title: A quaternary mechanism enables the complex biological functions of octameric human UDP-glucose pyrophosphorylase, a key enzyme in cell metabolism.
abstract: In mammals, UDP-glucose pyrophosphorylase (UGP) is the only enzyme capable of activating glucose-1-phosphate (Glc-1-P) to UDP-glucose (UDP-Glc), a metabolite located at the intersection of virtually all metabolic pathways in the mammalian cell. Despite the essential role of its product, the molecular basis of UGP function is poorly understood. Here we report the crystal structure of human UGP in complex with its product UDP-Glc. Beyond providing first insight into the active site architecture, we describe the substrate binding mode and intermolecular interactions in the octameric enzyme that are crucial to its activity. Importantly, the quaternary mechanism identified for human UGP in this study may be common for oligomeric sugar-activating nucleotidyltransferases. Elucidating such mechanisms is essential for understanding nucleotide sugar metabolism and opens the perspective for the development of drugs that specifically inhibit simpler organized nucleotidyltransferases in pathogens.
authors: Institute for Cellular Chemistry, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors: Jana Indra
authors: JI
authors: Führing
authors: Institute for Cellular Chemistry, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors: Johannes Thomas
authors: JT
authors: Cramer
authors: Institute for Cellular Chemistry, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors: Julia
authors: J
authors: Schneider
authors: Research Division for Structural Analysis, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors: Petra
authors: P
authors: Baruch
authors: Institute for Cellular Chemistry, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors: Rita
authors: R
authors: Gerardy-Schahn
authors: 1] Research Division for Structural Analysis, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany [2] Institute for Biophysical Chemistry, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors: Roman
authors: R
authors: Fedorov
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D005947:Glucose / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D053858:Metabolic Networks and Pathways; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D055503:Protein Multimerization; D055550:Protein Stability; D021122:Protein Subunits; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013816:Thermodynamics; D005957:UTP-Glucose-1-Phosphate Uridylyltransferase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014532:Uridine Diphosphate Glucose / Q000737:chemistry / Q000378:metabolism
chemical_list: D021122:Protein Subunits; D005957:UTP-Glucose-1-Phosphate Uridylyltransferase; D005947:Glucose; D014532:Uridine Diphosphate Glucose