2.4.1.292: GalNAc-alpha-(1->4)-GalNAc-alpha-(1->3)-diNAcBac-PP-undecaprenol alpha-1,4-N-acetyl-D-galactosaminyltransferase
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Reaction
3 UDP-N-acetyl-alpha-D-galactosamine + = 3 UDP +
Synonyms
PglH, pglH2
ECTree
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General Information
General Information on EC 2.4.1.292 - GalNAc-alpha-(1->4)-GalNAc-alpha-(1->3)-diNAcBac-PP-undecaprenol alpha-1,4-N-acetyl-D-galactosaminyltransferase
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evolution
malfunction
metabolism
physiological function
additional information
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PglH is a glycosyltransferase protein containing the conserved EX7E sequence motif
evolution
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genotyping, overview. The variable presence of two open reading frames (ORFs) in the pgl locus includes a putative glycosyltransferase gene, pglG, in addition to a glucosyltransferase-expressing gene, pglH. Polymorphisms exist at the gene level described for pglH and pglH2, where only one nonsynonymous mutation is accountable for the glycoform switch from Glc to GlcNAc. lacking these two ORFs retain the first 40 bp of pglG and the last 100 bp of pglH. Homologous recombination within the pgl loci, through genomic analysis of 100 African serogroup A isolates in Ethiopia in 2014, is detected representing the clonal replacement of hypervirulent meningococcal clone sequence type 7 (ST-7) by the ST-2859 descendant clone. Major polymorphism in pgl gene content within a small geographic area. This recombination event seems to emphasizes the role of protein glycosylation diversity in immune evasion. Polymorphisms exist at the gene level described for pglH and pglH2, where only one nonsynonymous mutation is accountable for the glycoform switch from Glc to GlcNAc. One subcluster has pglH while the other has the pglH2 variant allele
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pglH mutants have significantly reduced ability to adhere to and invade human epithelial Caco-2 cells, the 81116 pglH mutant is also severely affected in its ability to colonize chicks
malfunction
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polymorphisms in PglH are associated with diminished glycosyltransferase activity
malfunction
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pgl genotypes and glycosylation phenotypes in meningococcal isolates and the changes occurring during short-term asymptomatic carriage, overview. Polymorphisms exist at the gene level described for pglH and pglH2, where only one nonsynonymous mutation is accountable for the glycoform switch from Glc to GlcNAc
malfunction
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pglH mutants have significantly reduced ability to adhere to and invade human epithelial Caco-2 cells, the 81116 pglH mutant is also severely affected in its ability to colonize chicks
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PglH is involved in the N-linked glycan structure formation, which is realized through a series of sequential glycosyl transfer reactions from uridine diphosphate-activated sugars to an undecaprenyl diphosphate carrier. Once undecaprenyl-diphospho-Bac2,4diNAc is formed by PglC, PglF, PglE, and PglD, sequential N-acetyl-galactosamine transfer reactions are catalyzed by PglA, PglJ and PglH to provide undecaprenyldiphospho-Bac2,4diNAc-GalNAc, undecaprenyldiphospho-Bac2,4diNAc-(GalNAc)2 and undecaprenyldiphospho-Bac2,4diNAc-(GalNAc)5, respectively
metabolism
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PglH is part of a general N-linked glycosylation pathway, encoded by the pgl gene cluster, which culminates in the transfer of a heptasaccharide: GalNAc-alpha1,4-GalNAc-alpha1,4-(Glcbeta1,3)-GalNAc-alpha1,4-GalNAc-alpha1,4-GalNAc-alpha1,3-Bac, where Bac is bacillosamine (2,4-diacetamido-2,4,6-trideoxyglucose), from a membrane-anchored undecaprenylpyrophosphate-linked donor to the asparagine side chain of proteins at the Asn-X-Ser/Thr motif. The glycosyltransferases, PglA, PglH, PglI, and PglJ, responsible for the biosynthesis of the Und-PP-linked heptasaccharide. Elongation of the trisaccharide with PglH results in a hexasaccharide revealing the polymerase activity of PglH
metabolism
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the Pgl pathway produces the N-linked glycan heptasaccharide GalNAc-alpha1,4-GalNAc-alpha1,4-(Glcbeta1,3)-GalNAc-alpha1,4-GalNAc-alpha1,4-GalNAc-alpha1,3-Bac2,4diNAc-1-Asn. The pathway begins with pyrophosphate bond formation between the Bac2,4diNAc phosphate and undecaprenylphosphate by Cj1124c (PglC) to form Bac2,4diNAc-alpha1-PP-Und. One N-acetylgalactosamine is linked to the polyisoprenediphosphate-bound N,N'-diacetylbacillosamine by Cj1125c (PglA) to form GalNAc-alpha1,3-Bac2,4diNAc-alpha1-PP-Und. Next, four additional GalNAc and one branching glucose are added sequentially to the isoprene-linked disaccharide by PglJ, PglH, and PglI, to form the heptasaccharide, overview
metabolism
the membrane-associated, processive and retaining glycosyltransferase PglH from Campylobacter jejuni is part of the biosynthetic pathway of the lipid-linked oligosaccharide (LLO) that serves as the glycan donor in bacterial protein N-glycosylation
metabolism
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the Pgl pathway produces the N-linked glycan heptasaccharide GalNAc-alpha1,4-GalNAc-alpha1,4-(Glcbeta1,3)-GalNAc-alpha1,4-GalNAc-alpha1,4-GalNAc-alpha1,3-Bac2,4diNAc-1-Asn. The pathway begins with pyrophosphate bond formation between the Bac2,4diNAc phosphate and undecaprenylphosphate by Cj1124c (PglC) to form Bac2,4diNAc-alpha1-PP-Und. One N-acetylgalactosamine is linked to the polyisoprenediphosphate-bound N,N'-diacetylbacillosamine by Cj1125c (PglA) to form GalNAc-alpha1,3-Bac2,4diNAc-alpha1-PP-Und. Next, four additional GalNAc and one branching glucose are added sequentially to the isoprene-linked disaccharide by PglJ, PglH, and PglI, to form the heptasaccharide, overview
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metabolism
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PglH is part of a general N-linked glycosylation pathway, encoded by the pgl gene cluster, which culminates in the transfer of a heptasaccharide: GalNAc-alpha1,4-GalNAc-alpha1,4-(Glcbeta1,3)-GalNAc-alpha1,4-GalNAc-alpha1,4-GalNAc-alpha1,3-Bac, where Bac is bacillosamine (2,4-diacetamido-2,4,6-trideoxyglucose), from a membrane-anchored undecaprenylpyrophosphate-linked donor to the asparagine side chain of proteins at the Asn-X-Ser/Thr motif. The glycosyltransferases, PglA, PglH, PglI, and PglJ, responsible for the biosynthesis of the Und-PP-linked heptasaccharide. Elongation of the trisaccharide with PglH results in a hexasaccharide revealing the polymerase activity of PglH
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metabolic conflict related to competition for a shared substrate between the opposing glycosyltransferases PglA and PglH
physiological function
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metabolic conflict related to competition for a shared substrate between the opposing glycosyltransferases PglA and PglH. Protein-linked PglH-derived disaccharides are immunogenic and antigenic, both diNAcBac- and GATDH-based PglH-derived glycans act as glycosyl donors in general, broad-spectrum protein glycosylation
physiological function
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the glycosyl transfer polymerase is related to the virulence of Campylobacter jejuni, PglH is a single active site processive polymerase, that utilizes product inhibition to limit sequential glycosyl transfer reactions, the reactions cease after the addition of just three GalNAc residues, overview. Processive mechanism under initial rate conditions, but product inhibition and product accumulation led to PglH release of intermediate products prior to complete conversion to the native ultimate product. A single active site is responsible for all three transferase reactions, requirement of the EX7E motif in catalysis. Increased binding affinity with increasing glycan size is proposed to provide PglH with a counting mechanism that does not allow the transfer of more than three GalNAc residues, mechanismm overview
physiological function
a null mutation in pglH leads to the expression of a di-N-acetylbacillosamine-monosaccharide glycoform. PglH participates in the synthesis of undecaprenyldiphosphate-di-Nacetylbacillosamine-glucose
physiological function
PglH catalyzes the transfer of exactly three alpha1,4 N-acetylgalactosamine (Gal-NAc) units to the growing LLO precursor, GalNAc-alpha1,4-GalNAc-alpha1,3-Bac-alpha1-PP-undecaprenyl. PglH contains an amphipathic helix (ruler helix) that has a dual role of facilitating membrane attachment and glycan counting. The ruler helix contains three positively charged side chains that can bind the diphosphate group of the LLO substrate and thus limit the addition of GalNAc units to three, glycan counting mechanism during PglH reaction, overview
physiological function
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PglH2 is a glucosyltransferase that acts on both N,N'-diacetylbacillosamine (diNAcBac) and glyceramido-acetamido trideoxyhexose (GATDH) to generate glucose GlcNAc-containing disaccharides
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Pgl genotypes and phenotypes of strains, overview
additional information
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Pgl genotypes and phenotypes of strains, overview. Epistatic interactions involving pglH at the intragenic and intergenic levels
additional information
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architecture of PglH and donor substrate binding, molecular dynamics simulations, mechanism of glycan counting by PglH, overview. The structure of PglH bound to UDP-GalNAc reveals the molecular details of the interactions with the donor substrate. The uridine moiety is positioned in a pocket formed by alpha12 and the loop connecting alpha10 and alpha11. There are two hydrogen bonds of the uracil moiety with the main chain of V247. The 2' and 3' hydroxyl groups of the ribose moiety form hydrogen bonds with E275, which is part of the conserved EX7E motif along with E267, which interacts with the N-acetyl group of GalNAc. The diphosphate moiety interacts via hydrogen bonds with R191, K196, and T271. R191 and K196 are conserved in the GT-B family and are proposed to stabilize the leaving group (UDP) following the transfer reaction. The T271 side chain is involved in phosphate binding but does not have a catalytic role unlike R191 and K196
additional information
architecture of PglH and donor substrate binding, molecular dynamics simulations, mechanism of glycan counting by PglH, overview. The structure of PglH bound to UDP-GalNAc reveals the molecular details of the interactions with the donor substrate. The uridine moiety is positioned in a pocket formed by alpha12 and the loop connecting alpha10 and alpha11. There are two hydrogen bonds of the uracil moiety with the main chain of V247. The 2' and 3' hydroxyl groups of the ribose moiety form hydrogen bonds with E275, which is part of the conserved EX7E motif along with E267, which interacts with the N-acetyl group of GalNAc. The diphosphate moiety interacts via hydrogen bonds with R191, K196, and T271. R191 and K196 are conserved in the GT-B family and are proposed to stabilize the leaving group (UDP) following the transfer reaction. The T271 side chain is involved in phosphate binding but does not have a catalytic role unlike R191 and K196
additional information
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more than 30 different glycoforms can be synthesized by combinations of glycosyltransferases and the O-acetylase within neisserial species