title: Identification, biochemical and structural evaluation of species-specific inhibitors against type I methionine aminopeptidases.
abstract: Methionine aminopeptidases (MetAPs) are essential enzymes that make them good drug targets in cancer and microbial infections. MetAPs remove the initiator methionine from newly synthesized peptides in every living cell. MetAPs are broadly divided into type I and type II classes. Both prokaryotes and eukaryotes contain type I MetAPs, while eukaryotes have additional type II MetAP enzyme. Although several inhibitors have been reported against type I enzymes, subclass specificity is scarce. Here, using the fine differences in the entrance of the active sites of MetAPs from Mycobacterium tuberculosis , Enterococcus faecalis , and human, three hotspots have been identified and pyridinylpyrimidine-based molecules were selected from a commercial source to target these hotspots. In the biochemical evaluation, many of the 38 compounds displayed differential behavior against these three enzymes. Crystal structures of four selected inhibitors in complex with human MetAP1b and molecular modeling studies provided the basis for the binding specificity.
authors.affiliation: Center for Chemical Biology, CSIR-Indian Institute of Chemical Technology , Tarnaka, Hyderabad AP-500 007, India.
authors.forename: Chandan
authors.initials: C
authors.lastname: Kishor
authors.forename: Tarun
authors.initials: T
authors.lastname: Arya
authors.forename: Ravikumar
authors.initials: R
authors.lastname: Reddi
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Chen
authors.forename: Venkateshwarlu
authors.initials: V
authors.lastname: Saddanapu
authors.forename: Anil Kumar
authors.initials: AK
authors.lastname: Marapaka
authors.forename: Rajesh
authors.initials: R
authors.lastname: Gumpena
authors.forename: Dawei
authors.initials: D
authors.lastname: Ma
authors.forename: Jun O
authors.initials: JO
authors.lastname: Liu
authors.forename: Anthony
authors.initials: A
authors.lastname: Addlagatta
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D013293:Enterococcus faecalis / Q000201:enzymology / Q000235:genetics; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D063208:Methionyl Aminopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000201:enzymology / Q000235:genetics; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D013237:Stereoisomerism
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011725:Pyridines; D011743:Pyrimidines; D063208:Methionyl Aminopeptidases; C030986:pyrimidine