Identification of Two GDP-6-deoxy-d-lyxo-4-hexulose Reductases Synthesizing GDP-d-rhamnose in Aneurinibacillus thermoaerophilus L420-91T

Kneidinger, Bernd; Graninger, Michael; Adam, Gerhard; Puchberger, Michael; Kosma, Paul; Zayni, Sonja; Messner, Paul

doi:10.1074/jbc.m010027200

Cited by 68 publications

(76 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, the natural pathways of GDP-D-rhamnose biosynthesis have been elucidated for a number of bacterial species and are found to involve conversion of GDP-D-mannose in a two-step process, utilizing a homologous GDP-mannose dehydratase and second reductase enzyme (65). A GMD from Aneurinibacillus thermoaerophilusthis was similarly reported to catalyze both dehydratase and reductase reactions to produce a rhamnose product, albeit less efficiently than the natural reductase enzyme (66).…”

Section: Resultsmentioning

confidence: 99%

Structure of the MUR1 GDP-Mannose 4,6-Dehydratase from Arabidopsis thaliana: Implications for Ligand Binding and Specificity

et al. 2002

View full text Add to dashboard Cite

GDP-D-mannose 4,6-dehydratase catalyzes the first step in the de novo synthesis of GDP-Lfucose, the activated form of L-fucose, which is a component of glycoconjugates in plants known to be important to the development and strength of stem tissues. We have determined the three-dimensional structure of the MUR1 dehydratase isoform from Arabidopsis thaliana complexed with its NADPH cofactor as well as with the ligands GDP and GDP-D-rhamnose. MUR1 is a member of the nucleosidediphosphosugar modifying subclass of the short-chain dehydrogenase/reductase enzyme family, having homologous structures and a conserved catalytic triad of Lys, Tyr, and Ser/Thr residues. MUR1 is the first member of this subfamily to be observed as a tetramer, the interface of which reveals a close and intimate overlap of neighboring NADP + -binding sites. The GDP moiety of the substrate also binds in an unusual syn conformation. The protein-ligand interactions around the hexose moiety of the substrate support the importance of the conserved triad residues and an additional Glu side chain serving as a general base for catalysis. Phe and Arg side chains close to the hexose ring may serve to confer substrate specificity at the O2 position. In the MUR1/GDP-D-rhamnose complex, a single unique monomer within the protein tetramer that has an unoccupied substrate site highlights the conformational changes that accompany substrate binding and may suggest the existence of negative cooperativity in MUR1 function.The 6-deoxy monosaccharide L-fucose is found as a component of glycoconjugates in organisms from bacteria to mammals and has a diverse range of functions. In humans, L-fucose is most notably an important constituent of glycoproteins such as the blood group antigens as well as cell surface carbohydrate ligands of the cell adhesion family of selectins involved in functions such as inflammation and the immune response (1). Among other organisms, L-fucosecontaining glycoconjugates are involved in developmental signaling in Drosophila (2), are critical components of bacterial cell walls where they may play a role in pathogenicity, and among rhizobial organisms, are components of Nod factors, influencing nodulation efficiency and host specificity (3, 4). In plants, L-fucose has important structural functions as a component of glycoproteins and cell wall polysaccharides, such as xyloglucan and rhamnogalacturonans I and II. Xyloglucan molecules cross-link cellulose microfibrils, one of the major load-bearing elements of the cell wall, and may be involved in the regulation of extension growth. It has been proposed that L-fucose may stabilize conformations that effectively bind cellulose (5, 6); however, this hypothesis has recently been challenged on the basis of the normal growth habit and wall strength of an Arabidopsis mutant specifically deficient in xyloglucan fucosylation (7). Although the function of rhamnogalacturonan II is unknown, the presence of fucose appears to be important for formation of the normal borate di-ester cross-linked f...

show abstract

Section: Resultsmentioning

confidence: 99%

Structure of the MUR1 GDP-Mannose 4,6-Dehydratase from Arabidopsis thaliana: Implications for Ligand Binding and Specificity

et al. 2002

View full text Add to dashboard Cite

show abstract

“…This intermediate is then converted by GFS into GDP-L-fucose, which can be converted by GDP-4-keto-6-deoxy-D-mannose reductase (RMD) into GDP-Drhamnose (Maki & Renkonen, 2004). Kneidinger et al (2001) found a bifunctional enzyme with both GMD and RMD activities in Aneurinibacillus thermoaerophilus. This enzyme shows 45 and 55 % identity with pRhico007 and pRhico008-009 products, respectively.…”

Section: Discussionmentioning

confidence: 99%

The Azospirillum brasilense Sp7 noeJ and noeL genes are involved in extracellular polysaccharide biosynthesis

et al. 2009

View full text Add to dashboard Cite

The Azospirillum brasilense Sp7 noeJ and noeL genes are involved in extracellular polysaccharide biosynthesis Azospirillum brasilense is a plant root-colonizing bacterium that exerts beneficial effects on the growth of many agricultural crops. Extracellular polysaccharides of the bacterium play an important role in its interactions with plant roots. The pRhico plasmid of A. brasilense Sp7, also named p90, carries several genes involved in synthesis and export of cell surface polysaccharides. We generated two Sp7 mutants impaired in two pRhico-located genes, noeJ and noeL, encoding mannose-6-phosphate isomerase and GDP-mannose 4,6-dehydratase, respectively. Our results demonstrate that in A. brasilense Sp7, noeJ and noeL are involved in lipopolysaccharide and exopolysaccharide synthesis. noeJ and noeL mutant strains were significantly altered in their outer membrane and cytoplasmic/periplasmic protein profiles relative to the wild-type strain. Moreover, both noeJ and noeL mutations significantly affected the bacterial responses to several stresses and antimicrobial compounds. Disruption of noeL, but not noeJ, affected the ability of the A. brasilense Sp7 to form biofilms. The pleiotropic alterations observed in the mutants could be due, at least partially, to their altered lipopolysaccharides and exopolysaccharides relative to the wild-type.

show abstract

“…GKDM is eventually converted to GDP-fucose by several downstream enzymatic reactions. In bacteria, however, GKDM can be reduced to form GDP-rhamnose by a GDP-4-keto-6-deoxy mannose reductase (RMD) 87 . GDP-rhamnose is a common component of bacterial cell surface glycans.…”

Section: Strategies To Produce Afucosylated Antibodiesmentioning

confidence: 99%

The “less-is-more” in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity

Pereira

Chan

Lin

et al. 2018

mAbs

267

211

View full text Add to dashboard Cite

Therapeutic monoclonal antibodies are the fastest growing class of biological therapeutics for the treatment of various cancers and inflammatory disorders. In cancer immunotherapy, some IgG1 antibodies rely on the Fc-mediated immune effector function, antibody-dependent cellular cytotoxicity (ADCC), as the major mode of action to deplete tumor cells. It is well-known that this effector function is modulated by the N-linked glycosylation in the Fc region of the antibody. In particular, absence of core fucose on the Fc N-glycan has been shown to increase IgG1 Fc binding affinity to the FcγRIIIa present on immune effector cells such as natural killer cells and lead to enhanced ADCC activity. As such, various strategies have focused on producing afucosylated antibodies to improve therapeutic efficacy. This review discusses the relevance of antibody core fucosylation to ADCC, different strategies to produce afucosylated antibodies, and an update of afucosylated antibody drugs currently undergoing clinical trials as well as those that have been approved.

show abstract

Identification of Two GDP-6-deoxy-d-lyxo-4-hexulose Reductases Synthesizing GDP-d-rhamnose in Aneurinibacillus thermoaerophilus L420-91T

Cited by 68 publications

References 50 publications

Structure of the MUR1 GDP-Mannose 4,6-Dehydratase from Arabidopsis thaliana: Implications for Ligand Binding and Specificity

Structure of the MUR1 GDP-Mannose 4,6-Dehydratase from Arabidopsis thaliana: Implications for Ligand Binding and Specificity

The Azospirillum brasilense Sp7 noeJ and noeL genes are involved in extracellular polysaccharide biosynthesis

The “less-is-more” in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity

Contact Info

Product

Resources

About