The design and synthesis of inhibitors of dethiobiotin synthetase as potential herbicides

Taylor, Wendy S.; Gibson, Katharine J.; Lorimer, George H.; Rayner, Dennis R.; Lockett, B. C.; Kranis, Kevin T.; Wexler, Barry A.; Marcovici-Mizrahi, Dana; Nudelman, Ayelet; Nudelman, Abraham; Marsilii, Eileen; Chi, Hongji; Wawrzak, Z.; Calabrese, Joseph R.; Huang, Weijun; Jia, Jia; Schneider, Günter; Lindqvist, Ylva; Yang, Guang

doi:10.1002/ps.2780550303

Cited by 9 publications

(12 citation statements)

References 24 publications

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“…Indeed, the E. coli enzymes’ crystal structures have served as the basis for several studies that attempted to define inhibitors of the plant biotin pathway for herbicide development (21–23). …”

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Structural Characterization of the Mycobacterium tuberculosis Biotin Biosynthesis Enzymes 7,8-Diaminopelargonic Acid Synthase and Dethiobiotin Synthetase,

et al. 2010

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Mycobacterium tuberculosis (Mtb) depends on biotin synthesis for survival during infection. In the absence of biotin, disruption of the biotin biosynthesis pathway results in cell death rather than growth arrest, an unusual phenotype for an Mtb auxotroph. Humans lack the enzymes for biotin production, making the proteins of this essential Mtb pathway promising drug targets. To this end, we have determined the crystal structures of the second and third enzymes of the Mtb biotin biosynthetic pathway, 7,8-diaminopelargonic acid synthase (DAPAS) and dethiobiotin synthetase (DTBS), at respective resolutions of 2.2 Å and 1.85 Å. Superimposition of the DAPAS structures bound either to the SAM analog sinefungin or to 7-keto-8-aminopelargonic acid (KAPA) allowed us to map the putative binding site for the substrates and to propose a mechanism by which the enzyme accommodates their disparate structures. Comparison of the DTBS structures bound to the substrate 7,8-diaminopelargonic acid (DAPA) or to ADP and the product dethiobiotin (DTB) permitted derivation of an enzyme mechanism. There are significant differences between the Mtb enzymes and those of other organisms; the Bacillus subtilis DAPAS, presented here at a high resolution of 2.2 Å, has active site variations and the Escherichia coli and Helicobacter pylori DTBS have alterations in their overall folds. We have begun to exploit the unique characteristics of the Mtb structures to design specific inhibitors against the biotin biosynthesis pathway in Mtb.

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Structural Characterization of the Mycobacterium tuberculosis Biotin Biosynthesis Enzymes 7,8-Diaminopelargonic Acid Synthase and Dethiobiotin Synthetase,

et al. 2010

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“…Because biotin synthesis is unique to plants and microorganisms, enzymes of this pathway are potential targets for the development of antimicrobial drugs and herbicides (19). Inhibitors of each of these enzymes have been characterized as either synthetic mechanism-based inhibitors (19,20) or natural products.…”

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“…Inhibitors of each of these enzymes have been characterized as either synthetic mechanism-based inhibitors (19,20) or natural products. Several antimicrobial compounds have been isolated from Streptomyces species that specifically inhibit DAPA synthase.…”

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Structural Basis for the Inhibition of the Biosynthesis of Biotin by the Antibiotic Amiclenomycin

Sandmark

Mann

Marquet

et al. 2002

Journal of Biological Chemistry

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The antibiotic amiclenomycin blocks the biosynthesis of biotin by inhibiting the pyridoxal-phosphate-dependent enzyme diaminopelargonic acid synthase. Inactivation of the enzyme is stereoselective, i.e. the cis isomer of amiclenomycin is a potent inhibitor, whereas the trans isomer is much less reactive. The crystal structure of the complex of the holoenzyme and amiclenomycin at 1.8 Å resolution reveals that the internal aldimine linkage between the cofactor and the side chain of the catalytic residue Lys-274 is broken. Instead, a covalent bond is formed between the 4-amino nitrogen of amiclenomycin and the C4 carbon atom of pyridoxal-phosphate. The electron density for the bound inhibitor suggests that aromatization of the cyclohexadiene ring has occurred upon formation of the covalent adduct. This process could be initiated by proton abstraction at the C4 carbon atom of the cyclohexadiene ring, possibly by the proximal side chain of Lys-274, leading to the tautomer Schiff base followed by the removal of the second allylic hydrogen. The carboxyl tail of the amiclenomycin moiety forms a salt link to the conserved residue Arg-391 in the substrate-binding site. Modeling suggests steric hindrance at the active site as the determinant of the weak inhibiting potency of the trans isomer.The biosynthesis of the vitamin biotin, a cofactor in biological carboxylation reactions, occurs in micro-organisms and plants and involves at least four different steps (Scheme 1) (1-12). The second step in this pathway, the conversion of 7-keto-8-aminopelargonic acid (KAPA) 1 into 7,8-diaminopelargonic acid (DAPA), is catalyzed by DAPA synthase, an aminotransferase that requires PLP as a cofactor (6, 7). DAPA synthase from Escherichia coli is a homodimer with a molecular mass of 94 kDa (6, 13) and contains 429 residues per monomer (14). The enzyme is unique among aminotransferases in that it uses S-adenosyl-L-methionine (SAM) as an amino group donor. The reaction catalyzed by DAPA synthase is typical of that of an aminotransferase and follows the general mechanism seen in other PLP-dependent enzymes (15).The crystal structure of DAPA synthase (16) shows that DAPA synthase belongs to the fold type I family of PLPdependent enzymes (17, 18). The monomer of DAPA synthase consists of two domains, a small domain comprising the N-and C-terminal part of the polypeptide chain (residues 1-49 and 330 -429) and a large domain formed by the intervening residues containing the cofactor-binding site. In the crystal, the two subunits of the homodimer of DAPA synthase are related by a 2-fold non-crystallographic axis (16). The PLP-binding site is located between the two domains of the monomer at the interface of the two subunits. In the enzyme-PLP complex, the cofactor is covalently linked to the ⑀-amino group of Lys-274, a residue functionally invariant in the whole family of fold-type I PLP-dependent enzymes.Because biotin synthesis is unique to plants and microorganisms, enzymes of this pathway are potential targets for the development of antimicr...

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“…Bacterial enzyme was used as a model for the dsign and synthesis of DTBS inhibitors as herbicides. (Rendina et al, 1999). In order to mimic the carbamate intermediate of the DTBS various carboxylates and phosphonates were prepared but poor level of inhibition thus weeak in vivo activities were detected.…”

Section: Research For Finding New Target Sitesmentioning

confidence: 99%

Molecular Mechanism of Action of Herbicides

Jablonkai¹

2011

Herbicides - Mechanisms and Mode of Action

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The design and synthesis of inhibitors of dethiobiotin synthetase as potential herbicides

Cited by 9 publications

References 24 publications

Structural Characterization of the Mycobacterium tuberculosis Biotin Biosynthesis Enzymes 7,8-Diaminopelargonic Acid Synthase and Dethiobiotin Synthetase,

Structural Characterization of the Mycobacterium tuberculosis Biotin Biosynthesis Enzymes 7,8-Diaminopelargonic Acid Synthase and Dethiobiotin Synthetase,

Structural Basis for the Inhibition of the Biosynthesis of Biotin by the Antibiotic Amiclenomycin

Molecular Mechanism of Action of Herbicides

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