title: Crystal structures and proposed structural/functional classification of three protozoan proteins from the isochorismatase superfamily.
abstract: We have determined the crystal structures of three homologous proteins from the pathogenic protozoans Leishmania donovani, Leishmania major, and Trypanosoma cruzi. We propose that these proteins represent a new subfamily within the isochorismatase superfamily (CDD classification cd004310). Their overall fold and key active site residues are structurally homologous both to the biochemically well-characterized N-carbamoylsarcosine-amidohydrolase, a cysteine hydrolase, and to the phenazine biosynthesis protein PHZD (isochorismase), an aspartyl hydrolase. All three proteins are annotated as mitochondrial-associated ribonuclease Mar1, based on a previous characterization of the homologous protein from L. tarentolae. This would constitute a new enzymatic activity for this structural superfamily, but this is not strongly supported by the observed structures. In these protozoan proteins, the extended active site is formed by inter-subunit association within a tetramer, which implies a distinct evolutionary history and substrate specificity from the previously characterized members of the isochorismatase superfamily. The characterization of the active site is supported crystallographically by the presence of an unidentified ligand bound at the active site cysteine of the T. cruzi structure.
authors.affiliation: Biomolecular Structure Center M/S 357742, University of Washington, Seattle, WA 98195, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Caruthers
authors.forename: Frank
authors.initials: F
authors.lastname: Zucker
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Worthey
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Myler
authors.forename: Fred
authors.initials: F
authors.lastname: Buckner
authors.forename: Wes
authors.initials: W
authors.lastname: Van Voorhuis
authors.forename: Chris
authors.initials: C
authors.lastname: Mehlin
authors.forename: Erica
authors.initials: E
authors.lastname: Boni
authors.forename: Tiffany
authors.initials: T
authors.lastname: Feist
authors.forename: Joseph
authors.initials: J
authors.lastname: Luft
authors.forename: Stacey
authors.initials: S
authors.lastname: Gulde
authors.forename: Angela
authors.initials: A
authors.lastname: Lauricella
authors.forename: Oleksandr
authors.initials: O
authors.lastname: Kaluzhniy
authors.forename: Lori
authors.initials: L
authors.lastname: Anderson
authors.forename: Isolde
authors.initials: I
authors.lastname: Le Trong
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Holmes
authors.forename: Thomas
authors.initials: T
authors.lastname: Earnest
authors.forename: Michael
authors.initials: M
authors.lastname: Soltis
authors.forename: Keith O
authors.initials: KO
authors.lastname: Hodgson
authors.forename: Wim G J
authors.initials: WG
authors.lastname: Hol
authors.forename: Ethan A
authors.initials: EA
authors.lastname: Merritt
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006867:Hydrolases / Q000737:chemistry* / Q000145:classification / Q000378:metabolism; D007893:Leishmania donovani / Q000201:enzymology; D018320:Leishmania major / Q000201:enzymology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015800:Protozoan Proteins / Q000737:chemistry* / Q000145:classification / Q000378:metabolism; D016415:Sequence Alignment; D040681:Structural Homology, Protein; D014349:Trypanosoma cruzi / Q000201:enzymology
chemical_list: D015800:Protozoan Proteins; D006867:Hydrolases; C064012:isochorismatase