Beta-Hexosaminidase

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{{STRUCTURE_2x0y| PDB=2x0y | SIZE=400| SCENE= |right|CAPTION=β-hexoaminidase dimer complex with inhibitor [[2x0y]] }}
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<StructureSection load='' size='350' side='right' scene='Beta-Hexosaminidase/Opening/3' caption='Human β-hexosaminidase (PDB code [[2gjx]])'>
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<applet load="" size="500" color="" frame="true" spin="on" Scene ="Beta-Hexosaminidase/Opening/3" align="right" caption="Crystal Structure of Human β-Hexosaminidase α and β chains, ([[2gjx]])"/>
 
=== {{Nowrap|Structure of Human β-Hexosaminidase A}} and its association with Tay-Sachs disease===
=== {{Nowrap|Structure of Human β-Hexosaminidase A}} and its association with Tay-Sachs disease===
<hr/>
<hr/>
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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.<ref>PMID:16698036</ref> The structure reveals an <scene name='Beta-Hexosaminidase/Subunits/4'>αβ-heterodimer</scene>, with each subunit having a functional active site. Only the <scene name='Beta-Hexosaminidase/Alpha/2'>α-subunit</scene> active site can hydrolyze GM2 gangliosides due to <scene name='Beta-Hexosaminidase/Gsep/6'>a flexible loop</scene> α<sub>280</sub>GSEP<sub>283</sub> structure that is removed post-translationaly from β, and to the presence of <scene name='Beta-Hexosaminidase/4234/5'>α-Asn 423 and α-Arg 424</scene>. The <scene name='Beta-Hexosaminidase/Gsep_out/3'>loop structure</scene> is involved in binding the GM2 activator protein, while <scene name='Beta-Hexosaminidase/424_b/1'>α-Arg424</scene> is critical for binding the carboxylate group of the N-acetyl-neuraminic acid residue of GM2. <scene name='Beta-Hexosaminidase/2_active/1'>Two active sites</scene> are present in the HexA dimer; one comprising residues from <scene name='Beta-Hexosaminidase/Active_alpha/1'>the α-subunit</scene> (R178 D207 H262 E323 D322 W373 W392 W460 Y421 R424 N423 E462) and a second one from residues of the <scene name='Beta-Hexosaminidase/Active_beta/1'>β-subunit</scene> (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 <scene name='Beta-Hexosaminidase/Glyco/1'>undergoes glycosylation</scene> 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. <scene name='Beta-Hexosaminidase/Opening/8'>Mutations</scene> in the α-subunit are associated with TS disease and with Late Onset Tay Sachs disease (LOTS) (<b><font color='#0865F1'>Chronic</font></b> & <b><font color='#F90D19'>Acute</font></b> clinical phenotype). Interestingly, <scene name='Beta-Hexosaminidase/Mut_2/2'>α-G269S</scene> is the most common mutation associated with LOTS 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.<ref>PMID:16698036</ref> The structure reveals an <scene name='Beta-Hexosaminidase/Subunits/4'>αβ-heterodimer</scene>, with each subunit having a functional active site. Only the <scene name='Beta-Hexosaminidase/Alpha/2'>α-subunit</scene> active site can hydrolyze GM2 gangliosides due to <scene name='Beta-Hexosaminidase/Gsep/6'>a flexible loop</scene> α<sub>280</sub>GSEP<sub>283</sub> structure that is removed post-translationaly from β, and to the presence of <scene name='Beta-Hexosaminidase/4234/5'>α-Asn 423 and α-Arg 424</scene>. The <scene name='Beta-Hexosaminidase/Gsep_out/3'>loop structure</scene> is involved in binding the GM2 activator protein, while <scene name='Beta-Hexosaminidase/424_b/1'>α-Arg424</scene> is critical for binding the carboxylate group of the N-acetyl-neuraminic acid residue of GM2. <scene name='Beta-Hexosaminidase/2_active/1'>Two active sites</scene> are present in the HexA dimer; one comprising residues from <scene name='Beta-Hexosaminidase/Active_alpha/1'>the α-subunit</scene> (R178 D207 H262 E323 D322 W373 W392 W460 Y421 R424 N423 E462) and a second one from residues of the <scene name='Beta-Hexosaminidase/Active_beta/1'>β-subunit</scene> (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 <scene name='Beta-Hexosaminidase/Glyco/1'>undergoes glycosylation</scene> 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. <scene name='Beta-Hexosaminidase/Opening/8'>Mutations</scene> in the α-subunit are associated with TS disease and with Late Onset Tay Sachs disease (LOTS) (<b><font color='#0865F1'>Chronic</font></b> & <b><font color='#F90D19'>Acute</font></b> clinical phenotype). Interestingly, <scene name='Beta-Hexosaminidase/Mut_2/2'>α-G269S</scene> is the most common mutation associated with LOTS disease. See also [[Beta-N-acetylhexosaminidase]] and [[Hexosaminidase (Hebrew)]].
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== 3D Structures of Beta-Hexosaminidase ==
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[[Beta-Hexosaminidase 3D structures]]
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</StructureSection>
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__NOTOC__
== 3D Structures of Beta-Hexosaminidase ==
== 3D Structures of Beta-Hexosaminidase ==
Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
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{{#tree:id=OrganizedByTopic|openlevels=0|
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[[2xpk]], [[2w1n]] – CpBHEXB – ''Clostridium perfringens''<br />
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*Beta-hexosaminidase
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[[2o4e]] – CpBHEXB - NMR<br />
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[[2v5c]], [[2v5d]] – CpBHEXB catalytic domain<br />
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[[2jh2]] – CpBHEXB cohesin-like module<br />
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[[3gh4]] – PaBHEX – Paenibacillus<br />
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[[3bmx]] – BHEX – ''Bacillus subtilis''<br />
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[[1tr9]] – VcBHEX – ''Vibrio cholerae''<br />
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[[1hp4]] – SpBHEX – ''Streptomyces plicatus''<br />
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[[2ltj]] – SpnBHEX G5 domain – ''Streptococcus pneumoniae'' – NMR<br />
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[[2yl5]] – SpnBHEX residues 627-1064<br />
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[[2yl6]], [[2yll]], [[3rpm]] – SpnBHEX residues 181-614<br />
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[[1qba]] – SmBHEX – ''Serratia marcescens''<br />
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[[3lmy]], [[1o7a]], [[1nou]] – hBHEXB β subunit – human<br />
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[[1o7a]] - hBHEXB β subunit<br />
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[[2gjx]] - hBHEXA α+β subunits<br />
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[[3nsm]] – OfBHEX residues 23-594 – ''Ostrinia furnacalis''<br />
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[[4ais]] – BtBHEXB – ''Bacteroides thetaiotaomicron''<br />
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[[4g6c]] – BcBHEX – ''Burkholderia cenocepacia''<br />
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[[4gvf]] - SeBHEX – ''Salmonella enterica''<br />
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[[3rcn]] – BHEX – ''Arthrobacter aurescens''
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===Binary complexes===
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**[[2gjx]] - hBHEXA α+β subunits - human<br />
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**[[3lmy]], [[1o7a]], [[1nou]], [[1o7a]] – hBHEXB β subunit <br />
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**[[5bro]] - hBHEXB β subunit (mutant)<br />
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**[[2xpk]], [[2w1n]] – CpBHEXB – ''Clostridium perfringens''<br />
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**[[2o4e]] – CpBHEXB - NMR<br />
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**[[2v5c]], [[2v5d]] – CpBHEXB catalytic domain<br />
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**[[2jh2]] – CpBHEXB cohesin-like module<br />
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**[[3gh4]] – PaBHEX – ''Paenibacillus''<br />
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**[[3bmx]] – BHEX – ''Bacillus subtilis''<br />
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**[[1tr9]] – VcBHEX – ''Vibrio cholerae''<br />
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**[[1hp4]] – SpBHEX – ''Streptomyces plicatus''<br />
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**[[2ltj]] – SpnBHEX G5 domain – ''Streptococcus pneumoniae'' – NMR<br />
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**[[2yl5]] – SpnBHEX residues 627-1064<br />
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**[[2yl6]], [[2yll]], [[3rpm]] – SpnBHEX catalytic domain<br />
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**[[1qba]] – SmBHEX – ''Serratia marcescens''<br />
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**[[3nsm]] – OfBHEX residues 23-594 – ''Ostrinia furnacalis''<br />
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**[[4ais]], [[6q63]] – BtBHEXB – ''Bacteroides thetaiotaomicron''<br />
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**[[4g6c]] – BcBHEX – ''Burkholderia cenocepacia''<br />
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**[[4gvg]] - SeBHEX – ''Salmonella enterica''<br />
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**[[3rcn]] – BHEX – ''Arthrobacter aurescens''<br />
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**[[5g1m]], [[5g2m]] - PaBHEXB – ''Pseudomonas aeruginosa''<br />
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**[[5g5u]], [[5g6t]] - PaBHEXB (mutant)<br />
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**[[5oar]] - BHEXB – yellow mold<br />
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**[[6jti]], [[6jtl]] – NgBHEX – ''Neisseria gonorrhoeae''<br />
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[[2gk1]] - hBHEXA α+β subunits + NGT<br />
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*Beta-hexosaminidase binary complexes
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[[1now]] - hBHEXB β subunit + GalNAc-isofagomine<br />
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[[1np0]] - hBHEXB β subunit + intermediate analog<br />
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[[3gh5]], [[3gh7]] - PaBHEX + GlcNAc<br />
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[[4gvf]], [[4gvh]], [[4gvi]] - SeBHEX + GlcNAc derivative<br />
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[[4hzm]] – SeBHEX + inhibitor<br />
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[[1m01]] - SpBHEX + GlcNAc <br />
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[[1m03]], [[1m04]] - SpBHEX (mutant) + GlcNAc<br />
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[[1jak]] - SpBHEX + inhibitor<br />
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[[1hp5]] - SpBHEX + intermediate analog<br />
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[[2x0y]], [[2wb5]], [[2vur]] - CpBHEXB + inhibitor<br />
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[[2ozn]] – CpBHEXB + hyaluronidase<br />
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[[3ozo]] – OfBHEX residues 23-594 + NGT<br />
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[[3ozp]] – OfBHEX residues 23-594 + PUGNac<br />
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[[3nsn]] - OfBHEX residues 23-594 + chitotriomycin<br />
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[[2xj7]] – BtBHEXB + castanospermine <br />
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[[2wzh]], [[2wzi]] - BtBHEXB (mutant) + oxazoline<br />
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[[2vvn]] - BtBHEX + thiazoline<br />
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[[2x0h]] - BtBHEXB Michaelis complex<br />
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[[2wca]], [[2vvs]] - BtBHEX + PUGNAc<br />
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[[2xm1]], [[2xm2]] - BtBHEXB + lactam derivative<br />
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[[4aiu]] - BtBHEXB + pyrazole derivative<br />
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[[2w66]], [[2w67]], [[2w4x]], [[2jiw]] – BtBHEXB + inhibitor<br />
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[[3gs6]], [[3gsm]], [[2oxn]] - VcBHEX + PUGNAc<br />
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[[1y65]] - VcBHEX + NAG<br />
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[[4gnv]] - BcBHEX + NAG<br />
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[[2yl8]] – SpnBHEX residues 181-614 (mutant) + NAG<br />
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[[2yl9]], [[2yla]] – SpnBHEX residues 627-1062 (mutant) + NAG<br />
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[[1c7s]] – SmBHEX + diNAG <br />
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[[1c7t]] - SmBHEX (mutant) + diNAG<br />
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[[3sur]] - PaBHEX + NAG derivative<br />
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[[3sus]] - PaBHEX + GAL-NAG derivative<br />
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[[3sut]] - PaBHEX + PUGNac<br />
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[[3suu]] - PaBHEX + GAL-PUGNac<br />
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[[3suv]] - PaBHEX + NHAC-DNJ<br />
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[[3suw]] - PaBHEX + NHAC-CAS
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**[[2gk1]] - hBHEXA α+β subunits + NGT<br />
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**[[1now]] - hBHEXB β subunit + GalNAc-isofagomine<br />
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**[[1np0]] - hBHEXB β subunit + intermediate analog<br />
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**[[3gh5]], [[3gh7]] - PaBHEX + GlcNAc<br />
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**[[4gvf]], [[4gvh]], [[4gvi]] - SeBHEX + GlcNAc derivative<br />
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**[[4hzm]] – SeBHEX + inhibitor<br />
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**[[1m01]] - SpBHEX + GlcNAc <br />
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**[[1m03]], [[1m04]] - SpBHEX (mutant) + GlcNAc<br />
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**[[1jak]] - SpBHEX + inhibitor<br />
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**[[1hp5]] - SpBHEX + intermediate analog<br />
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**[[2x0y]], [[2wb5]], [[2vur]] - CpBHEXB + inhibitor<br />
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**[[2ozn]] – CpBHEXB + hyaluronidase<br />
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**[[3ozo]] – OfBHEX residues 23-594 + NGT<br />
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**[[3ozp]] – OfBHEX residues 23-594 + PUGNac<br />
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**[[3nsn]] - OfBHEX residues 23-594 + chitotriomycin<br />
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**[[3wmb]], [[3wmc]] - OfBHEX + inhibitor<br />
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**[[5y0v]] - OfBHEX + berberine<br />
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**[[5y1b]] - OfBHEX (mutant) + berberine derivative<br />
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**[[2xj7]] – BtBHEXB + castanospermine <br />
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**[[2wzh]], [[2wzi]] - BtBHEXB (mutant) + oxazoline<br />
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**[[2vvn]] - BtBHEX + thiazoline<br />
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**[[2x0h]] - BtBHEXB Michaelis complex<br />
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**[[2wca]], [[2vvs]] - BtBHEX + PUGNAc<br />
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**[[2xm1]], [[2xm2]] - BtBHEXB + lactam derivative<br />
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**[[4aiu]] - BtBHEXB + pyrazole derivative<br />
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**[[2w66]], [[2w67]], [[2w4x]], [[2jiw]] – BtBHEXB + inhibitor<br />
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**[[3gs6]], [[3gsm]], [[2oxn]] - VcBHEX + PUGNAc<br />
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**[[1y65]] - VcBHEX + NAG<br />
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**[[4gnv]] - BcBHEX + NAG<br />
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**[[4mss]], [[5utr]] – BcBHEX + inhibitor<br />
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**[[6dte]] – BcBHEX + cyclophellitol<br />
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**[[5utp]], [[5utq]] – BcBHEX + PUGNAc<br />
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**[[2yl8]] – SpnBHEX catalytic domain (mutant) + NAG<br />
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**[[4az5]], [[4az6]], [[4az7]], [[4az8]], [[4azc]], [[4azg]], [[4azh]] – SpnBHEX catalytic domain + inhibitor<br />
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**[[4azi]] – SpnBHEX catalytic domain (mutant) + inhibitor<br />
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**[[2yl9]], [[2yla]] – SpnBHEX residues 627-1062 (mutant) + NAG<br />
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**[[1c7s]] – SmBHEX + diNAG <br />
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**[[1c7t]] - SmBHEX (mutant) + diNAG<br />
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**[[3sur]] - PaBHEX + NAG derivative<br />
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**[[3sus]] - PaBHEX + GAL-NAG derivative<br />
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**[[3sut]] - PaBHEX + PUGNac<br />
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**[[3suu]] - PaBHEX + GAL-PUGNac<br />
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**[[3suv]] - PaBHEX + NHAC-DNJ<br />
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**[[3suw]] - PaBHEX + NHAC-CAS<br />
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**[[5g5k]] - PaBHEX + jirimycin derivative<br />
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**[[5ly7]] - PaBHEX (mutant) + jirimycin derivative<br />
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**[[6jtk]] – Ng BHEX + Glc derivative<br />
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**[[6jtj]] – Ng BHEX + NAG derivative<br />
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}}
==References==
==References==
<references/>
<references/>
[[Category:Topic Page]]
[[Category:Topic Page]]
__NOEDITSECTION__
__NOEDITSECTION__

Current revision

Human β-hexosaminidase (PDB code 2gjx)

Drag the structure with the mouse to rotate


3D Structures of Beta-Hexosaminidase

Updated on 04-August-2022

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
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