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Key research themes
1. What are the biochemical pathways, enzyme specificities, and structural determinants governing protein C-mannosylation?
This research area focuses on elucidating the molecular and biochemical basis of protein C-mannosylation, a distinct form of glycosylation involving a covalent carbon-carbon bond between mannose and tryptophan residues. Understanding the biosynthetic pathways, substrate recognition sequences, the cellular machinery involved, and structural requirements is essential because C-mannosylation affects a broad spectrum of mammalian proteins with diverse physiological roles.
Key finding: Identified the recognition sequence WXXW, specifying that the first tryptophan is C-mannosylated, and experimentally demonstrated that dolichylphosphate mannose (Dol-P-Man) serves as the mannose donor in the ER-based... Read more
Key finding: Revealed that TMTC family proteins (TMTC1-4) localize in ER with conserved topology and conserved sequence motifs characteristic of GT-C clan glycosyltransferases, functionally establishing these as a new class of... Read more
Key finding: Functionally characterized yeast mannosyltransferases KTR4, KTR5, and KTR7 as components involved in the maturation of both N-linked and O-linked glycan structures. Using heterologous expression and genetic complementation... Read more
2. How do structural and mechanistic features of mannan-degrading enzymes vary across glycoside hydrolase families, particularly in newly described families such as GH134?
Research under this theme investigates the enzymology, structural biology, and catalytic mechanisms of β-mannanases responsible for hydrolyzing β-1,4-mannans, which are important plant polysaccharides. Understanding differences in protein folds, active site configurations, and stereochemical mechanisms among diverse glycoside hydrolase families informs both fundamental enzymology and industrial applications in biomass processing.
Key finding: Discovered that GH134 family β-mannanases possess an unprecedented lysozyme-like fold distinct from previously characterized GH families. Through crystallographic and mass spectrometric analyses, the study demonstrated that... Read more
Key finding: Structural determination at atomic resolution revealed that GH134 β-mannanases share fold similarity with GH22 C-type lysozymes but function mechanistically as inverting enzymes lacking the canonical nucleophile, implying a... Read more
3. What molecular insights enable the design and synthesis of mannose-containing glycomimetics and inhibitors targeting mannosidases and mannose-binding proteins?
This theme encompasses synthetic chemistry strategies and structure-activity relationship studies focused on mannose analogues designed to target mannose-processing enzymes and mannose interaction domains, aiming at therapeutic applications including enzyme inhibition and anti-infective agent development. The investigations consider synthetic routes, stereochemical control, binding interactions, and inhibitor selectivity.
Key finding: Identified that C-linked mannosides with flexible alkene linkers and ortho-substituted biphenyl aglycone moieties bind the FimH lectin of pathogenic E. coli with affinities comparable or superior to O-mannoside analogs.... Read more
Key finding: Synthesized and characterized 1,4-imino-d-lyxitols modified at C-5 and assessed their potency and selectivity against four α-mannosidases, notably identifying 6-deoxy-DIM as a nanomolar inhibitor of AMAN-2. N-arylalkyl... Read more
Key finding: Developed a rapid, versatile synthesis of α(1–2)mannobiosides using an orthogonal protection strategy with benzoyl and acetyl groups, compatible with azido functionalities enabling subsequent CuAAC click conjugations. This... Read more
Key finding: Revisited multiple synthetic protocols for 1-O-propargyl-α-D-mannopyranoside and identified that one-step acid-catalyzed propargylation yields mixtures including undescribed by-products, while a three-step... Read more