Synthesis of Inhibitors of Imidazole Glycerol Phosphate Dehydratase

Mori, Ichiro; Iwasaki, Genji; Kimura, Yoko; Matsunaga, Shunyo; Ogawa, Atsuko; Nakano, Toshihito; Buser, Hans‐Peter; Hatano, Manabu; Tada, Sachiyo; Hayakawa, Kenji

doi:10.1021/ja00120a029

Cited by 28 publications

(20 citation statements)

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“…5) to the systems analyzed by Martin (carboxylic and amino groups are substituted to the same carbon atom) and to the system described by Siatecki and co-workers (phosphonate group is present), we decided to compare both approaches (namely two different sets of vicinal proton coupling constants proposed in their papers) and the population distribution data obtained are given in Table 2. The population distributions calculated for the CH(X)CH(A)H(B) and for PCH(A)H(B) systems are close to each other with the differences between particular sets being <11% (1)(2)(3)(4)(5). Only in one case was the difference as high as 20% (4).…”

Section: Resultsmentioning

confidence: 51%

“…The population distributions calculated for the CH(X)CH(A)H(B) and for PCH(A)H(B) systems are close to each other with the differences between particular sets being <11% (1)(2)(3)(4)(5). Only in one case was the difference as high as 20% (4). In all cases the most stable conformer is the one in which phosphonic and carboxylic groups are in trans positions to each other.…”

Section: Resultsmentioning

confidence: 56%

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1H NMR studies of rotational isomerism in phosphonic analogues of aspartic acid

2000

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Section: Resultsmentioning

confidence: 51%

Section: Resultsmentioning

confidence: 56%

1H NMR studies of rotational isomerism in phosphonic analogues of aspartic acid

2000

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“…Imidazole glycerol-phosphate dehydratase (IGPD) 1 catalyzes the sixth step in this pathway, the dehydration of imidazole glycerol phosphate (IGP) to imidazole acetol phosphate (1). Several IGPD inhibitors have been identified, including derivatives of triazole propyl phosphonic acid (2)(3)(4). Some of the inhibitors have substantial herbicidal activity (5).…”

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confidence: 99%

Crystal Structure of Imidazole Glycerol-phosphate Dehydratase

Sinha

Chaudhuri

Burgner

et al. 2004

Journal of Biological Chemistry

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Imidazole glycerol-phosphate dehydratase (IGPD) catalyzes the sixth step of histidine biosynthesis. The enzyme is of fundamental biochemical interest, because it catalyzes removal of a non-acidic hydrogen atom in the dehydration reaction. It is also a potential target for development of herbicides. IGPD is a metalloenzyme in which transition metals induce aggregation and are required for catalysis. Addition of 1 equivalent of Mn 2؉ / subunit is shown by analytical ultracentrifugation to induce the formation of 24-mers from trimeric IGPD. Two histidine-rich motifs may participate in metal binding and aggregation. The 2.3-Å crystal structure of metal-free trimeric IGPD from the fungus Filobasidiella neoformans reveals a novel fold containing an internal repeat, apparently the result of gene duplication. The 95-residue ␣/␤ half-domain occurs in a few other proteins, including the GHMP kinase superfamily (galactohomoserine-mevalonate-phosphomevalonate), but duplication to form a compact domain has not been seen elsewhere. Conserved residues cluster at two types of sites in the trimer, each site containing a conserved histidine-rich motif. A model is proposed for the intact, active 24-mer in which all highly conserved residues, including the histidine-rich motifs in both the N-and C-terminal halves of the polypeptide, cluster at a common site between trimers. This site is a candidate for the active site and also for metal binding leading to aggregation of trimers. The structure provides a basis for further studies of enzyme function and mechanism and for development of more potent and specific herbicides.

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“…[12][13][14] Fujisawa et al 15 5), respectively, possess antibacterial activity. 18 Racemic b-hydroxyphosphonic acid 6 called Zeneca 1, 19 containing a N-linked triazole via a three carbon chain to a phosphonic group, has shown inhibition of the enzyme imidazole glicerol phosphate dehydratase; 20 an enzyme involved in the biosynthesis of the essential plant amino acids histidine. 21 The synthesis of phosphorous analogues of GABOB, carnitine and statine, named as c-amino-b-hydroxypropylphosphonic acid or phosphogabob (GABOB P ) 7, c-trimethylammonium-b-hydroxypropylphosphonic acid (phosphocarnitine) 8, 22 and phosphostatine 9, respectively, are also of great interest.…”

Section: Introductionmentioning

confidence: 99%