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Structures of trehalose-6-phosphate synthase, Tps1, from the fungal pathogen Cryptococcus neoformans: A target for antifungals.
Washington, Erica J; Zhou, Ye; Hsu, Allen L; Petrovich, Matthew; Tenor, Jennifer L; Toffaletti, Dena L; Guan, Ziqiang; Perfect, John R; Borgnia, Mario J; Bartesaghi, Alberto; Brennan, Richard G.
Afiliação
  • Washington EJ; Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710.
  • Zhou Y; Department of Computer Science, Duke University, Durham, NC 27708.
  • Hsu AL; Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, Department of Health and Human Services, NIH, Research Triangle Park, NC 27709.
  • Petrovich M; Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, Department of Health and Human Services, NIH, Research Triangle Park, NC 27709.
  • Tenor JL; Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC 27710.
  • Toffaletti DL; Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC 27710.
  • Guan Z; Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710.
  • Perfect JR; Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC 27710.
  • Borgnia MJ; Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, Department of Health and Human Services, NIH, Research Triangle Park, NC 27709.
  • Bartesaghi A; Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710.
  • Brennan RG; Department of Computer Science, Duke University, Durham, NC 27708.
Proc Natl Acad Sci U S A ; 121(32): e2314087121, 2024 Aug 06.
Article em En | MEDLINE | ID: mdl-39083421
ABSTRACT
Invasive fungal diseases are a major threat to human health, resulting in more than 1.5 million annual deaths worldwide. The arsenal of antifungal therapeutics remains limited and is in dire need of drugs that target additional biosynthetic pathways that are absent from humans. One such pathway involves the biosynthesis of trehalose. Trehalose is a disaccharide that is required for pathogenic fungi to survive in their human hosts. In the first step of trehalose biosynthesis, trehalose-6-phosphate synthase (Tps1) converts UDP-glucose and glucose-6-phosphate to trehalose-6-phosphate. Here, we report the structures of full-length Cryptococcus neoformans Tps1 (CnTps1) in unliganded form and in complex with uridine diphosphate and glucose-6-phosphate. Comparison of these two structures reveals significant movement toward the catalytic pocket by the N terminus upon ligand binding and identifies residues required for substrate binding, as well as residues that stabilize the tetramer. Intriguingly, an intrinsically disordered domain (IDD), which is conserved among Cryptococcal species and closely related basidiomycetes, extends from each subunit of the tetramer into the "solvent" but is not visible in density maps. We determined that the IDD is not required for C. neoformans Tps1-dependent thermotolerance and osmotic stress survival. Studies with UDP-galactose highlight the exquisite substrate specificity of CnTps1. In toto, these studies expand our knowledge of trehalose biosynthesis in Cryptococcus and highlight the potential of developing antifungal therapeutics that disrupt the synthesis of this disaccharide or the formation of a functional tetramer and the use of cryo-EM in the structural characterization of CnTps1-ligand/drug complexes.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Trealose / Cryptococcus neoformans / Glucosiltransferases / Antifúngicos Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Trealose / Cryptococcus neoformans / Glucosiltransferases / Antifúngicos Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article