carbohydrate. Therefore, humans can produce high antibody titers against α-Gal. Anti-α-Gal IgE antibodies have been associated with tick-induced allergy (i.e. α-Gal syndrome) and anti-α-Gal IgG/IgM antibodies may be involved in protection against malaria, leishmaniasis and Chagas disease. The α-Gal on tick salivary proteins plays an important role in the etiology of the α-Gal syndrome. However, whether ticks are able to produce endogenous α-Gal remains currently unknown. In this study, the Ixodes scapularis genome was searched for galactosyltransferases and three genes were identified as potentially involved in the synthesis of α-Gal. Heterologous gene expression in α-Gal-negative cells and gene knockdown in ticks confirmed that these genes were involved in α-Gal synthesis and are essential for tick feeding. Furthermore, these genes were shown to play an important role in tick-pathogen interactions. Results suggested that tick cells increased α-Gal levels in response to Anaplasma phagocytophilum infection to control bacterial infection. These results provided the molecular basis of endogenous α-Gal production in ticks and suggested that tick galactosyltransferases are involved in vector development, tick-pathogen interactions and possibly the etiology of α-Gal syndrome in humans.

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Section: Resultsmentioning

confidence: 99%

Tick galactosyltransferases are involved in α-Gal synthesis and play a role during Anaplasma phagocytophilum infection and Ixodes scapularis tick vector development

Cabezas-Cruz

Espinosa

Alberdi

et al. 2018

Sci Rep

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“…We also attempted to evaluate the effect of NOR mutation (c.631C>G) on activity of the Gb3/CD77 synthase in vivo and how it relates to our earlier studies ex vivo and in vitro [ 5 – 7 ]. In our study on a transfected cell line[ 7 ], activity of the consensus Gb3/CD77 synthase was higher than activity of the p.Q211E mutein, in contrast to our results with the purified recombinant variants of the enzyme.…”

Section: Discussionmentioning

confidence: 99%

“…While it is well-established that the P k antigen is synthesised by Gb3/CD77 synthase (α1,4-galactosyltransferase, P1/P k synthase, encoded by A4GALT )[ 4 ], P1 has only recently been unequivocally shown to be a product of the same enzyme[ 5 ]. In addition, c.631C>G mutation in A4GALT , leading to p.Q211E substitution in Gb3/CD77 synthase (rs397514502), alters the enzyme specificity, rendering it able to synthesise all the three P1PK system antigens: P k , P1 and NOR[ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Single nucleotide polymorphisms in A4GALT spur extra products of the human Gb3/CD77 synthase and underlie the P1PK blood group system

et al. 2018

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Contrary to the mainstream blood group systems, P1PK continues to puzzle and generate controversies over its molecular background. The P1PK system comprises three glycosphingolipid antigens: Pk, P1 and NOR, all synthesised by a glycosyltransferase called Gb3/CD77 synthase. The Pk antigen is present in most individuals, whereas P1 frequency is lesser and varies regionally, thus underlying two common phenotypes: P1, if the P1 antigen is present, and P2, when P1 is absent. Null and NOR phenotypes are extremely rare. To date, several single nucleotide polymorphisms (SNPs) have been proposed to predict the P1/P2 status, but it has not been clear how important they are in general and in relation to each other, nor has it been clear how synthesis of NOR affects the P1 phenotype. Here, we quantitatively analysed the phenotypes and A4GALT transcription in relation to the previously proposed SNPs in a sample of 109 individuals, and addressed potential P1 antigen level confounders, most notably the red cell membrane cholesterol content. While all the SNPs were associated with the P1/P2 blood type and rs5751348 was the most reliable, we found large differences in P1 level within groups defined by their genotype and substantial intercohort overlaps, which shows that the P1PK blood group system still eludes full understanding.

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“…Since there is no obvious glycosyltransferase gene candidate, we suggest that α -galactosylceramide in humans may be a secondary product of a promiscuous enzyme. Examples of such unfaithful glycosyltransferases are known (Kaczmarek et al 2014, 2016; Suchanowska et al 2012; Togayachi et al 2001; Westman et al 2015). Typically, in comparison to the main enzyme products, such secondary products occur in minute quantities, which may be unmeasurable when using classical biochemical methods, yet important in biological environment (Kain et al 2014, 2015).…”

Section: Endogenous Lipids Presented By Cd1 Moleculesmentioning

confidence: 99%

CD1: A Singed Cat of the Three Antigen Presentation Systems

Kaczmarek

Paściak

Szymczak-Kulus

et al. 2017

Arch. Immunol. Ther. Exp.

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Contrary to general view that the MHC Class I and II are the kapellmeisters of recognition and response to antigens, there is another big player in that part of immunity, represented by CD1 glycoproteins. In contrast to MHC Class I or II, which present peptides, CD1 molecules present lipids. Humans express five CD1 proteins (CD1a-e), four of which (CD1a-d) are trafficked to the cell surface, where they may display lipid antigens to T-cell receptors. This interaction may lead to both non-cognate and cognate T cell help to B cells, the latter eliciting anti-lipid antibody response. All CD1 proteins can bind a broad range of structurally different exogenous and endogenous lipids, but each shows a preference to one or more lipid classes. This unorthodox binding behavior is the result of elaborate architectures of CD1 binding clefts and distinct intracellular trafficking routes. Together, these features make CD1 system a versatile player in immune response, sitting at the crossroads of innate and adaptive immunity. While CD1 system may be involved in numerous infectious, inflammatory, and autoimmune diseases, its involvement may lead to opposite outcomes depending on different pathologies. Despite these ambiguities and complexity, CD1 system draws growing attention and continues to show glimmers of therapeutic potential. In this review, we summarize the current knowledge about CD1 proteins, their structures, lipid-binding profiles, and roles in immunity, and evaluate the role of CD1 proteins in eliciting humoral immune response.

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Human Gb3/CD77 synthase reveals specificity toward two or four different acceptors depending on amino acid at position 211, creating Pk, P1 and NOR blood group antigens

Cited by 23 publications

References 26 publications

Tick galactosyltransferases are involved in α-Gal synthesis and play a role during Anaplasma phagocytophilum infection and Ixodes scapularis tick vector development

Tick galactosyltransferases are involved in α-Gal synthesis and play a role during Anaplasma phagocytophilum infection and Ixodes scapularis tick vector development

Single nucleotide polymorphisms in A4GALT spur extra products of the human Gb3/CD77 synthase and underlie the P1PK blood group system

CD1: A Singed Cat of the Three Antigen Presentation Systems

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