Mycobacterium tuberculosis molecules by Dr. PI

, or dehydroquinase, catalyzes the conversion of 3-dehydroquinate into 3-dehydroshikimate. This is the third step in the shikimate pathway for the biosynthesis of aromatic amino acids from chorismate. The atoms shown in red are deduced from phosphoenolpyruvate that was added in the first step of the .
aroQ reaction scheme

Two classes of dehydroquinases exist, known as types I and II. They are unrelated at the sequence level and they utilize completely different mechanisms to catalyse the same overall reaction. Class I enzymes catalyze a cis-dehydration via a a imine intermediate, while the class II enzymes catalyse a trans-dehydration via an enolate intermediate. AroQ (synonyme AroD) codes for a type II enzyme, belonging to . They are found in some bacteria such as actinomycetales and in some fungi. Their enzymatic classification is .

The proteins involved in aromatic amino acid biosynthesis are listed in group below (AroQ = AroD).

Class-II enzymes are homododecameric enzymes of about 17 kDa. This model shows a single subunit of M. tuberculosis with a substrate analogue bound in the active site. The consists of a five-stranded parallel β-sheet core flanked by four α-helices. The strand order of the β-sheet is and The are on one side of the sheet and are on the other. The in the polypeptide chain between residues 19 and 25 is due to weak electron density for the residues in the flexible loop.

The is bound in the active site near the C-termini of the β-strands .The residues near the are contributing to a stepwise dehydrogenation. The first step of the reaction mechanism is a base-catalized abstraction of the axial proton at C2 . This is probably performed by the conserved residue . Its basicity is elevated by the proximity of the caroxylate sidechain of the conserved . The residues Arg 19 and Tyr 24, both located on the flexible loop, have been identified by mutagenesis studies to be essential for enyzme activity. is likely to be involved in stabilization of the enolate intermediate and is in suitable position to bind the substrate carboxylate. Additional conserved residues are Tyr 24, .

The biological unit of the Type II dehydroquinase is build of twelve sununits. It is a docedamer in whitch the subunits are arranged as a tetramer of trimers. Within each trimer there are strong electrostatic interactions. The interaction between the different trimers involves the palindromic sequence Gly-Val-Ile-Val Gly of residues .

spin / | | 3D model needs Jmol

The structural model was obtained from PDB entry , and the description from . Click here to search for at PDB.

is a peptide of with a and a It has a Dehydroquinase II site at position 9-27 and several other putative .

Comparison to the genome of reveals only very low homology to a few genes. In highly conserved homologues are encountered, namely in M. leprae, and various bacterial species and filamentous fungi. Several bacterial 3-dehydroquinate dehydratases (type I DHQase) are completely different from the M. tuberculosis AroQ (type II DHQase). This gene is not present in animals, as they do not synthesize aromatic amino acids via the shikimate pathway, making it a potential drug target. Links to different database entries are found in the .

The gene is encoded in a In the M. tuberculosis laboratory strain H37Rv the gene is a known as which corresponds to gene in the clinical isolate CDC 1551. It can be found on .

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On the circular M. tuberculosis chromosome (synomyme aroD) lies at . It is followed by several other genes which are involved in aromatic amino acid metabolism.

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blueTB molecules are published by Paul Imboden, Dr. PI Bioconsulting. Authorization to photocopy or reproduce this entry for personal use is granted. Copyright @ 2005 Paul Imboden, Dr. PI Bioconsulting. Last modified May 17, 2008 . Disclaimer: blueTB and the author reserves the right to modify and cancel any statement in these documents and regrets, that he cannot accept any responsibility for the consequences of any such changes. to the best of my knowledge all information is correct, but I cannot accept liability for any errors. References for this blueTB entry are:

Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, Gordon SV, Eiglmeier K, Gas S, Barry CE 3rd, Tekaia F, Badcock K, Basham D, Brown D, Chillingworth T, Connor R, Davies R, Devlin K, Feltwell T, Gentles S, Hamlin N, Holroyd S, Hornsby T, Jagels K, Barrell BG, et al. Nature, 393:537-44 (1998) and the Mycobacterium tuberculosis sequencing project from the Sanger Centre.

Whole-genome comparison of Mycobacterium tuberculosis clinical and laboratory strains. Fleischmann RD, Alland D, Eisen JA, Carpenter L, White O, Peterson J, DeBoy R, Dodson R, Gwinn M, Haft D, Hickey E, Kolonay JF, Nelson WC, Umayam LA, Ermolaeva M, Salzberg SL, Delcher A, Utterback T, Weidman J, Khouri H, Gill J, Mikula A, Bishai W, Jacobs Jr WR Jr, Venter JC, Fraser CM. J Bacteriol. 184:5479-90 (2002) and the Mycobacterium tuberculosis sequencing project from TIGR .

3. Dr. PI's Mtbook, The Mycobacterium tuberculosis genome in a book. Paul Imboden, Dr.PI Bioconsulting. mtbook.drpi.ch/ Release 1.8.0 Jan 2004, which itself is based mainly on reference 1.

The two types of 3-dehydroquinase have distinct structures but catalyze the same overall reaction. Gourley DG, Shrive AK, Polikarpov I, Krell T, Coggins JR, Hawkins AR, Isaacs NW, Sawyer L. Nat Struct Biol. 6:521-5 (1999).

The Mycobacterium tuberculosis shikimate pathway genes: evolutionary relationship between biosynthetic and catabolic 3-dehydroquinases. Garbe T, Servos S, Hawkins A, Dimitriadis G, Young D, Dougan G, Charles I. Mol Gen Genet.228:385-92 (1991).

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