Glucuronidase

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Revision as of 07:55, 11 July 2019

β-glucuronidase complex with glucouronic acid, glycerol and PO4 ion (PDB code 3vnz).

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This tutorial illustrates the quaternary structures of the human and E. coli β-glucuronidase enzyme.

1 Function
2 Relevance
3 Disease
4 Structural highlights
5 3D Structures of glucuronisidase

Function

β-glucuronidase is a ubiquitous enzyme that catalyzes the hydrolysis of a glucuronide moiety from a variety of substrates. This enzyme is present throughout biological systems, including bacteria up through humans^[1]. α-glucuronidase catalyzes the conversion of α-D-glucuronoside to alcohol and D-glucuronate^[2].

Relevance

The E. coli form of β-glucuronidase (, PDB ID 3lpf^[3]) is associated with the side effects seen with administration of the cancer chemotherapy drug CPT-11. This drug gets converted to SN38, a topoisomerase inhibitor, by the liver. The body adds a glucuronide group to this molecule (now SN38-G) to mark it for elimination, which partially occurs through the intestine. Once in the intestine, bacterial β-glucuronidase cleaves the glucuronide from the SN38-G, releasing the SN38 into the intestinal lumen. The released SN38 prevents cell division, compromising the epithelial lining of the intestines, a painful and dangerous side-effect of CPT-11 administration.

Selective inhibition of bacterial β-glucuronidase is desired to alleviate this side-effect of CPT-11 treatment, hopefully without inhibiting the human form of the enzyme^[4].

Disease

Deficiencies in the human form of β-glucuronidase (, PDB ID 3hn3^[5]) is associated with a disease known as Sly Syndrome (AKA Mucopolysaccharidosis VII -- MPS VII). This disease is characterized by mental retardation, short stature, macrocephaly, and enlarged joints. As is commonly seen with genetic disorders, patients with this disease present a spectrum of symptom severity, but the disease is always ultimately fatal.

Structural highlights

The structure of E. coli β-glucuronidase contains 4 identical subunits ().

The structure of the enzyme contains both α-helix (blue) and β-sheet (yellow) forms of , with the β-sheets arranged in β-barrels in an immunoglobulin-like fold.

The of BGUS contains ^[6].

3D Structures of glucuronisidase

Glucuronisidase 3D structures

References

↑ Jain S, Drendel WB, Chen ZW, Mathews FS, Sly WS, Grubb JH. Structure of human beta-glucuronidase reveals candidate lysosomal targeting and active-site motifs. Nat Struct Biol. 1996 Apr;3(4):375-81. PMID:8599764
↑ Nagy T, Emami K, Fontes CM, Ferreira LM, Humphry DR, Gilbert HJ. The membrane-bound alpha-glucuronidase from Pseudomonas cellulosa hydrolyzes 4-O-methyl-D-glucuronoxylooligosaccharides but not 4-O-methyl-D-glucuronoxylan. J Bacteriol. 2002 Sep;184(17):4925-9. PMID:12169619
↑ doi: https://dx.doi.org/10.2210/pdb3lpf/pdb
↑ Sparreboom A, de Jonge MJ, de Bruijn P, Brouwer E, Nooter K, Loos WJ, van Alphen RJ, Mathijssen RH, Stoter G, Verweij J. Irinotecan (CPT-11) metabolism and disposition in cancer patients. Clin Cancer Res. 1998 Nov;4(11):2747-54. PMID:9829738
↑ doi: https://dx.doi.org/10.2210/pdb3hn3/pdb
↑ Michikawa M, Ichinose H, Momma M, Biely P, Jongkees S, Yoshida M, Kotake T, Tsumuraya Y, Withers SG, Fujimoto Z, Kaneko S. Structural and biochemical characterization of glycoside hydrolase family 79 beta-glucuronidase from Acidobacterium capsulatum. J Biol Chem. 2012 Apr 20;287(17):14069-77. Epub 2012 Feb 24. PMID:22367201 doi:http://dx.doi.org/10.1074/jbc.M112.346288

^[1] ^[2]

Proteopedia Page Contributors and Editors (what is this?)

Michal Harel, Kimberly Lane, Alexander Berchansky

Retrieved from "http://52.214.119.220/wiki/index.php/Glucuronidase"

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 </StructureSection>
-== 3D Structures of glucuronisidase ==
-Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
-{{#tree:id=OrganizedByTopic|openlevels=0|
-*'''α-D-glucuronidase'''
-**[[1gqi]] – PcAGUS – ''Pseudomonas cellulosa'' <br />
-**[[1k9d]], [[1mqp]] – GsAGUS – ''Geobacillus stearothermophilus'' <br />
-**[[1mqr]] – GsAGUS (mutant)  <br />
-**[[4c90]], [[4c91]] – AGUS – ''Bacteroides ovatus''  <br />
-**[[5c70]] – AoAGUS – ''Aspergillus oryzae''  <br />
-**[[6ncy]] – FsAGUS – ''Fusicatenibacter saccharivorans''  <br />
-*α-D-glucuronidase binary complex
-**[[1gqj]] – PcAGUS + xylobiose <br />
-**[[1gqk]] – PcAGUS + glucuronic acid <br />
-**[[1mqq]] – GsAGUS + glucuronic acid <br />
-**[[1k9e]] – GsAGUS (mutant) + methyl-glucuronic acid <br />
-**[[1k9f]] – GsAGUS (mutant) + aldotetraouronic acid <br />
-**[[1h41]] – PcAGUS (mutant) + aldotriuronic acid <br />
-**[[5c71]] – AoAGUS + glycyrrhetinic acid monoglucuronide<br />
-**[[6ncz]] – FsAGUS + glucuronide derivative <br />
-*α-D-glucuronidase ternary complex
-**[[1gql]] – AGUS + glucuronic acid + xylotriose – ''Cellvibrio japonicus''<br />
-**[[1l8n]] – GsAGUS (mutant) + methyl-glucuronic acid + xylotriose<br />
-*'''β-glucuronidase'''
-**[[1bhg]], [[3hn3]] – hBGUS – human <br />
-**[[3k46]] – EcBGUS – ''Escherichia coli'' <br />
-**[[3k4a]] – EcBGUS (mutant) <br />
-**[[3vny]] – AcBGUS – ''Acidobacterium capsulatum'' <br />
-**[[4jkk]], [[4jkl]] – BGUS – ''Streptococcus agalactiae'' <br />
-**[[6mvg]], [[6ec6]], [[5z18]] – RgBGUS – ''Ruminococcus gnavus'' <br />
-**[[6eca]] – BGUS – ''Lactobacillus rhamnosus''<br />
-**[[6d7j]] – BGUS – ''Parabacterioides merdae'' <br />
-*β-glucuronidase complex
-**[[3vnz]] – AcBGUS + glucuronic acid <br />
-**[[3vo0]] – AcBGUS + glucuronic acid derivative<br />
-**[[5g0m]], [[5g0q]] – AcBGUS + acyl cyclophellitol aziridine <br />
-**[[5l77]] – AcBGUS (mutant) + probe<br />
-**[[3k4d]] – EcBGUS + glucaro-D-lactam <br />
-**[[3lpf]], [[3lpg]], [[4jhz]], [[5czk]] – EcBGUS + inhibitor <br />
-**[[4jkm]] – CpBGUS + MBP – ''Clostridium perfringens'' <br />
-**[[6cxs]] – CpBGUS + MBP + inhibitor<br />
-**[[6d4o]] – BGUS + glucuronic acid derivative – ''Eubacterium eligens''<br />
-**[[5z19]] – RgBGUS (mutant) + uronic isofagomine <br />
-}}
 == References ==

Glucuronidase

From Proteopedia

Revision as of 07:55, 11 July 2019

Contents

Function

Relevance

Disease

Structural highlights

3D Structures of glucuronisidase

References

Proteopedia Page Contributors and Editors (what is this?)

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