J Michael Sauder - Structure of a microsporidian methionine aminopeptidase type 2 complexed with fumagillin and TNP-470

Version 1

      Publication Details (including relevant citation   information):

      Mol Biochem Parasitol (2009) 168: 158-167.

      Alvarado JJ, Nemkal A, Sauder JM, Russell M, Akiyoshi DE, Shi W,   Almo SC, Weiss LM

      Abstract:

      Microsporidia are protists that have been reported to cause   infections  in both vertebrates and invertebrates. They have   emerged as human  pathogens particularly in patients that   are immunosuppressed and cases  of gastrointestinal   infection, encephalitis, keratitis, sinusitis,  myositis and   disseminated infection are well described in the    literature. While benzimidazoles are active against many species   of  microsporidia, these drugs do not have significant   activity against  Enterocytozoon bieneusi. Fumagillin and   its analogues have been  demonstrated to have activity   invitro and in animal models of  microsporidiosis and human   infections due to E. bieneusi. Fumagillin and  its analogues   inhibit methionine aminopeptidase type 2. Encephalitozoon    cuniculi MetAP2 (EcMetAP2) was cloned and expressed as an active   enzyme  using a baculovirus system. The crystal structure of   EcMetAP2 was  determined with and without the bound   inhibitors fumagillin and TNP-470.  This structure   classifies EcMetAP2 as a member of the MetAP2c family.  The   EcMetAP2 structure was used to generate a homology model of the   E.  bieneusi MetAP2. Comparison of microsporidian MetAP2   structures with  human MetAP2 provides insights into the   design of inhibitors that might  exhibit specificity for   microsporidian MetAP2.

      Address (URL): http://www.ncbi.nlm.nih.gov/pubmed/19660503