Structural highlights
2y76 is a 1 chain structure with sequence from "bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
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| Ligands: | , |
| Related: | 1h0r, 2y71, 2xb8, 1h05, 1h0s, 2dhq, 2y77 |
| Activity: | 3-dehydroquinate dehydratase, with EC number 4.2.1.10 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[AROQ_MYCTU] Catalyzes a trans-dehydration via an enolate intermediate (By similarity).[HAMAP-Rule:MF_00169]
Publication Abstract from PubMed
The synthesis of high-affinity reversible competitive inhibitors of Mycobacterium tuberculosis type II dehydroquinase, an essential enzyme in Mycobacterium tuberculosis bacteria, is reported. The inhibitors reported here are mimics of the enol intermediate and the effect of substitution on C2 was studied. The crystal structures of Mycobacterium tuberculosis type II dehydroquinase in complex with three of the reported inhibitors are also described. The results show that an aromatic substituent on C2 prevents the closure of the active site by impeding the hydrogen-bonding interaction of Arg108 with the essential Tyr24 of the flexible loop, the residue that initiates catalysis. Chemical modifications of the reported acids were also carried out to improve internalization into Mycobacterium tuberculosis through an ester prodrug approach. Propyl esters proved to be the most efficient in achieving optimal in vitro activities.
A Prodrug Approach for Improving Antituberculosis Activity of Potent Mycobacterium tuberculosis Type II Dehydroquinase Inhibitors.,Tizon L, Otero JM, Prazeres VF, Llamas-Saiz AL, Fox GC, van Raaij MJ, Lamb H, Hawkins AR, Ainsa JA, Castedo L, Gonzalez-Bello C J Med Chem. 2011 Aug 3. PMID:21780742[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Tizon L, Otero JM, Prazeres VF, Llamas-Saiz AL, Fox GC, van Raaij MJ, Lamb H, Hawkins AR, Ainsa JA, Castedo L, Gonzalez-Bello C. A Prodrug Approach for Improving Antituberculosis Activity of Potent Mycobacterium tuberculosis Type II Dehydroquinase Inhibitors. J Med Chem. 2011 Aug 3. PMID:21780742 doi:10.1021/jm2006063
