Beta-Hexosaminidase

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=== {{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===
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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 [[Hexosaminidase (Hebrew)]].
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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)]].
== 3D Structures of Beta-Hexosaminidase ==
== 3D Structures of Beta-Hexosaminidase ==
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*Beta-hexosaminidase
*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 />
**[[2xpk]], [[2w1n]] – CpBHEXB – ''Clostridium perfringens''<br />
**[[2xpk]], [[2w1n]] – CpBHEXB – ''Clostridium perfringens''<br />
**[[2o4e]] – CpBHEXB - NMR<br />
**[[2o4e]] – CpBHEXB - NMR<br />
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**[[2yl5]] – SpnBHEX residues 627-1064<br />
**[[2yl5]] – SpnBHEX residues 627-1064<br />
**[[2yl6]], [[2yll]], [[3rpm]] – SpnBHEX catalytic domain<br />
**[[2yl6]], [[2yll]], [[3rpm]] – SpnBHEX catalytic domain<br />
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**[[1qba]] – SmBHEX – ''Serratia marcescens''<br />
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**[[1qba]] – SmBHEX – ''Serratia marcescens''<br />
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**[[3lmy]], [[1o7a]], [[1nou]], [[1o7a]] – hBHEXB β subunit – human<br />
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**[[5bro]] - hBHEXB β subunit (mutant)<br />
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**[[2gjx]] - hBHEXA α+β subunits<br />
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**[[3nsm]] – OfBHEX residues 23-594 – ''Ostrinia furnacalis''<br />
**[[3nsm]] – OfBHEX residues 23-594 – ''Ostrinia furnacalis''<br />
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**[[4ais]] – BtBHEXB – ''Bacteroides thetaiotaomicron''<br />
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**[[4ais]], [[6q63]] – BtBHEXB – ''Bacteroides thetaiotaomicron''<br />
**[[4g6c]] – BcBHEX – ''Burkholderia cenocepacia''<br />
**[[4g6c]] – BcBHEX – ''Burkholderia cenocepacia''<br />
**[[4gvg]] - SeBHEX – ''Salmonella enterica''<br />
**[[4gvg]] - SeBHEX – ''Salmonella enterica''<br />
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**[[5g5u]], [[5g6t]] - PaBHEXB (mutant)<br />
**[[5g5u]], [[5g6t]] - PaBHEXB (mutant)<br />
**[[5oar]] - BHEXB – yellow mold<br />
**[[5oar]] - BHEXB – yellow mold<br />
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**[[6jti]], [[6jtl]] – NgBHEX – ''Neisseria gonorrhoeae''<br />
*Beta-hexosaminidase binary complexes
*Beta-hexosaminidase binary complexes
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**[[4gnv]] - BcBHEX + NAG<br />
**[[4gnv]] - BcBHEX + NAG<br />
**[[4mss]], [[5utr]] – BcBHEX + inhibitor<br />
**[[4mss]], [[5utr]] – BcBHEX + inhibitor<br />
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**[[6dte]] – BcBHEX + cyclophellitol<br />
**[[5utp]], [[5utq]] – BcBHEX + PUGNAc<br />
**[[5utp]], [[5utq]] – BcBHEX + PUGNAc<br />
**[[2yl8]] – SpnBHEX catalytic domain (mutant) + NAG<br />
**[[2yl8]] – SpnBHEX catalytic domain (mutant) + NAG<br />
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**[[5g5k]] - PaBHEX + jirimycin derivative<br />
**[[5g5k]] - PaBHEX + jirimycin derivative<br />
**[[5ly7]] - PaBHEX (mutant) + jirimycin derivative<br />
**[[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 />
}}
}}
==References==
==References==

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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