Human N-Acetylgalactosamine 4-Sulfate 6-O-Sulfotransferase cDNA Is Related to Human B Cell Recombination Activating Gene-associated Gene

Ohtake, Shiori; Ito, Yuki; Fukuta, Masakazu; Habuchi, Osami

doi:10.1074/jbc.m104922200

Cited by 100 publications

(84 citation statements)

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“…However, Cpxm2 lacks several of the predicted active site residues required for enzyme activity and may function instead as a phospholipid-binding protein (Xin et al 1998a(Xin et al , b, 1997. The Chst15 gene has highest sequence identity to human and rat type II transmembrane N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase (GalNAc4S6ST) found in the Golgi system required for biogenesis of glycoproteins (Ohtake et al 2001). It catalyzes the transfer of sulfate from 3′-phosphoadenosine 5′-phosphosulfate to position 6 of the non-reducing GalNAc(4SO(4)) residues contained in proteins such as chondroitin sulfate A and dermatan sulfate (Ohtake et al 2001(Ohtake et al , 2003.…”

Section: Discussionmentioning

confidence: 99%

“…The Chst15 gene has highest sequence identity to human and rat type II transmembrane N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase (GalNAc4S6ST) found in the Golgi system required for biogenesis of glycoproteins (Ohtake et al 2001). It catalyzes the transfer of sulfate from 3′-phosphoadenosine 5′-phosphosulfate to position 6 of the non-reducing GalNAc(4SO(4)) residues contained in proteins such as chondroitin sulfate A and dermatan sulfate (Ohtake et al 2001(Ohtake et al , 2003. The extent of contribution of each of these genes to the head bobber phenotype will require further investigation.…”

Section: Discussionmentioning

confidence: 99%

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Head Bobber: An Insertional Mutation Causes Inner Ear Defects, Hyperactive Circling, and Deafness

Somma

Alger

McGuire

et al. 2012

JARO

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The head bobber transgenic mouse line, produced by pronuclear integration, exhibits repetitive head tilting, circling behavior, and severe hearing loss. Transmitted as an autosomal recessive trait, the homozygote has vestibular and cochlea inner ear defects. The space between the semicircular canals is enclosed within the otic capsule creating a vacuous chamber with remnants of the semicircular canals, associated cristae, and vestibular organs. A poorly developed stria vascularis and endolymphatic duct is likely the cause for Reissner's membrane to collapse post-natally onto the organ of Corti in the cochlea. Molecular analyses identified a single integration of~3 tandemly repeated copies of the transgene, a short duplicated segment of chromosome X and a 648 kb deletion of chromosome 7(F3). The three known genes (Gpr26, Cpxm2, and Chst15) in the deleted region are conserved in mammals and expressed in the wild-type inner ear during vestibular and cochlea development but are absent in homozygous mutant ears. We propose that genes critical for inner ear patterning and differentiation are lost at the head bobber locus and are candidate genes for human deafness and vestibular disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Head Bobber: An Insertional Mutation Causes Inner Ear Defects, Hyperactive Circling, and Deafness

Somma

Alger

McGuire

et al. 2012

JARO

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“…We assume this to be the result of an elevated N-acetylgalactosamine-4-O-sulfate 6-O-sulfotransferase (GalNAc4S-6ST) activity (20). It has been speculated that GalNAc4S-6ST is involved in the formation of nonreducing terminal GalNAc(4S,6S) residues found in CS chains (20). In our patients, this enzyme may partially fill the gap created by the loss of C6ST-1 function.…”

Section: Discussionmentioning

confidence: 99%

“…We also found a minor signal of ⌬HexA-GalNAc(4S,6S) in the patients, which was absent from two controls. We assume this to be the result of an elevated N-acetylgalactosamine-4-O-sulfate 6-O-sulfotransferase (GalNAc4S-6ST) activity (20). It has been speculated that GalNAc4S-6ST is involved in the formation of nonreducing terminal GalNAc(4S,6S) residues found in CS chains (20).…”

Section: Discussionmentioning

confidence: 99%

Loss of chondroitin 6-O-sulfotransferase-1 function results in severe human chondrodysplasia with progressive spinal involvement

Thiele

Sakano

Kitagawa

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

173

143

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We studied two large consanguineous families from Oman with a distinct form of spondyloepiphyseal dysplasia (SED Omani type). By using a genome-wide linkage approach, we were able to map the underlying gene to a 4.5-centimorgan interval on chromosome 10q23. We sequenced candidate genes from the region and identified a missense mutation in the chondroitin 6-O-sulfotransferase (C6ST-1) gene (CHST3) changing an arginine into a glutamine (R304Q) in the well conserved 3 -phosphoadenosine 5 -phosphosulfate binding site. C6ST-1 catalyzes the modifying step of chondroitin sulfate (CS) synthesis by transferring sulfate to the C-6 position of the N-acetylgalactosamine of chondroitin. From the crystal structures of other sulfotransferases, it could be inferred that Arg-304 is essential for the structure of the cosubstrate binding site. We used recombinant C6ST-1 to show that the identified missense mutation completely abolishes C6ST-1 activity. Disaccharide composition analysis of CS chains by anion-exchange HPLC shows that both ⌬HexA-GalNAc(6S) and ⌬HexA(2S)-GalNAc(6S) were significantly reduced in the patient's cells and that ⌬HexA-GalNAc(4S,6S), undetectable in controls, was elevated. Analysis of the patient's urine shows marked undersulfation of CS, in particular reduction in 6-O-sulfated disaccharide and an increase in the nonsulfated unit. Our results indicate that the mutation in CHST3 described here causes a specific but generalized defect of CS chain sulfation resulting in chondrodysplasia with major involvement of the spine.

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“…Chondroitin 6-sulfotransferase (C6ST) transfers sulfate to the 0S unit and generates the 6S unit (5). N-Acetylgalactosamine 4-sulfate 6-sulfotransferase (GalNAc4S-6ST) catalyzes further sulfation from the 4S unit to generate the diSE unit (6). Uronosyl 2-sulfotransferase (UA2ST) transfers sulfate to an uronic acid residue at the 2-O-position and generates diSD and diSB units from 6S and IdoUA-GalNAc(4S) units, respectively (6).…”

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confidence: 99%

Construction of a Chondroitin Sulfate Library with Defined Structures and Analysis of Molecular Interactions

Sugiura

Shioiri

Chiba

et al. 2012

Journal of Biological Chemistry

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Background: Chondroitin sulfate (CS) is a linear polysaccharide, composed of repeating disaccharide units and modified with sulfate groups at various positions.Results: A CS library was constructed with defined structures using CS polymerase and sulfotransferases. Conclusion: The CS library provided details of interactions with CS-binding molecules. Significance: Chemo-enzymatic synthesis provides a useful tool for studying the biological functions of CS.Chondroitin sulfate (CS) is a linear acidic polysaccharide, composed of repeating disaccharide units of glucuronic acid and N-acetyl-D-galactosamine and modified with sulfate residues at different positions, which plays various roles in development and disease. Here, we chemo-enzymatically synthesized various CS species with defined lengths and defined sulfate compositions, from chondroitin hexasaccharide conjugated with hexamethylenediamine at the reducing ends, using bacterial chondroitin polymerase and recombinant CS sulfotransferases, including chondroitin-4-sulfotransferase 1 (C4ST-1), chondroitin-6-sulfotransferase 1 (C6ST-1), N-acetylgalactosamine 4-sulfate 6-sulfotransferase (GalNAc4S-6ST), and uronosyl 2-sulfotransferase (UA2ST). Sequential modifications of CS with a series of CS sulfotransferases revealed their distinct features, including their substrate specificities. Reactions with chondroitin polymerase generated non-sulfated chondroitin, and those with C4ST-1 and C6ST-1 generated uniformly sulfated CS containing >95% 4S and 6S units, respectively. GalNAc4S-6ST and UA2ST generated highly sulfated CS possessing ϳ90% corresponding disulfated disaccharide units. Sequential reactions with UA2ST and GalNAc4S-6ST generated further highly sulfated CS containing a mixed structure of disulfated units. Surprisingly, sequential reactions with GalNAc4S-6ST and UA2ST generated a novel CS molecule containing ϳ29% trisulfated disaccharide units. Enzyme-linked immunosorbent assay and surface plasmon resonance analysis using the CS library and natural CS products modified with biotin at the reducing ends, revealed details of the interactions of CS species with anti-CS antibodies, and with CS-binding molecules such as midkine and pleiotrophin. Chemo-enzymatic synthesis enables the generation of CS chains of the desired lengths, compositions, and distinct structures, and the resulting library will be a useful tool for studies of CS functions. Chondroitin sulfate (CS)2 is a glycosaminoglycan that is a linear acidic polysaccharide composed of repeating disaccharide units (-4 D-glucuronic acid (GlcUA) ␤ 1-3 N-acetyl-dgalactosamine (GalNAc)␤1-) n and modified with sulfate groups at various positions on the sugar residues (1). The average molecular weight (M r ) of CS is 10,000ϳ100,000 consisting of 40ϳ400 saccharide residues as a mature molecule (Table 1).The major disaccharide structures (see Fig. 1A) of CS are as follows: a non-sulfated unit (0S, GlcUA-GalNAc), a monosulfated unit at the C-4 position of the GalNAc residue (4S, GlcUA-GalNAc(4S)), a monosulfated unit at ...

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Human N-Acetylgalactosamine 4-Sulfate 6-O-Sulfotransferase cDNA Is Related to Human B Cell Recombination Activating Gene-associated Gene

Cited by 100 publications

References 44 publications

Head Bobber: An Insertional Mutation Causes Inner Ear Defects, Hyperactive Circling, and Deafness

Head Bobber: An Insertional Mutation Causes Inner Ear Defects, Hyperactive Circling, and Deafness

Loss of chondroitin 6-O-sulfotransferase-1 function results in severe human chondrodysplasia with progressive spinal involvement

Construction of a Chondroitin Sulfate Library with Defined Structures and Analysis of Molecular Interactions

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