title: Large scale analysis of the mutational landscape in β-glucuronidase: A major player of mucopolysaccharidosis type VII.
abstract: The lysosomal storage disorders are a group of 50 unique inherited diseases characterized by unseemly lipid storage in lysosomes. These malfunctions arise due to genetic mutations that result in deficiency or reduced activities of the lysosomal enzymes, which are responsible for catabolism of biological macromolecules. Sly syndrome or mucopolysaccharidosis type VII is a lysosomal storage disorder associated with the deficiency of β-glucuronidase (EC 3.2.1.31) that catalyzes the hydrolysis of β-D-glucuronic acid residues from the non-reducing terminal of glycosaminoglycan. The effects of the disease causing mutations on the framework of the sequences and structure of β-glucuronidase (GUSBp) were analyzed utilizing a variety of bioinformatic tools. These analyses showed that 211 mutations may result in alteration of the biological activity of GUSBp, including previously experimentally validated mutations. Finally, we refined 90 disease causing mutations, which presumably cause a significant impact on the structure, function, and stability of GUSBp. Stability analyses showed that mutations p.Phe208Pro, p.Phe539Gly, p.Leu622Gly, p.Ile499Gly and p.Ile586Gly caused the highest impact on GUSBp stability and function because of destabilization of the protein structure. Furthermore, structures of wild type and mutant GUSBp were subjected to molecular dynamics simulation to examine the relative structural behaviors in the explicit conditions of water. In a broader view, the use of in silico approaches provided a useful understanding of the effect of single point mutations on the structure-function relationship of GUSBp.
authors.affiliation: Department of Chemistry, Durban University of Technology, Durban 4000, South Africa.
authors.forename: Faez Iqbal
authors.initials: FI
authors.lastname: Khan
authors.affiliation: Department of Chemistry, Durban University of Technology, Durban 4000, South Africa.
authors.forename: Mohd
authors.initials: M
authors.lastname: Shahbaaz
authors.affiliation: Department of Chemistry, Durban University of Technology, Durban 4000, South Africa.
authors.forename: Krishna
authors.initials: K
authors.lastname: Bisetty
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
authors.forename: Abdul
authors.initials: A
authors.lastname: Waheed
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
authors.forename: William S
authors.initials: WS
authors.lastname: Sly
authors.affiliation: Center for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India.
authors.forename: Faizan
authors.initials: F
authors.lastname: Ahmad
authors.affiliation: Center for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India. Electronic address: mihassan@jmi.ac.in.
authors.forename: Md Imtaiyaz
authors.initials: MI
authors.lastname: Hassan
mesh_terms: D019943:Amino Acid Substitution; D003198:Computer Simulation; D005966:Glucuronidase / Q000737:chemistry / Q000235:genetics; D006801:Humans; D056004:Molecular Dynamics Simulation; D016538:Mucopolysaccharidosis VII / Q000201:enzymology / Q000235:genetics; D020125:Mutation, Missense; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D005966:Glucuronidase
keywords: Enzyme deficiency; Lysosomal storage diseases; MD simulation; Mucopolysaccharidosis type VII; Mutation analysis; Sly syndrome; β-glucuronidase