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PubMed2006

The structure of MbtI from Mycobacterium tuberculosis, the first enzyme in the biosynthesis of the siderophore mycobactin, reveals it to be a salicylate synthase.

The ability to acquire iron from the extracellular environment is a key determinant of pathogenicity in mycobacteria. Mycobacterium tuberculosis acquires iron exclusively via the siderophore mycobactin T, the biosynthesis of which depends on the production of salicylate from chorismate. Salicylate production in other bacteria is either a two-step process involving an isochorismate synthase (chorismate isomerase) and a pyruvate lyase, as observed for Pseudomonas aeruginosa, or a single-step conversion catalyzed by a salicylate synthase, as with Yersinia enterocolitica. Here we present the structure of the enzyme MbtI (Rv2386c) from M. tuberculosis, solved by multiwavelength anomalous diffraction at a resolution of 1.8 A, and biochemical evidence that it is the salicylate synthase necessary for mycobactin biosynthesis. The enzyme is critically dependent on Mg2+ for activity and produces salicylate via an isochorismate intermediate. MbtI is structurally similar to salicylate synthase (Irp9) from Y. enterocolitica and the large subunit of anthranilate synthase (TrpE) and shares the overall architecture of other chorismate-utilizing enzymes, such as the related aminodeoxychorismate synthase PabB. Like Irp9, but unlike TrpE or PabB, MbtI is neither regulated by nor structurally stabilized by bound tryptophan. The structure of MbtI is the starting point for the design of inhibitors of siderophore biosynthesis, which may make useful lead compounds for the production of new antituberculosis drugs, given the strong dependence of pathogenesis on iron acquisition in M. tuberculosis.

Amino Acid Sequence↗
PubMed1973

Intergeneric complementation of anthranilate synthase subunits.

Partially purified subunits of anthranilate synthase were prepared from Bacillus subtilis and Pseudomonas aeruginosa. The large component from B. subtilis (I(B)) complements well with the small component from P. aeruginosa (II(P)) to reconstitute a glutamine-reactive anthranilate synthase. This interaction can be demonstrated with crude extracts from a B. subtilis trpX mutant and a P. aeruginosa trpA mutant. Complementation was also observed with the large component from P. aeruginosa (I(P)) and the small subunit from B. subtilis (II(B)). At saturation the heterologous complex I(B)II(P) has 93% of the activity of the homologous complex I(B)II(B), whereas the hybrid I(P)II(B) is only 22% as active as the homologous complex I(P)II(P).

Ammonia↗
PubMed1983

Tryptophan biosynthesis in the marine luminous bacterium Vibrio harveyi.

Tryptophan biosynthetic enzyme levels in wild-type Vibrio harveyi and a number of tryptophan auxotrophs of this species were coordinately regulated over a 100-fold range of specific activities. The tryptophan analog indoleacrylic acid evoked substantial derepression of the enzymes in wild-type cells. Even higher enzyme levels were attained in auxotrophs starved for tryptophan, regardless of the location of the block in the pathway. A derepressed mutant selected by resistance to 5-fluorotryptophan was found to have elevated basal levels of trp gene expression; these basal levels were increased only two- to threefold by tryptophan limitation. The taxonomic implications of these and other biochemical results support previous suggestions that the marine luminous bacteria are more closely related to enteric bacteria than to other gram-negative taxa.

Aldose-Ketose Isomerases↗
PubMed2000

A novel degradative pathway of 2-nitrobenzoate via 3-hydroxyanthranilate in Pseudomonas fluorescens strain KU-7.

A bacterial strain KU-7, identified as a Pseudomonas fluorescens by 16S rDNA sequencing, was one of the 12 new isolates that are able to grow on 2-nitrobenzoate as a sole source of carbon, nitrogen, and energy. Resting cells of KU-7 were found to accumulate ammonia in the medium indicating that degradation of 2-NBA proceeds through a reductive route. Metabolite analyses by thin layer chromatography and high pressure liquid chromatography indicated that 3-hydroxyanthranilate is an intermediate of 2-nitrobenzoate metabolism in KU-7 cells. This offers an alternative route to 2-nitrobenzoate metabolism since anthranilate (2-aminobenzoate) or catechol were detected as intermediates in other bacteria. Crude extracts of KU-7 cells converted 2-nitrobenzoate to 3-hydroxyanthranilate with oxidation of 2 mol of NADPH. Ring cleavage of 3-hydroxyanthranilate produced a transient yellow product, identified as 2-amino-3-carboxymuconic 6-semialdehyde, that has a maximum absorbance at 360 nm. The initial enzymes of the 2-nitrobenzoate degradation pathway were found to be inducible since succinate-grown cells produced very low enzyme activities. A pathway for 2-nitrobenzoate degradation in KU-7 was proposed.

3-Hydroxyanthranilic Acid↗
PubMed1969

Anthranilate synthetase, an enzyme specified by the tryptophan operon of Escherichia coli: Comparative studies on the complex and the subunits.

The properties of the anthranilate synthetase complex and its separated subunits were compared in catalyzing the anthranilate synthetase reaction, chorismate + l-glutamine or NH(4) (+) --> anthranilate, and the transferase reaction, anthranilate + 5'-phosphorylribosyl-1-pyrophosphate --> phosphoribosyl anthranilate. It is shown that anthranilate synthetase component I is activated by normal anthranilate synthetase component II, a component II(CRM) (CRM = immunologically cross-reacting material), and by a presumed fragment of component II produced by a deletion mutant. Significant differences between the complex and its subunits are demonstrated with respect to substrate affinity, thermostability, feedback inhibitor sensitivity, and activity in the presence of various divalent cations. Of particular interest are the findings that the transferase activity of component II is only inhibitable by l-tryptophan when the component is in the complex and that this inhibition does not appear to depend upon the feedback-sensitive site of component I.

Alkaline Phosphatase↗
PubMed1977

[Experience with etofenamate in sport injuries (author's transl)].

Experience with 2-(2-hydroxyethoxy)-ethyl-N-(a,a,a-trifluoro-m-tolyl)-anthranilate (etofenamate; active principle of Rheumon Gel) in the treatment of traumatic injury to the ankle joint is reported. In testing the effect of the product, volumetric measurements were carried out using an apparatus that permits highly accurate assessment by a simple and rapid method of measurement. The studies were carried out as a double blind trial. The result of the study shows that compared with placebo gel the increase in volume due to haematoma is reduced statistically significantly more rapidly under treatment with etofenamate. No localized or generalized side effects were observed.

Adolescent↗
PubMed1990

Heterologous expression and epitope mapping of a human small nuclear ribonucleoprotein-associated Sm-B'/B autoantigen.

The U snRNP associated B'/B polypeptides are primary targets of Sm autoantibodies in patients with systemic lupus erythematosus. We have bacterially expressed a Sm-B'/B autoantigen from Raji cells as a fusion with the anthranilate synthase protein from Escherichia coli. The recombinant Sm-B'/B fusion displays comparable immunologic reactivity to the native protein when tested with both monoclonal and polyclonal antibodies. To map Sm-B'/B epitopes, we constructed a series of 12 anthranilate synthase fusions spanning different regions of Sm-B'/B and tested such fusions on immunoblots against a panel of characterized sera. In this manner, we have identified six epitopes, five of which overlap the proline-rich carboxyl-terminus of the protein. Some of these epitopes appear to be conformational. The human sera tested can be divided, according to the epitopes they recognize, into six groups. Finally, we have shown that anti-Sm recognition of the (U1)RNP-specific A protein is attributable to cross-reactivity between the Sm-B'/B and A autoantigens.

Amino Acid Sequence↗
PubMed1985

Reverse-phase h.p.l.c. separation, quantification and preparation of bilirubin and its conjugates from native bile. Quantitative analysis of the intact tetrapyrroles based on h.p.l.c. of their ethyl anthranilate azo derivatives.

We describe a facile and sensitive reverse-phase h.p.l.c. method for analytical separation of biliary bile pigments and direct quantification of unconjugated bilirubin (UCB) and its monoglucuronide (BMG) and diglucuronide (BDG) conjugates in bile. The method can be 'scaled up' for preparative isolation of pure BDG and BMG from pigment-enriched biles. We employed an Altex ultrasphere ODS column in the preparative steps and a Waters mu-Bondapak C18 column in the separatory and analytical procedures. Bile pigments were eluted with ammonium acetate buffer, pH 4.5, and a 20 min linear gradient of 60-100% (v/v) methanol at a flow rate of 2.0 ml/min for the preparative separations and 1.0 ml/min for the analytical separations. Bile pigments were eluted in order of decreasing polarity (glucuronide greater than glucose greater than xylose conjugates greater than UCB) and were chemically identified by t.l.c. of their respective ethyl anthranilate azo derivatives. Quantification of UCB was carried out by using a standard curve relating a range of h.p.l.c. integrated peak areas to concentrations of pure crystalline UCB. A pure crystalline ethyl anthranilate azo derivative of UCB (AZO . UCB) was employed as a single h.p.l.c. reference standard for quantification of BMG and BDG. We demonstrate that: separation and quantification of biliary bile pigments are rapid (approximately 25 min); bile pigment concentrations ranging from 1-500 microM can be determined 'on line' by using 5 microliters of bile without sample pretreatment; bilirubin conjugates can be obtained preparatively in milligram quantities without degradation or contamination by other components of bile. H.p.l.c. analyses of a series of mammalian biles show that biliary UCB concentrations generally range from 1 to 17 microM. These values are considerably lower than those estimated previously by t.l.c. BMG is the predominant, if not exclusive, bilirubin conjugate in the biles of a number of rodents (guinea pig, hamster, mouse, prairie dog) that are experimental models of both pigment and cholesterol gallstone formation. Conjugated bilirubins in the biles of other animals (human, monkey, pony, cat, rat and dog) are chemically more diverse and include mono-, di- and mixed disconjugates of glucuronic acid, xylose and glucose in proportions that give distinct patterns for each species.

Animals↗
PubMed1988

Regulation of tryptophan biosynthesis in Caulobacter crescentus.

We present an analysis of the expression of the trpE gene and the trpFBA operon in the dimorphic bacterium Caulobacter crescentus. The catalytic activity of component I of anthranilate synthase, the product of the trpE gene, was efficiently inhibited by tryptophan, the end product of the pathway, which suggests that tryptophan biosynthesis is likely controlled at the pathway level in C. crescentus. However, trpFBA mRNA levels and trpE enzyme levels did not vary significantly in wild-type C. crescentus in response to the presence of tryptophan in the growth medium or to growth in minimal versus rich medium. This lack of regulation of the trpE, trpF, trpB, and trpA genes is consistent with the idea that oligotrophic bacteria, such as C. crescentus, do not utilize regulatory mechanisms that greatly alter the biosynthetic capabilities in exponentially growing cells. In contrast, mRNA levels from the 5'-untranslated region and the upstream gene (usg) coding region increased dramatically in C. crescentus trpD or hisB auxotrophs starved for tryptophan or histidine, respectively. Surprisingly, concomitant increases in mRNA levels were not detected from the trpF, trpB, or trpA coding regions downstream in the operon. Thus, severe starvation of C. crescentus for amino acids appears to elicit a strong, general transcriptional response that is not observed in bacteria growing exponentially in medium lacking amino acids.

Culture Media↗
PubMed1992

Mapping of the immunoreactive domains of a small nuclear ribonucleoprotein-associated Sm-D autoantigen.

The Sm-D(D1) small nuclear ribonucleoprotein (snRNP) polypeptide is a major target of autoantibodies diagnostic for systemic lupus erythematosus. The cDNA encoding the protein from Raji cells was expressed in Escherichia coli as a fusion protein with anthranilate synthase (TrpE-Sm-D). When tested by protein blot, the recombinant polypeptide was strongly immunoreactive under defined blotting conditions, which appear to facilitate the refolding of the polypeptide into a native conformation. Multiple translational fusions between the trpE gene and fragments encompassing the length of the Sm-D coding sequence were constructed for epitope mapping. The results describe two general patterns of anti-Sm reactivity: (i) antibodies that recognize only the full-length antigen and are presumably directed against discontinuous epitopes, and (ii) antibodies that recognize the carboxy terminus of the antigen which embodies an extended/charged structure.

Amino Acid Sequence↗
PubMed1976

Isolation and characterization of mutations creating high-efficiency transcription initiation signals within the trp operon of Escherichia coli.

Two different mutational events generate promoter-active deoxyribonucleic acid sequences within the trp operon of Escherichia coli, probably through single base-pair changes. The mutations, obtained after ethyl methane sulfonate mutagenesis by selecting for elevated lac gene expression in a trp-lac fusion, are cis dominant and trans recessive with respect to their effects on the synthesis of downstream enzymes. One of the mutants (trpD11), obtained repeatedly under the selective conditions employed, prevents the formation of active phosphoribosyltransferase. The second mutation, trp3B, has no effects on any trp enzyme. By deletion mapping, trpD11 was localized near the operator-distal end of trpD, outside the segment of deoxyribonucleic acid that contains the low-efficiency internal promoter trpP2. Reversion to prototrophy of trpD11 was greatly stimulated by 2-aminopurine and ethyl methane sulfonate. Tests with suppressors indicated that trpD11 is a UAA (ochre) nonsense mutation. Under repression conditions, strains harboring either lesion in a normal trp operon synthesize the tryptophan biosynthetic enzymes in a noncoordinate fashion. The products of the operator-distal structural genes trpC, trpB, and trpA are formed at rates approximately 15-fold higher than those of wild type. The enzymes encoded by operator-proximal genes trpE and trpD are low or not detectable. Under derepression conditions, coordinate expression of the operon was observed.

Alleles↗
PubMed1994

Metabolism and Synthesis of Indole-3-Acetic Acid (IAA) in Zea mays (Levels of IAA during Kernel Development and the Use of in Vitro Endosperm Systems for Studying IAA Biosynthesis).

Kernels of Zea mays on an intact plant accumulate indole-3-acetic acid (IAA) at the rate of 190 ng g-1 fresh weight h-1. Of the IAA synthesized, 97% is in the esterified form and less than 3% remains as the free acid. The site of biosynthesis of the IAA, whether synthesized in the leaf and transported to the kernel, or in the kernel and remaining in the kernel, has not been established. In an attempt to determine the locus of synthesis, we grew isolated kernels on agar media not containing tryptophan or other possible aromatic precursors of IAA and observed IAA synthesis of 99 ng g-1 fresh weight h-1, approximately 52% of the in situ rate. Thus, the kernel contains all of the enzymes required for de novo aromatic biosynthesis of IAA and its ester conjugates. Furthermore, endosperm cells in suspension culture, grown on hormone-free media and in the absence of aromatic precursors, are able to synthesize IAA at a rate of 9.2 ng g-1 fresh weight h-1, or 4.8% of the in situ rate. This finding establishes that all of the enzymes of IAA biosynthesis occur in the endosperm and that the endosperm is a site of IAA biosynthesis. Isolated endosperm, prepared from developing kernels, synthesized IAA from labeled anthranilate at a rate of 8.6 ng g-1 fresh weight h-1, or 4.5% of the in situ rate. Frozen endosperm preparations maintained the ability to synthesize labeled IAA from labeled anthranilate. The identity of the synthesized IAA was established by mass spectral analysis. We suggest that endosperm preparations of Z. mays are suitable for study of the mechanism(s) of IAA biosynthesis because they (a) have high rates of synthesis; (b) show stability to freezing, enabling enzyme storage; (c) provide a system with a known rate of in situ synthesis; and (d) are available in large amounts for use as an enzyme source.

Journal Article↗
PubMed1990

Crystallization and structure solution at 4 A resolution of the recombinant synthase domain of N-(5'-phosphoribosyl)anthranilate isomerase:indole-3-glycerol-phosphate synthase from Escherichia coli complexed to a substrate analogue.

The recombinant synthase domain of the bifunctional enzyme N-(5'-phosphoribosyl)anthranilate isomerase:indole-3-glycerol-phosphate synthase from Escherichia coli has been crystallized, and the structure has been solved at 4 A resolution. Two closely related crystal forms grown from ammonium sulphate diffract to 2 A resolution. One form (space group R32, a = 163 A, alpha = 29.5 degrees) contains the unliganded synthase domain; the second crystal form (space group P6(3)22, a = 144 A, c = 158 A) is co-crystallized with the substrate analogue N-(5'-phosphoribit-1-yl)anthranilate. The structure of the synthase-inhibitor complex has been solved by the molecular replacement method. This achievement represents the first successful use of a (beta alpha)8-barrel monomer as a trial model. The recombinant synthase domain associates as a trimer in the crystal, the molecules being related by a pseudo-crystallographic triad. The interface contacts between the three domains are mediated by those residues that are also involved in the domain interface of the bifunctional enzyme. This system provides a model for an interface which is used in both intermolecular and intramolecular domain contacts.

Aldose-Ketose Isomerases↗
PubMed1990

[Enhancing effect of chuangxinmycin on synthesis of enzymes in tryptophan synthesis pathway of chuangxinmycin-resistant mutant strain of E. coli].

Chuangxinmycin (CXM) and L-trp cause repression of trp-operon in wild strain of E. coli and indolepropanic acid (IPA) causes derepression of this strain. In CXM-resistant mutant strain, CXM and IPA both cause derepression, and interaction of CXM and IPA is competitive. However, L-trp results in neither repression nor derepression in the mutant, but it can counteract the activity of CXM or IPA. These results suggest that there are repression and derepression sites on repressor of E. coli. CXM can bind to both sites, but mainly to repression site. The structure of repression site of the CXM-resistant mutant is altered, so that CXM can not bind to the repression site and binds mainly to the derepression site, thus leading to the derepression of trp-operon.

Anthranilate Synthase↗
PubMed1993

7-Chlorokynurenate, an antagonist of the glycine binding site on the NMDA receptor, inhibits memory formation in day-old chicks (Gallus domesticus).

Unilateral intracranial injection into the left intermediate and medial hyperstriatum ventrale of 100 mumol.liter-1 7-chlorokynurenate, a highly selective antagonist of the glycine site on the N-methyl-D-aspartate receptor, prevents acquisition of memory for one-trial passive avoidance training in day-old chicks, in which the aversive stimulus is an unpleasant tasting substance, methyl anthranilate. Injections were given 30 min pretraining and the chicks were tested 30 min or 1 or 3 h post-training. Unilateral injections into the left intermediate and medial hyperstriatum ventrale were found to significantly block memory acquisition when birds were tested at all three time points, but unilateral injections in the right intermediate and medial hyperstriatum ventrale had no significant effect. Bilateral injections did not significantly increase the memory block. Injections of 7-chlorokynurenate given 5 min post-training failed to produce amnesia for the avoidance task when chicks were tested either 30 min or 1 h after training.

Animals↗
PubMed1978

[Changes in opposite directions of tryptophanpyrrolase and 3-OH-anthranilic oxidase after a loading dose of tryptophan].

A loading dose of tryptophan induces a marked increase of tryptophan-pyrrolase (substrate induction) and a decrease of 3-OH-anthranilic-oxidase values in rat liver; in the kidneys of the same experimental animals the 3-OH-anthranilic-oxydase is instead unchanged. In other experimental conditions (surrenectomized or pyridoxine depleted rats, with or without tryptophan loading; with prednisolone loading) a more or less important substrate induction is always reported, whereas no variation occurs in the values of 3-OH-anthranilic-oxydase. These data are not sufficient to state whether there is a connection between the opposite responses of the two enzymatic activities obtained after tryptophan loading in rat liver homogenate. On the other hand, it should be kept in mind that they do not represent the overall effect induced by the aminoacid loading, but refer only to one moment of the action exerted by the loading itself. In order to acquire a thorough knowledge of the observations made so far and to formulate some assumptions which may be helpful for the interpretation of the relevant mechanisms, it is necessary to investigate the kinetics of both enzymes, and to study their regulatory mechanisms in particular after tryptophan loading.

3-Hydroxyanthranilic Acid↗
PubMed1977

[Clinical trial of the new percutaneously active antirheumatic etofenamate. Summarising report (author's transl)].

2-(2-Hydroxyethoxy)ethyl-N-(a,a,a-trifluoro-m-tolyl)anthranilate (etofenamate, Rheumon Gel), a percutaneously active antirheumatic containing etofenamate as active principle has been subjected to clinical studies in both hospitalized and out-patients in various types of rheumatic disease. These trials included double-blind studies against placebo gel, controlled comparative studies against two topical commercial products (ointmentI: combination of 2-hydroxyethyl salicylate and p-menthan-3-ol; ointment II: 3,5-dioxo-1,2-diphenyl-4-n-butylpyrazolidine) and open trials for efficacy and tolerance. Of the 760 patients taking part in the trials, 556 were treated with Rheumon Gel.

Administration, Topical↗
PubMed1993

Molecular cloning and nucleotide sequence of a putative trpDC(F)BA operon in Buchnera aphidicola (endosymbiont of the aphid Schizaphis graminum).

A 8,392-nucleotide-long DNA fragment from Buchnera aphidicola (endosymbiont of the aphid Schizaphis graminum) contained five genes of the tryptophan biosynthetic pathway [trpDC(F)BA] which code for enzymes converting anthranilate to tryptophan. These genes are probably arranged as a single transcription unit. Downstream of the trp genes were ORF-V, ORF-VI, and P14, three open reading frames which in Escherichia coli are also found downstream of the trp operon. Upstream of the B. aphidicola trp genes were two unidentified open reading frames, one of which potentially codes for a membrane-spanning protein with a leader sequence. Evidence for the presence of trpB in the endosymbionts of eight additional species of aphids and two species of whiteflies was obtained. These results as well as those of A. E. Douglas and W. A. Prosser (J. Insect Physiol. 38:565-568, 1992) suggest that aphid endosymbionts are capable of synthesizing tryptophan, which is required by the aphid host.

Amino Acid Sequence↗