title: Structural analysis of arabinose-5-phosphate isomerase from Bacteroides fragilis and functional implications.
abstract: The crystal structure of arabinose-5-phosphate isomerase (API) from Bacteroides fragilis (bfAPI) was determined at 1.7 Å resolution and was found to be a tetramer of a single-domain sugar isomerase (SIS) with an endogenous ligand, CMP-Kdo (cytidine 5'-monophosphate-3-deoxy-D-manno-oct-2-ulosonate), bound at the active site. API catalyzes the reversible isomerization of D-ribulose 5-phosphate to D-arabinose 5-phosphate in the first step of the Kdo biosynthetic pathway. Interestingly, the bound CMP-Kdo is neither the substrate nor the product of the reaction catalyzed by API, but corresponds to the end product in the Kdo biosynthetic pathway and presumably acts as a feedback inhibitor for bfAPI. The active site of each monomer is located in a surface cleft at the tetramer interface between three monomers and consists of His79 and His186 from two different adjacent monomers and a Ser/Thr-rich region, all of which are highly conserved across APIs. Structure and sequence analyses indicate that His79 and His186 may play important catalytic roles in the isomerization reaction. CMP-Kdo mimetics could therefore serve as potent and specific inhibitors of API and provide broad protection against many different bacterial infections.
authors.affiliation: Joint Center for Structural Genomics, http://www.jcsg.org, USA.
authors.forename: Hsiu Ju
authors.initials: HJ
authors.lastname: Chiu
authors.affiliation: Joint Center for Structural Genomics, http://www.jcsg.org, USA.
authors.forename: Joanna C
authors.initials: JC
authors.lastname: Grant
authors.affiliation: Joint Center for Structural Genomics, http://www.jcsg.org, USA.
authors.forename: Carol L
authors.initials: CL
authors.lastname: Farr
authors.affiliation: Joint Center for Structural Genomics, http://www.jcsg.org, USA.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Jaroszewski
authors.affiliation: Joint Center for Structural Genomics, http://www.jcsg.org, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Knuth
authors.affiliation: Joint Center for Structural Genomics, http://www.jcsg.org, USA.
authors.forename: Mitchell D
authors.initials: MD
authors.lastname: Miller
authors.affiliation: Joint Center for Structural Genomics, http://www.jcsg.org, USA.
authors.forename: Marc André
authors.initials: MA
authors.lastname: Elsliger
authors.affiliation: Joint Center for Structural Genomics, http://www.jcsg.org, USA.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Deacon
authors.affiliation: Joint Center for Structural Genomics, http://www.jcsg.org, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Godzik
authors.affiliation: Joint Center for Structural Genomics, http://www.jcsg.org, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Lesley
authors.affiliation: Joint Center for Structural Genomics, http://www.jcsg.org, USA.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
mesh_terms: D019747:Aldose-Ketose Isomerases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001441:Bacteroides fragilis / Q000737:chemistry*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D003568:Cytidine Monophosphate / Q000031:analogs & derivatives / Q000737:chemistry; D006639:Histidine / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013400:Sugar Acids / Q000737:chemistry
chemical_list: D001426:Bacterial Proteins; D013400:Sugar Acids; C094610:cytidine-5'-monophosphate-3-deoxy-manno-octulosonic acid; D006639:Histidine; D019747:Aldose-Ketose Isomerases; C041486:arabinose-5-phosphate isomerase; D003568:Cytidine Monophosphate
keywords: Gram negative; Kdo (3-deoxy-d-manno-oct-2-ulosonate); arabinose 5-phosphate; lipopolysaccharide; structural genomics; sugar isomerase