Structural highlights
6bm7 is a 6 chain structure with sequence from Tryb2. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
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| Ligands: | , , , , |
| NonStd Res: | |
| Gene: | Tb927.6.4410, Tb927.6.4460 (TRYB2) |
| Activity: | Adenosylmethionine decarboxylase, with EC number 4.1.1.50 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[DCAMP_TRYBB] Probably has no catalytic activity due to the loss of several residues required for processing and catalysis (PubMed:17485680). Forms a complex with S-adenosylmethionine decarboxylase AdoMetDC which is essential to activate AdoMetDC (PubMed:17485680, PubMed:18949025). Required for the biosynthesis of the polyamine spermidine (PubMed:18949025). Required for growth and survival during the bloodstream life cycle stage (PubMed:18949025).[1] [2]
Publication Abstract from PubMed
New therapeutic options are needed for treatment of human African trypanosomiasis (HAT) caused by protozoan parasite Trypanosoma brucei. S-Adenosylmethionine decarboxylase (AdoMetDC) is an essential enzyme in the polyamine pathway of T. brucei. Previous attempts to target this enzyme were thwarted by the lack of brain penetration of the most advanced series. Herein, we describe a T. brucei AdoMetDC inhibitor series based on a pyrimidineamine pharmacophore that we identified by target-based high-throughput screening. The pyrimidineamines showed selectivity for T. brucei AdoMetDC over the human enzyme, inhibited parasite growth in whole-cell assay, and had good predicted blood-brain barrier penetration. The medicinal chemistry program elucidated structure-activity relationships within the series. Features of the series that were required for binding were revealed by determining the X-ray crystal structure of TbAdoMetDC bound to one analog. The pyrimidineamine series provides a novel starting point for an anti-HAT lead optimization.
Species-Selective Pyrimidineamine Inhibitors of Trypanosoma brucei S-Adenosylmethionine Decarboxylase.,Volkov OA, Brockway AJ, Wring SA, Peel M, Chen Z, Phillips MA, De Brabander JK J Med Chem. 2017 Dec 22. doi: 10.1021/acs.jmedchem.7b01654. PMID:29271204[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Willert EK, Fitzpatrick R, Phillips MA. Allosteric regulation of an essential trypanosome polyamine biosynthetic enzyme by a catalytically dead homolog. Proc Natl Acad Sci U S A. 2007 May 15;104(20):8275-80. doi:, 10.1073/pnas.0701111104. Epub 2007 May 7. PMID:17485680 doi:http://dx.doi.org/10.1073/pnas.0701111104
- ↑ Willert EK, Phillips MA. Regulated expression of an essential allosteric activator of polyamine biosynthesis in African trypanosomes. PLoS Pathog. 2008 Oct;4(10):e1000183. doi: 10.1371/journal.ppat.1000183. Epub, 2008 Oct 24. PMID:18949025 doi:http://dx.doi.org/10.1371/journal.ppat.1000183
- ↑ Volkov OA, Brockway AJ, Wring SA, Peel M, Chen Z, Phillips MA, De Brabander JK. Species-Selective Pyrimidineamine Inhibitors of Trypanosoma brucei S-Adenosylmethionine Decarboxylase. J Med Chem. 2017 Dec 22. doi: 10.1021/acs.jmedchem.7b01654. PMID:29271204 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b01654
