Beta-Hexosaminidase

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spinqualitylabelsall models Crystal Structure of Human β-Hexosaminidase α and β chains, (2gjx) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Contents 1 Structure of Human β-Hexosaminidase A and its association with Tay-Sachs disease 2 3D Structures of Beta-Hexosaminidase 2.1 Binary complexes 3 References

Structure of Human β-Hexosaminidase A and its association with Tay-Sachs disease

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β-Hexosaminidase A is a lysosomal enzyme essential for the degradation of GM2 gangliosides. Deficiency of lysosomal β-Hexosaminidase A due to inherited defects in the α-subunit gene results in Tay-Sachs (TS) disease. The 3D structure of β-Hexosaminidase A was determined by the group of Michael N.G. James at the University of Alberta, Edmonton, Canada.^[1] The structure reveals an , with each subunit having a functional active site. Only the active site can hydrolyze GM2 gangliosides due to α₂₈₀GSEP₂₈₃ structure that is removed post-translationaly from β, and to the presence of . The is involved in binding the GM2 activator protein, while is critical for binding the carboxylate group of the N-acetyl-neuraminic acid residue of GM2. are present in the HexA dimer; one comprising residues from (R178 D207 H262 E323 D322 W373 W392 W460 Y421 R424 N423 E462) and a second one from residues of the (R211 D240 H294 E355 D354 W405 W424 Y450 L453 D452 E491 W489). These active sites are located at the opening of TIM barrels at the interface between the α and β-subunits. The HexA on the α and β-subunits; α-Asn 115, α-Asn 157 and α-Asn 295 β-Asn 84, β-Asn 142, β-Asn 190 and β-Asn 327. in the α-subunit are associated with TS disease and with Late Onset Tay Sachs disease (LOTS) (Chronic & Acute clinical phenotype). Interestingly, is the most common mutation associated with LOTS disease.

3D Structures of Beta-Hexosaminidase

Updated on 15-August-2013

2xpk, 2w1n – CpBHEXB – Clostridium perfringens
2o4e – CpBHEXB - NMR
2v5c, 2v5d – CpBHEXB catalytic domain
2jh2 – CpBHEXB cohesin-like module
3gh4 – PaBHEX – Paenibacillus
3bmx – BHEX – Bacillus subtilis
1tr9 – VcBHEX – Vibrio cholerae
1hp4 – SpBHEX – Streptomyces plicatus
2ltj – SpnBHEX G5 domain – Streptococcus pneumoniae – NMR
2yl5 – SpnBHEX residues 627-1064
2yl6, 2yll, 3rpm – SpnBHEX catalytic domain
1qba – SmBHEX – Serratia marcescens
3lmy, 1o7a, 1nou – hBHEXB β subunit – human
1o7a - hBHEXB β subunit
2gjx - hBHEXA α+β subunits
3nsm – OfBHEX residues 23-594 – Ostrinia furnacalis
4ais – BtBHEXB – Bacteroides thetaiotaomicron
4g6c – BcBHEX – Burkholderia cenocepacia
4gvf - SeBHEX – Salmonella enterica
3rcn – BHEX – Arthrobacter aurescens

Binary complexes

2gk1 - hBHEXA α+β subunits + NGT
1now - hBHEXB β subunit + GalNAc-isofagomine
1np0 - hBHEXB β subunit + intermediate analog
3gh5, 3gh7 - PaBHEX + GlcNAc
4gvf, 4gvh, 4gvi - SeBHEX + GlcNAc derivative
4hzm – SeBHEX + inhibitor
1m01 - SpBHEX + GlcNAc
1m03, 1m04 - SpBHEX (mutant) + GlcNAc
1jak - SpBHEX + inhibitor
1hp5 - SpBHEX + intermediate analog
2x0y, 2wb5, 2vur - CpBHEXB + inhibitor
2ozn – CpBHEXB + hyaluronidase
3ozo – OfBHEX residues 23-594 + NGT
3ozp – OfBHEX residues 23-594 + PUGNac
3nsn - OfBHEX residues 23-594 + chitotriomycin
2xj7 – BtBHEXB + castanospermine
2wzh, 2wzi - BtBHEXB (mutant) + oxazoline
2vvn - BtBHEX + thiazoline
2x0h - BtBHEXB Michaelis complex
2wca, 2vvs - BtBHEX + PUGNAc
2xm1, 2xm2 - BtBHEXB + lactam derivative
4aiu - BtBHEXB + pyrazole derivative
2w66, 2w67, 2w4x, 2jiw – BtBHEXB + inhibitor
3gs6, 3gsm, 2oxn - VcBHEX + PUGNAc
1y65 - VcBHEX + NAG
4gnv - BcBHEX + NAG
2yl8 – SpnBHEX catalytic domain (mutant) + NAG
4az5, 4az6, 4az7, 4az8, 4azc, 4azg, 4azh – SpnBHEX catalytic domain + inhibitor
4azi – SpnBHEX catalytic domain (mutant) + inhibitor
2yl9, 2yla – SpnBHEX residues 627-1062 (mutant) + NAG
1c7s – SmBHEX + diNAG
1c7t - SmBHEX (mutant) + diNAG
3sur - PaBHEX + NAG derivative
3sus - PaBHEX + GAL-NAG derivative
3sut - PaBHEX + PUGNac
3suu - PaBHEX + GAL-PUGNac
3suv - PaBHEX + NHAC-DNJ
3suw - PaBHEX + NHAC-CAS

References

1. ↑ Lemieux MJ, Mark BL, Cherney MM, Withers SG, Mahuran DJ, James MN. Crystallographic structure of human beta-hexosaminidase A: interpretation of Tay-Sachs mutations and loss of GM2 ganglioside hydrolysis. J Mol Biol. 2006 Jun 16;359(4):913-29. Epub 2006 Apr 27. PMID:16698036 doi:http://dx.doi.org/10.1016/j.jmb.2006.04.004