ABSTRACT
N-Myristoyltransferase (NMT) is an enzyme which translocates the 14-carbon saturated fatty acid myristate from myristoyl-CoA to the N-terminal glycine of substrate peptides. This myristoylation process is involved in protein modification in various eukaryotes, including animals and fungi. Furthermore, this enzyme has been shown to be essential to the growth of various species, such as Saccharomyces cerevisiae, which indicates that NMT is an attractive target for the development of a novel antifungal drug. In this study, the crystal structure of a ternary complex of NMT from Aspergillus fumigatus with S-(2-oxo)pentadecyl-CoA, a myristoyl-CoA analogue cofactor, and a synthetic inhibitor is reported at a resolution of 2.1â Å. The results advance the understanding of the specificity of NMT inhibitors and provide valuable information for structure-based drug design.
Subject(s)
Acyltransferases/chemistry , Aspergillus fumigatus/enzymology , Acyl Coenzyme A/metabolism , Acyltransferases/antagonists & inhibitors , Acyltransferases/metabolism , Amino Acid Sequence , Aspergillus fumigatus/chemistry , Aspergillus fumigatus/metabolism , Crystallography, X-Ray , Models, Molecular , Molecular Sequence Data , Sequence AlignmentABSTRACT
Since factor Xa (fXa) plays a pivotal role in the blood coagulation cascade, inhibition of fXa is thought to be an effective treatment for a variety of thrombotic events. (2S)-2-[4-[[(3S)-1-Acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amidino-2-naphthyl)propanoic acid hydrochloride pentahydrate (DX-9065a) was previously found in our laboratory as a novel orally active factor Xa inhibitor. DX-9065a exhibits a strong inhibitory activity toward fXa by occupying the substrate recognition (called S1) sites and aryl binding sites of fXa. Herein we describe conversions of the amidinonaphthalene and the acetimidoylpyrrolidine moieties of DX-9065a. Some compounds showed remarkably increased in vitro anti-factor Xa and PRCT activities compared with those of DX-9065a. The most promising compound 38 showed four times the prolongation of APTT against DX-9065a after oral administration to rats.