Beta-Hexosaminidase

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<applet load="" size="600" color="" frame="true" spin="on" Scene ="Beta-Hexosaminidase/Opening/3" align="right" caption="Crystal Structure of Human β-Hexosaminidase, ([[2gjx]])"/>
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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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===Structure of Human β-Hexosaminidase A and its association with Tay-Sachs disease===
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=== {{Nowrap|Structure of Human β-Hexosaminidase A}} and its association with Tay-Sachs disease===
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&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;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 in 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 a flexible loop α280GSEP283 structure that is removed post-translational from β, and to the presence of αAsn423 and αArg424. The loop structure is involved in binding the GM2 activator protein, while αArg424 is critical for binding the carboxylate group of the N-acetyl-neuraminic acid residue of GM2. Two active sites are present in HexA dimmer; one comprising residues from the α-subunit (R178 D207 H262 E323 D322 W373 W392 W460 Y421 R424 N423 E462) and a second one from residues of the β-subunit (R211 D240 H294 E355 D354 W405 W424 Y450 L453 D452 E491 W489). These active sites are located at the opening of a TIM barrels at the interface between the α and β-subunits. The HexA undergoes glycosylation at the α and β-subunits; αAsn115, αAsn157 and αAsn295 βAsn84, βAsn142, βAsn190 and βAsn327. Mutations (see Table) in the a-subunit are associate with TS disease and with Late Onset Tay Sachs disease (LOTS). Interestingly, αGly269S 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__
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== 3D Structures of Beta-Hexosaminidase ==
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Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
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{{#tree:id=OrganizedByTopic|openlevels=0|
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*Beta-hexosaminidase
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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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*Beta-hexosaminidase binary complexes
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===References===
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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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}}
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==References==
<references/>
<references/>
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[[Category:Topic Page]]
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Current revision

Human β-hexosaminidase (PDB code 2gjx)

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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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