2Y71

Structure of Mycobacterium tuberculosis type II dehydroquinase complexed with (1R,4S,5R)-1,4,5-trihydroxy-3-((5-methylbenzo(b) thiophen-2-yl)methoxy)cyclohex-2-enecarboxylate

Summary for 2Y71

• Entry DOI: 10.2210/pdb2y71/pdb
• Related: 1H05 1H0R 1H0S 2DHQ 2XB8 2Y76 2Y77
• Descriptor: 3-DEHYDROQUINATE DEHYDRATASE, (1R,4S,5R)-1,4,5-trihydroxy-3-[(5-methyl-1-benzothiophen-2-yl)methoxy]cyclohex-2-ene-1-carboxylic acid, SODIUM ION, ... (5 entities in total)
• Functional Keywords: lyase, amino acid biosynthesis
• Biological source: MYCOBACTERIUM TUBERCULOSIS
• Total number of polymer chains: 1
• Total formula weight: 16553.42

Authors

Otero, J.M.,Llamas-Saiz, A.L.,Fox, G.C.,Tizon, L.,Prazeres, V.F.V.,Lamb, H.,Hawkins, A.R.,Ainsa, J.A.,Castedo, L.,Gonzalez-Bello, C.,van Raaij, M.J. (deposition date: 2011-01-28, release date: 2011-08-17, Last modification date: 2023-12-20)

Primary citation

Tizon, L.,Otero, J.M.,Prazeres, V.F.,Llamas-Saiz, A.L.,Fox, G.C.,van Raaij, M.J.,Lamb, H.,Hawkins, A.R.,Ainsa, J.A.,Castedo, L.,Gonzalez-Bello, C.
A prodrug approach for improving antituberculosis activity of potent Mycobacterium tuberculosis type II dehydroquinase inhibitors.
J. Med. Chem., 54:6063-6084, 2011

PubMed Abstract: 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.

PubMed: 21780742
DOI: 10.1021/jm2006063

Experimental method

X-RAY DIFFRACTION (1.5 Å)