4Y6S

Structure of Plasmodium falciparum DXR in complex with a beta-substituted fosmidomycin analogue, RC134, and manganese

Summary for 4Y6S

• Entry DOI: 10.2210/pdb4y6s/pdb
• Related: 4Y67 4Y6P 4Y6R
• Descriptor: 1-deoxy-D-xylulose 5-phosphate reductoisomerase, apicoplast, MANGANESE (II) ION, [(2R)-4-[hydroxy(methyl)amino]-2-(4-methylphenyl)-4-oxobutyl]phosphonic acid, ... (4 entities in total)
• Functional Keywords: enzyme-inhibitor complex, mep pathway, isoprenoid biosynthesis, oxidoreductase
• Biological source: Plasmodium falciparum (isolate 3D7)
• Cellular location: Plastid, apicoplast : Q8IKG4
• Total number of polymer chains: 2
• Total formula weight: 97013.33

Authors

Sooriyaarachchi, S.,Bergfors, T.,Jones, T.A.,Mowbray, S.L. (deposition date: 2015-02-13, release date: 2015-04-01, Last modification date: 2024-05-08)

Primary citation

Chofor, R.,Sooriyaarachchi, S.,Risseeuw, M.D.,Bergfors, T.,Pouyez, J.,Johny, C.,Haymond, A.,Everaert, A.,Dowd, C.S.,Maes, L.,Coenye, T.,Alex, A.,Couch, R.D.,Jones, T.A.,Wouters, J.,Mowbray, S.L.,Van Calenbergh, S.
Synthesis and Bioactivity of beta-Substituted Fosmidomycin Analogues Targeting 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase.
J.Med.Chem., 58:2988-3001, 2015

PubMed Abstract: Blocking the 2-C-methyl-d-erythrithol-4-phosphate (MEP) pathway for isoprenoid biosynthesis offers interesting prospects for inhibiting Plasmodium or Mycobacterium spp. growth. Fosmidomycin (1) and its homologue FR900098 (2) potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this pathway. Here we introduced aryl or aralkyl substituents at the β-position of the hydroxamate analogue of 2. While direct addition of a β-aryl moiety resulted in poor inhibition, longer linkers between the carbon backbone and the phenyl ring were generally associated with better binding to the enzymes. X-ray structures of the parasite Dxr-inhibitor complexes show that the "longer" compounds generate a substantially different flap structure, in which a key tryptophan residue is displaced, and the aromatic group of the ligand lies between the tryptophan and the hydroxamate's methyl group. Although the most promising new Dxr inhibitors lack activity against Escherichia coli and Mycobacterium smegmatis, they proved to be highly potent inhibitors of Plasmodium falciparum in vitro growth.

PubMed: 25781377
DOI: 10.1021/jm5014264

Experimental method

X-RAY DIFFRACTION (2.1 Å)