Angiogenesis inhibitors specific for methionine aminopeptidase 2 as drugs for malaria and leishmaniasis.
Methionine aminopeptidase 2 (MetAP2) is responsible for the hydrolysis of the initiator methionine molecule from the majority of newly synthesized proteins. We have cloned the MetAP2 gene from the malaria parasite Plasmodium falciparum (PfMetAP2; GenBank accession number AF348320). The cloned PfMetAP2 has no intron, consists of 1,544 bp and encodes a protein of 354 amino acids with a molecular mass of 40,537 D and an overall base composition of 72.54% A + T. PfMetAP2 has 40% sequence identity with human MetAP2 and 45% identity with yeast MetAP2, and is located in chromosome 14 of P. falciparum. The three-dimensional structure of Pf MetAP2 has been modeled based on the crystal structure of human MetAP2, and several amino acid side chains protruding into the binding pocket that differ between the plasmodial and human enzyme have been identified. The specific MetAP2 inhibitors, fumagillin and TNP-470, potently blocked in vitro growth of P. falciparum and Leishmania donavani, with IC(50) values similar to the prototype drugs. Furthermore, in the case of P. falciparum, the chloroquine-resistant strains are equally susceptible to these two compounds.
Zhang
Pent
P
Walter Reed Army Institute of Research, Silver Spring, MD 20910-7500, USA.
Nicholson
Diarmuid E
DE
Bujnicki
Janusz M
JM
Su
Xinzhuan
X
Brendle
James J
JJ
Ferdig
Michael
M
Kyle
Dennis E
DE
Milhous
Wilbur K
WK
Chiang
Peter K
PK
D000595:Amino Acid Sequence; D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D001665:Binding Sites; D003001:Cloning, Molecular; D003510:Cyclohexanes; D016054:DNA, Protozoan / Q000235:genetics; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D007893:Leishmania donovani / Q000187:drug effects; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics*; D008969:Molecular Sequence Data; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D012717:Sesquiterpenes / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D000981:Antiprotozoal Agents; D003510:Cyclohexanes; D016054:DNA, Protozoan; D005231:Fatty Acids, Unsaturated; D012717:Sesquiterpenes; C026211:fumagillin; D000626:Aminopeptidases; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases; D000077609:O-(Chloroacetylcarbamoyl)fumagillol