View source for Beta-glucuronidase

{{for|α-glucuronidase|alpha-glucuronidase}}
{{redirect|GUSB|the airport with this IATA code|Sambailo Airport}}
{{enzyme
| Name = beta-glucuronidase
| EC_number = 3.2.1.31
| CAS_number = 9001-45-0
| IUBMB_EC_number = 3/2/1/31
| GO_code = 0004566
| image = Beta-Glucuronidase Homotetramer.jpg
| width = 
| caption = Glucuronidase [[tetrameric protein|Homotetramer]]<br/>(assumed biological unit)<ref name="Jain">{{PDB|1BHG}}; {{cite journal |vauthors=Jain S, Drendel WB, Chen ZW, Mathews FS, Sly WS, Grubb JH | title = Structure of human beta-glucuronidase reveals candidate lysosomal targeting and active-site motifs | journal = Nat. Struct. Biol. | volume = 3 | issue = 4 | pages = 375–81 |date=April 1996 | pmid = 8599764 | doi = 10.1038/nsb0496-375| url = | issn = }}</ref>
}}
{{infobox protein
| name = glucuronidase, beta
| caption = Beta-glucuronidase asymmetric unit showing active site residues Glu451, Tyr504, and Glu540, along with the potentially supporting Asn450 residue<ref name=Jain/>
| image = Beta Glucuronidase Dimer.jpg
| width = 
| HGNCid = 4696
| Symbol = GUSB
| AltSymbols = 
| EntrezGene = 2990
| OMIM = 611499
| RefSeq = NM_000181
| UniProt = P08236
| PDB = 
| ECnumber = 3.2.1.31
| Chromosome = 7
| Arm = q
| Band = 11.21
| LocusSupplementaryData = 
}}
'''Beta-glucuronidases''' are members of the [[glycosidase]] family of [[enzyme]]s that [[catalyze]] breakdown of complex [[carbohydrates]].<ref name=Catalysis>{{cite book |last = Sinnott |first = Michael, ed. |title = Comprehensive Biological Catalysis |volume=1 |publisher = Academic Press |year = 1998 |location = Manchester, UK |pages = 119–138 |isbn = 0-12-646864-8}}</ref> Human β-glucuronidase is a type of glucuronidase (a member of glycosidase Family 2) that catalyzes [[hydrolysis]] of β-D-[[glucuronic acid]] residues from the non-reducing end of [[Glycosaminoglycan|mucopolysaccharides]] (also referred to as [[glycosaminoglycan]]s) such as [[heparan sulfate]].<ref name="Catalysis"/><ref name=McCarter>{{cite journal | doi=10.1016/0959-440X(94)90271-2 |vauthors=McCarter JD, Withers SG | title=Mechanisms of enzymatic glycoside hydrolysis | journal=Curr Opin Struct Biol | volume=4 | issue=6 | pages=885–892 | year=1994 | pmid=7712292}}</ref><ref name=Sinnott>{{cite journal | doi=10.1021/cr00105a006 | author=Sinnott ML | title=Catalytic mechanisms of enymatic glycosyl transfer | journal=Chem Rev | volume=90 | pages=1171–1202 | year=1990}}</ref> Human β-glucuronidase is located in the [[lysosome]].<ref name = Metabolic>{{cite book |last = Nyhan |first = William L. |author2=Bruce Barshop|author3=Pinar Ozand |title = Atlas of Metabolic Diseases |edition=2 |publisher = Hodder Arnold |year = 2005 |location = London, UK |pages = 501–503, 546–550 |isbn = 0-340-80970-1}}</ref> In the gut, brush border β-glucuronidase converts conjugated [[bilirubin]] to the unconjugated form for reabsorption. Beta-glucuronidase is also present in breast milk, which contributes to [[neonatal jaundice]]. The protein is encoded by the '''''GUSB''''' gene.<ref name="pmid3468507">{{cite journal |vauthors=Oshima A, Kyle JW, Miller RD, Hoffmann JW, Powell PP, Grubb JH, Sly WS, Tropak M, Guise KS, Gravel RA | title = Cloning, sequencing, and expression of cDNA for human beta-glucuronidase | journal = Proc Natl Acad Sci U S A | volume = 84 | issue = 3 | pages = 685–9 |date=Mar 1987 | pmid = 3468507 | pmc = 304280 | doi =10.1073/pnas.84.3.685  }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: GUSB glucuronidase, beta| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2990| accessdate = }}</ref>

== Structure ==
Human β-glucuronidase is synthesized as an 80 [[kDa]] [[monomer]] (653 [[amino acids]]) before [[proteolysis]] removes 18 amino acids from the [[C-terminal]] end to form a 78 kDa monomer.<ref name=IslamA>{{cite journal | vauthors=Islam MR, Grubb JH, Sly WS | title=C-terminal processing of human beta-glucuronidase. The propeptide is required for full expression of catalytic activity, intracellular retention, and proper phosphorylation. | journal=J Biol Chem | volume=268 | issue=16 | pages=12193–12198 | year=1993 | pmid=8226771}}</ref><ref name=Shipley>{{cite journal |vauthors=Shipley JM, Grubb JH, Sly WS | title=The role of glycosylation and phosphorylation in the expression of active human β-glucuronidase | journal=J Biol Chem | volume=268 | issue=16 | pages=12193–12198 | year=1993 | pmid=8505339}}</ref>
Beta-glucuronidase exists as a 332 kDa [[tetrameric protein|homotetramer]].<ref name=Sakon>{{cite journal |vauthors=Kim HW, Mino K, Ishikawa K |title=Crystallization and preliminary X-ray analysis of endoglucanase from Pyrococcus horikoshii |journal=Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. |volume=64 |issue=Pt 12 |pages=1169–71 |date=December 2008 |pmid=19052378 |pmc=2593689 |doi=10.1107/S1744309108036919 |url=}}</ref>  Beta-glucuronidase contains several notable structural formations, including a type of [[beta barrel]] known as a jelly roll barrel and a [[TIM barrel]].<ref name = Jain />

==Mechanism of catalysis==

Human β-glucuronidase is [[Homology (biology)|homologous]] to the ''[[Escherichia coli]]'' enzyme [[β-galactosidase]].<ref name=HenrissatB>{{cite journal |vauthors=Henrissat B, Bairoch A | title=New families in the classification of glycosyl hydrolases | journal=Biochem J | volume=293 | pages=781–788 | year=1993 | pmid=8352747 | pmc=1134435 | doi=10.1042/bj2930781}}</ref><ref name=HenrissatA>{{cite journal | author=Henrissat B | title=A classification of glycosyl hydrolases based on amino-acid sequence similarities | journal=Biochem J | volume=280 | pages=309–316 | year=1991 | pmid=1747104 | pmc=1130547 | doi=10.1042/bj2800309}}</ref> This homologous relationship, along with the knowledge that glycosidases often perform hydrolysis catalyzed by two acidic [[Residue (chemistry)|residues]], enabled the development of a mechanistic hypothesis. This hypothesis proposes that the two [[glutamic acid]] residues Glu540 and Glu451 are the [[nucleophilic]] and [[acidic]] residues, respectively, and that the [[tyrosine]] residue Tyr504 is also involved in catalysis.  
In support of this hypothesis, experimental [[mutations]] in any of these three residues result in large decreases of enzymatic activity. Increased activity of an E451A  mutant enzyme (where Glu451 is replaced with an [[alanine]] residue) after addition of [[azide]] is consistent with Glu451 as the acid/base residue.<ref name=Islam>{{cite journal |doi=10.1074/jbc.274.33.23451 |vauthors=Islam MR, Tomatsu S, Shah GN, Grubb JH, Sanjeev J, Sly WS | title=Active site residues of human β-glucuronidase. Evidence for Glu(540) as the nucleophile and Glu(451) as the acid-base residue. |journal=J Biol Chem |volume=274 |issue=33 |pages=23451–23455 |year=1999 |pmid=10438523}}</ref>  Using analysis of labeled β-glucuronidase [[peptides]] after hydrolysis of a substrate that enters a very stable intermediate stage, researchers have determined that Glu540 is the nucleophilic residue.<ref name=Wong>{{cite journal | doi=10.1074/jbc.273.51.34057 |vauthors=Wong AW, He S, Grubb JH, Sly WS, Withers SG | title=Identification of Glu-540 as the catalytic nucleophile of human β-glucuronidase using electrospray mass spectrometry | journal=J Biol Chem | volume=273 | issue=51 |  pages=34057–34062 | year=1996 | pmid=9852062}}</ref>

Though the particular type of [[nucleophilic substitution]] employed by β-glucuronidase is unclear, evidence for the mechanisms of their homologues in the glycosidase family suggests that these reactions are qualitatively [[SN2|S<sub>N</sub>2 reactions]].  The reactions proceed through a [[transition state]] with [[oxocarbenium]] ion characteristics.  Initially, these mechanisms, because of this oxocarbenium characteristic of the transition state, were suggested to be [[SN1|S<sub>N</sub>1 reactions]] proceeding through a discrete oxocarbenium ion [[reaction intermediate|intermediate]]. However, more recent evidence suggests that these oxocarbenium ion states have lifetimes of 10 femtoseconds - 0.1 nanoseconds (similar to that of a [[quantum vibration|bond vibration]] period).  These lifetimes are too short to assign to a reaction intermediate.   From this evidence, it appears that these reactions, while having an S<sub>N</sub>1 appearance due to the oxocarbenium ion characteristics of their transition states, must be qualitatively S<sub>N</sub>2 reactions.<ref name="Catalysis"/>

The specific activity of Tyr504 in the catalytic mechanism is unclear.<ref name=Islam/> Through comparison to the structural data of the homologous enzyme [[xylanase]], it has been suggested that Tyr504 of β-glucuronidase might stabilize the leaving nucleophile (Glu540) or modulate its activity.<ref name=EzCatDB/>

In addition to these residues, a conserved [[asparagine]] residue (Asn450) has been suggested to stabilize the substrate through the action of a hydrogen bond at the 2-hydroxyl group of the sugar substrate.<ref name=Sakon/><ref name=HenrissatC/>
{{Clear}}
{{Gallery
| title =
| width = 225
| height = 225
| lines = 4
| Image:Heparan sulfate.JPG|Repeating unit of the heparan sulfate [[Substrate (biochemistry)|substrate]] of β-glucuronidase
| Image:Beta Glucuronidase Active Site Pocket.jpg|Surface depiction of active site pocket of β-glucuronidase with catalytic residues shown<ref name=Jain/>
| Image:Mechanism Of Beta Glucuronidase.JPG|Mechanism of β-glucuronidase hydrolysis of a sugar substrate with high energy [[transition state]]s showing oxocarbenium ion character depicted<ref name=Wong/>
| Image:File-Predicted Tyr 504 activity in Beta Glucuronidase.JPG|Potential stabilization of the nucleophilic residue Glu540 by Tyr504 in β-glucuronidase<ref name=EzCatDB>{{cite web |url=http://mbs.cbrc.jp/EzCatDB/search/get.do?dbcode=T00066 |title=EzCatDB: T00066 |work=EzCatDB: A Database of Catalytic Mechanisms |accessdate=2008-12-12 |deadurl=yes |archiveurl=https://web.archive.org/web/20090617045022/http://mbs.cbrc.jp/EzCatDB/search/get.do?dbcode=T00066 |archivedate=2009-06-17 |df= }}</ref>
| Image:Predicted Asn 450 activity in beta glucuronidase.JPG|Predicted activity of the conserved Asn450 residue in stabilization of the β-glucuronidase sugar substrate<ref name=Sakon/><ref name=HenrissatC>{{cite journal | doi=10.1073/pnas.92.15.7090 |vauthors=Henrissat B, Callebaut I, Fabrega S, Lehn P, Mornon JP, Davies G | title=Conserved catalytic machinery and the prediction of a common fold for several families of glycosyl hydrolases | journal=Proc Natl Acad Sci USA | volume=92 | issue=15 | pages=7090–7094 | year=1995 | pmid=7624375 | pmc=41477}}</ref>
| Image:Possible Salt Bridge Human Beta Glucuronidase.jpg|Potential salt bridge between Glu352 and Arg216 in human beta-glucuronidase<ref name=Jain/><ref name=Fyfe/>
}}

==Sly syndrome==
{{main article|Sly syndrome}}
Deficiencies in β-glucuronidase result in the non recessive inherited [[metabolic disease]] known as [[Sly syndrome]] or [[Mucopolysaccharidosis]] VII.  A deficiency in this enzyme results in the build-up of non-hydrolyzed mucopolysaccharides in the patient.  This disease can be extremely debilitating for the patient or can result in [[hydrops fetalis]] prior to birth.  In addition, mental retardation, short stature, coarse facial features, spinal abnormalities, and enlargement of liver and spleen are observed in surviving patients.<ref name = Metabolic/> This disease has been modeled in a strain of mice as well as a family of dogs.<ref name=Birkenmeier>{{cite journal | doi=10.1172/JCI114010 | author=Birkenmeier EH | author-link2 = Muriel Davisson  | author2=Davisson MT  | author3=Beamer WG | author4=Ganschow RE | author5=Vogler CA | author6=Gwynn B | author7=Lyford KA | author8=Maltais LM | author9=Wawrzyniak CJ | title=Murine mucopolysaccaaridosis type VII: Characterization of a mouse with beta-glucuronidase deficiency | journal=J Clin Invest | volume=83 | issue=4 | pages=1258–1266 | year=1989 | pmid=2495302 | pmc=303816}}</ref><ref name=Haskins>{{cite journal |vauthors=Haskins ME, Desnick RJ, DiFerrante N, Jezyk PF, Patterson DF | title=β-glucuronidase deficiency in a dog: A model of human mucopolysaccharidosis VII | journal=Pediatr Res | volume=18 | issue=10 | pages=980–984 | year=1984 | pmid=6436780 | doi=10.1203/00006450-198410000-00014}}</ref> More recently researchers have discovered a feline family that exhibits deficiencies in β-glucuronidase activity.  The source of this reduction of activity  has been identified as an E351K mutation (Glu351 is mutated to a lysine residue). Glu351 is conserved in mammalian species, which suggests an important function for this residue.  Examination of the human [[X-ray crystallography|X-ray crystal]] structure suggests that this residue (Glu352 in the human enzyme), which is buried deep within the [[TIM barrel]] [[protein domain|domain]], may be important for stabilization of the [[tertiary structure]] of the enzyme.<ref name=Fyfe>{{cite journal | doi=10.1006/geno.1999.5825 |vauthors=Fyfe JC, Kurzhals RL, Lassaline ME, Henthorn PS, Alur PR, Wang P, Wolfe JH, Giger U, Haskins ME, Patterson DF, Sun H, Jain S, Yuhki N | title=Molecular basis of feline β-glucuronidase deficiency: An animal model of mucopolysaccharidosis VII | journal=Genomics | volume=58 | issue=2 | pages=121–128 | year=1999 | pmid=10366443}}</ref> In the crystal structure, it appears that Arg216, a member of the jelly roll domain of the protein, forms a [[Salt bridge (protein)|salt bridge]] with Glu352; therefore, Glu352 is likely involved in stabilizing the interaction between two different three-dimensional domains of the enzyme.<ref name=Jain/>

==Molecular applications: use as a reporter gene==
In [[molecular biology]], β-glucuronidase is used as a [[reporter gene]] to monitor [[gene expression]] in mammalian and plant cells. Monitoring β-glucuronidase activity through the use of a [[GUS assay]] allows determination of the spatial and temporal expression of the gene in question.<ref name="pmid7867935">{{cite journal |vauthors=Marathe SV, McEwen JE | title = Vectors with the gus reporter gene for identifying and quantitating promoter regions in Saccharomyces cerevisiae | journal = Gene | volume = 154 | issue = 1 | pages = 105–7 |date=February 1995 | pmid = 7867935 | doi = 10.1016/0378-1119(94)00845-J| url = | issn = }}</ref>

* Molecular graphics images were produced using the UCSF Chimera package from the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIH P41 RR-01081).<ref name="Petterson">{{cite journal |vauthors=Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE | title = UCSF Chimera--a visualization system for exploratory research and analysis | journal = J Comput Chem | volume = 25 | issue = 13 | pages = 1605–12 |date=October 2004 | pmid = 15264254 | doi = 10.1002/jcc.20084 | url = | issn = }}</ref>

==See also==
*[[Alpha-glucuronidase]]
*[[Glucuronosyl-disulfoglucosamine glucuronidase]]
*[[Glycyrrhizinate beta-glucuronidase]]

==References==
{{reflist|2}}

== Further reading ==
{{refbegin | 2}}
* {{cite journal  | author=George J.|title=Elevated serum beta-glucuronidase reflects hepatic lysosomal fragility following toxic liver injury in rats. |journal=Biochem Cell Biol  |volume=86|issue= 3 |pages= 235–243. |year= 2008 |pmid= 18523484 |doi= 10.1139/O08-038 }}
{{PBB_Further_reading 
| citations = 
*{{cite journal  |vauthors=Bell CE, Sly WS, Brot FE |title=Human beta-glucuronidase deficiency mucopolysaccharidosis: identification of cross-reactive antigen in cultured fibroblasts of deficient patients by enzyme immunoassay. |journal=J. Clin. Invest. |volume=59 |issue= 1 |pages= 97–105 |year= 1977 |pmid= 401508 |doi=10.1172/JCI108627  | pmc=333336  }}
*{{cite journal   |vauthors=Tanaka J, Gasa S, Sakurada K, etal |title=Characterization of the subunits and sugar moiety of human placental and leukemic beta-glucuronidase. |journal=Biol. Chem. Hoppe-Seyler |volume=373 |issue= 1 |pages= 57–62 |year= 1992 |pmid= 1311180 |doi=  10.1515/bchm3.1992.373.1.57}}
*{{cite journal   |vauthors=Wolfe JH, Sands MS, Barker JE, etal |title=Reversal of pathology in murine mucopolysaccharidosis type VII by somatic cell gene transfer. |journal=Nature |volume=360 |issue= 6406 |pages= 749–53 |year= 1993 |pmid= 1465145 |doi= 10.1038/360749a0 }}
*{{cite journal   |vauthors=Tomatsu S, Fukuda S, Sukegawa K, etal |title=Mucopolysaccharidosis type VII: characterization of mutations and molecular heterogeneity. |journal=Am. J. Hum. Genet. |volume=48 |issue= 1 |pages= 89–96 |year= 1991 |pmid= 1702266 |doi=  | pmc=1682743  }}
*{{cite journal   |vauthors=Shipley JM, Miller RD, Wu BM, etal |title=Analysis of the 5' flanking region of the human beta-glucuronidase gene. |journal=Genomics |volume=10 |issue= 4 |pages= 1009–18 |year= 1991 |pmid= 1916806 |doi=10.1016/0888-7543(91)90192-H  }}
*{{cite journal   |vauthors=Ono M, Taniguchi N, Makita A, etal |title=Phosphorylation of beta-glucuronidases from human normal liver and hepatoma by cAMP-dependent protein kinase. |journal=J. Biol. Chem. |volume=263 |issue= 12 |pages= 5884–9 |year= 1988 |pmid= 2833520 |doi=  }}
*{{cite journal   |vauthors=Guise KS, Korneluk RG, Waye J, etal |title=Isolation and expression in Escherichia coli of a cDNA clone encoding human beta-glucuronidase. |journal=Gene |volume=34 |issue= 1 |pages= 105–10 |year= 1985 |pmid= 3924735 |doi=10.1016/0378-1119(85)90300-2  }}
*{{cite journal  |vauthors=Ho YC, Ho LH, Ho KJ |title=Human hepatic beta-glucuronidase: an enzyme kinetic study. |journal=Enzyme |volume=33 |issue= 1 |pages= 9–17 |year= 1985 |pmid= 3987656 |doi=  }}
*{{cite journal   |vauthors=Shipley JM, Klinkenberg M, Wu BM, etal |title=Mutational analysis of a patient with mucopolysaccharidosis type VII, and identification of pseudogenes. |journal=Am. J. Hum. Genet. |volume=52 |issue= 3 |pages= 517–26 |year= 1993 |pmid= 7680524 |doi=  | pmc=1682147  }}
*{{cite journal  |vauthors=Vervoort R, Lissens W, Liebaers I |title=Molecular analysis of a patient with hydrops fetalis caused by beta-glucuronidase deficiency, and evidence for additional pseudogenes. |journal=Hum. Mutat. |volume=2 |issue= 6 |pages= 443–5 |year= 1994 |pmid= 8111412 |doi= 10.1002/humu.1380020604 }}
*{{cite journal  |vauthors=Wu BM, Sly WS |title=Mutational studies in a patient with the hydrops fetalis form of mucopolysaccharidosis type VII. |journal=Hum. Mutat. |volume=2 |issue= 6 |pages= 446–57 |year= 1994 |pmid= 8111413 |doi= 10.1002/humu.1380020605 }}
*{{cite journal  |vauthors=Maruyama K, Sugano S |title=Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. |journal=Gene |volume=138 |issue= 1–2 |pages= 171–4 |year= 1994 |pmid= 8125298 |doi=10.1016/0378-1119(94)90802-8  }}
*{{cite journal  |vauthors=Moullier P, Bohl D, Heard JM, Danos O |title=Correction of lysosomal storage in the liver and spleen of MPS VII mice by implantation of genetically modified skin fibroblasts |journal=Nat. Genet. |volume=4 |issue= 2 |pages= 154–9 |year= 1993 |pmid= 8348154 |doi= 10.1038/ng0693-154 }}
*{{cite journal  |vauthors=Shipley JM, Grubb JH, Sly WS |title=The role of glycosylation and phosphorylation in the expression of active human beta-glucuronidase |journal=J. Biol. Chem. |volume=268 |issue= 16 |pages= 12193–8 |year= 1993 |pmid= 8505339 |doi=  }}
*{{cite journal  |vauthors=Nishimura Y, Kato K, Himeno M |title=Biochemical characterization of liver microsomal, Golgi, lysosomal, and serum beta-glucuronidases in dibutyl phosphate-treated rats |journal=J. Biochem. |volume=118 |issue= 1 |pages= 56–66 |year= 1996 |pmid= 8537326 |doi=  }}
*{{cite journal   |vauthors=Jain S, Drendel WB, Chen ZW, etal |title=Structure of human beta-glucuronidase reveals candidate lysosomal targeting and active-site motifs |journal=Nat. Struct. Biol. |volume=3 |issue= 4 |pages= 375–81 |year= 1996 |pmid= 8599764 |doi=10.1038/nsb0496-375  }}
*{{cite journal   |vauthors=Vervoort R, Islam MR, Sly WS, etal |title=Molecular analysis of patients with beta-glucuronidase deficiency presenting as hydrops fetalis or as early mucopolysaccharidosis VII |journal=Am. J. Hum. Genet. |volume=58 |issue= 3 |pages= 457–71 |year= 1996 |pmid= 8644704 |doi=  | pmc=1914559  }}
*{{cite journal  |vauthors=Bonaldo MF, Lennon G, Soares MB |title=Normalization and subtraction: two approaches to facilitate gene discovery |journal=Genome Res. |volume=6 |issue= 9 |pages= 791–806 |year= 1997 |pmid= 8889548 |doi=10.1101/gr.6.9.791  }}
*{{cite journal  |vauthors=Dentino AR, Raj PA, De Nardin E |title=Subtle differences between human and rabbit neutrophil receptors shown by the secretagogue activity of constrained formyl peptides |journal=Arch. Biochem. Biophys. |volume=337 |issue= 2 |pages= 267–74 |year= 1997 |pmid= 9016822 |doi= 10.1006/abbi.1996.9791 }}
}}
{{refend}}
{{PDB Gallery|geneid=2990}}

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==External links==
* {{MeshName|Glucuronidase}}
* [http://www.reportergene.com/search/label/other%20reporters Updated research on reporter glucuronidase] and other reporters from Reportergene
* [https://web.archive.org/web/20090617045022/http://mbs.cbrc.jp/EzCatDB/search/get.do?dbcode=T00066 Database of Catalytic Mechanism Research] and other information on beta-glucuronidase

{{Glycosaminoglycan catabolism}}
{{Sugar hydrolases}}
{{Enzymes}}
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[[Category:EC 3.2.1]]