Glucuronidase
This tutorial illustrates the quaternary structures of the human and E. coli β-glucuronidase enzyme. Functionβ-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]. RelevanceThe E. coli form of β-glucuronidase (overall structure, 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]. DiseaseDeficiencies in the human form of β-glucuronidase (overall structure, 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 highlightsThe structure of E. coli β-glucuronidase contains 4 identical subunits (homotetramer). The structure of the enzyme contains both α-helix (blue) and β-sheet (yellow) forms of secondary structure, with the β-sheets arranged in β-barrels in an immunoglobulin-like fold. The catalytic pocket of BGUS contains two catalytic Glu residues[6]. 3D Structures of glucuronidase
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