title: Structures of substrate- and inhibitor-bound adenosine deaminase from a human malaria parasite show a dramatic conformational change and shed light on drug selectivity.
abstract: Plasmodium and other apicomplexan parasites are deficient in purine biosynthesis, relying instead on the salvage of purines from their host environment. Therefore, interference with the purine salvage pathway is an attractive therapeutic target. The plasmodial enzyme adenosine deaminase (ADA) plays a central role in purine salvage and, unlike mammalian ADA homologs, has a further secondary role in methylthiopurine recycling. For this reason, plasmodial ADA accepts a wider range of substrates, as it is responsible for deamination of both adenosine and 5'-methylthioadenosine. The latter substrate is not accepted by mammalian ADA homologs. The structural basis for this natural difference in specificity between plasmodial and mammalian ADA has not been well understood. We now report crystal structures of Plasmodium vivax ADA in complex with adenosine, guanosine, and the picomolar inhibitor 2'-deoxycoformycin. These structures highlight a drastic conformational change in plasmodial ADA upon substrate binding that has not been observed for mammalian ADA enzymes. Further, these complexes illuminate the structural basis for the differential substrate specificity and potential drug selectivity between mammalian and parasite enzymes.
authors.affiliation: Medical Structural Genomics of Pathogenic Protozoa Consortium, University of Washington, Seattle, WA 98195-7742, USA.
authors.forename: Eric T
authors.initials: ET
authors.lastname: Larson
authors.forename: Wei
authors.initials: W
authors.lastname: Deng
authors.forename: Brian E
authors.initials: BE
authors.lastname: Krumm
authors.forename: Alberto
authors.initials: A
authors.lastname: Napuli
authors.forename: Natascha
authors.initials: N
authors.lastname: Mueller
authors.forename: Wesley C
authors.initials: WC
authors.lastname: Van Voorhis
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Buckner
authors.forename: Erkang
authors.initials: E
authors.lastname: Fan
authors.forename: Angela
authors.initials: A
authors.lastname: Lauricella
authors.forename: George
authors.initials: G
authors.lastname: DeTitta
authors.forename: Joseph
authors.initials: J
authors.lastname: Luft
authors.forename: Frank
authors.initials: F
authors.lastname: Zucker
authors.forename: Wim G J
authors.initials: WG
authors.lastname: Hol
authors.forename: Christophe L M J
authors.initials: CL
authors.lastname: Verlinde
authors.forename: Ethan A
authors.initials: EA
authors.lastname: Merritt
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000243:Adenosine Deaminase / Q000737:chemistry*; D058892:Adenosine Deaminase Inhibitors; D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000378:metabolism; D001059:Apoproteins / Q000737:chemistry; D001665:Binding Sites; D002384:Catalysis / Q000187:drug effects; D018360:Crystallography, X-Ray; D006801:Humans; D007473:Ion Channels / Q000378:metabolism; D008288:Malaria / Q000201:enzymology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010271:Parasites / Q000201:enzymology*; D010963:Plasmodium falciparum / Q000201:enzymology; D010966:Plasmodium vivax / Q000201:enzymology*; D017433:Protein Structure, Secondary; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D012266:Ribose / Q000378:metabolism; D016415:Sequence Alignment; D013379:Substrate Specificity / Q000187:drug effects
chemical_list: D058892:Adenosine Deaminase Inhibitors; D000962:Antimalarials; D001059:Apoproteins; D007473:Ion Channels; D000644:Quaternary Ammonium Compounds; D012266:Ribose; D000243:Adenosine Deaminase; D000241:Adenosine