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81.
Sabine Kirner Philip E. Hammer D. Steven Hill Annett Altmann Ilona Fischer Laura J. Weislo Mike Lanahan Karl-Heinz van Pée James M. Ligon 《Journal of bacteriology》1998,180(7):1939-1943
Pyrrolnitrin is a secondary metabolite derived from tryptophan and has strong antifungal activity. Recently we described four genes, prnABCD, from Pseudomonas fluorescens that encode the biosynthesis of pyrrolnitrin. In the work presented here, we describe the function of each prn gene product. The four genes encode proteins identical in size and serology to proteins present in wild-type Pseudomonas fluorescens, but absent from a mutant from which the entire prn gene region had been deleted. The prnA gene product catalyzes the chlorination of l-tryptophan to form 7-chloro-l-tryptophan. The prnB gene product catalyzes a ring rearrangement and decarboxylation to convert 7-chloro-l-tryptophan to monodechloroaminopyrrolnitrin. The prnC gene product chlorinates monodechloroaminopyrrolnitrin at the 3 position to form aminopyrrolnitrin. The prnD gene product catalyzes the oxidation of the amino group of aminopyrrolnitrin to a nitro group to form pyrrolnitrin. The organization of the prn genes in the operon is identical to the order of the reactions in the biosynthetic pathway.The antibiotic pyrrolnitrin [3-chloro-4-(2′-nitro-3′-chlorophenyl)pyrrole] (PRN) is produced by many pseudomonads and has broad-spectrum antifungal activity (1, 5, 12–14, 17). PRN has been implicated as an important mechanism of biological control of fungal plant pathogens by several Pseudomonas strains (12–14), including P. fluorescens BL915, from which the prn genes were isolated (10).Tryptophan was identified as the precursor for PRN, based on the feeding of cultures with isotopically labeled and substituted tryptophan (2, 7, 8, 17, 25). Biosynthetic pathways were proposed as early as 1967 (7) and have been refined on the basis of tracer studies and the isolation of intermediates (Fig. (Fig.1)1) (2, 8, 17, 19, 23, 25). Recently, Hammer et al. (9) described the cloning and characterization of a 5.8-kb DNA region which encodes the PRN biosynthetic pathway. This DNA region confers the ability to produce PRN when expressed heterologously in Escherichia coli and contains four genes, prnABCD, each of which is required for PRN production. In the research described here, we used mutants in which each of the four genes was disrupted and strains which overexpress the individual genes to elucidate the function of each gene product in PRN biosynthesis. Open in a separate windowFIG. 1Biosynthetic pathways for PRN as proposed by van Pée et al. (23) (A) and by Chang et al. (2) (B). The reactions catalyzed by the PRN biosynthetic enzymes encoded by the prnABCD genes are indicated above the appropriate reaction arrows.
Open in a separate window
Open in a separate windowa+, PRN detected; −, PRN not detected. Hohaus et al. (11) presented additional evidence of the chlorinating activity of the prnA gene product, specifically, the chlorination of l-tryptophan to form 7-CLT by cell extracts from P. fluorescens strains which expressed the prnA gene, but which did not contain any of the other prn genes. To clarify which isomer was produced, Hohaus et al. (11) extracted 7-CLT from the bacteria and oxidized it to the corresponding indole-3-pyruvic acid with amino acid oxidases. Since the isolated 7-CLT was degraded by l-amino acid oxidase, but not by d-amino acid oxidase (11), it must be in the l configuration. The deduced amino acid sequence for prnA contains a consensus NAD binding site (9), and, indeed, NADH is a required cofactor for the prnA gene product.Cultures of BL915ΔORF2 produced 7-CLT, but 7-chloro-d-tryptophan (11) and other PRN biosynthetic intermediates were not detected (Fig. (Fig.3).3). BL915ΔORF2 produced PRN when supplied with exogenous MDA or APRN, but not when supplied with 7-CT (Table (Table2).2). When prnB was expressed in strain BL915ΔORF1–4, exogenously supplied 7-CT was converted to MDA (Fig. (Fig.4).4). These results indicate that the prnB gene product catalyzes the rearrangement of the indole ring to a phenylpyrrole and the decarboxylation of 7-CLT to convert 7-CLT to MDA. While it is somewhat surprising that a single enzyme carries out both the ring rearrangement and decarboxylation, Chang et al. (2) postulated a mechanism for such a reaction on a single enzyme some 16 years ago. The prnB gene product also catalyzed the production of APP (Fig. (Fig.4),4), presumably by using tryptophan as a substrate. Open in a separate windowFIG. 4In vivo conversion of PRN biosynthetic intermediates by the products of single prn genes. Individual genes were expressed on plasmids in the host strain BL915ΔORF1–4, and biosynthetic intermediates were added to the culture medium as indicated. Culture extracts were separated by TLC on silica plates with toluene as the mobile phase. Metabolites were visualized with van Urk’s reagent. Arrows indicate the positions of APP (dark green), MDA (olive green), APRN (reddish brown), and PRN (purple).MDA accumulated in cultures of BL915ΔORF3, but APP, APRN, and PRN were not detected (Fig. (Fig.3).3). BL915ΔORF3 was able to produce PRN when supplied with APRN in the culture medium, but not when supplied with 7-CT or MDA (Table (Table2).2). Strain BL915ΔORF1–4 expressing prnC converted exogenously supplied MDA to APRN (Fig. (Fig.4).4). These data indicate that the prnC gene product catalyzes the chlorination of MDA to form APRN. Cell extracts of the P. fluorescens strain which overexpresses the prnC gene (but does not contain the other prn genes) can also catalyze the chlorination of MDA to form APRN (11).The prnC gene is homologous to the chl gene from Streptomyces aureofaciens, which encodes a chlorinating enzyme for tetracycline biosynthesis (3, 9). Like prnA, the prnC deduced amino acid sequence contains a consensus NAD binding region (9), and NADH is required for the chlorination of MDA (11). While both prnA and prnC encode halogenating enzymes, they show no homology to previously cloned haloperoxidases (9) or to each other. Furthermore, in contrast to haloperoxidases (16), the two NADH-dependent halogenating enzymes in the PRN biosynthesis pathway are substrate specific (i.e., the tryptophan halogenase does not catalyze the chlorination of MDA and vice versa) (11).APRN accumulated in cultures of BL915ΔORF4 (Fig. (Fig.3),3), and this mutant was not able to produce PRN when supplied with any of the known PRN biosynthetic intermediates. Strain BL915ΔORF1–4 expressing prnD converted exogenously supplied APRN to PRN (Fig. (Fig.4).4). These results indicate that the prnD gene product catalyzes the oxidation of the amino group of APRN to a nitro group forming PRN. In vitro experiments by Kirner and van Pée (15) had suggested that this reaction is catalyzed by a chloroperoxidase; however, gene disruption experiments demonstrated that chloroperoxidases are not involved in PRN biosynthesis in vivo (16). Instead, this oxidation is more likely to be catalyzed by a class IA oxygenase (20), as suggested by the homology of prnD with these enzymes (9).We have shown that each prn gene encodes a protein found in the wild-type BL915 strain and have demonstrated in vivo that these four gene products carry out four biochemical steps which convert l-tryptophan to PRN. None of the conversions were observed in strain BL915ΔORF1–4, from which the entire 5.8-kb prn gene region has been deleted (Fig. (Fig.4).4). The arrangement of the genes in the operon is identical to the sequence of reactions in the biosynthetic pathway proposed by van Pée et al. (23) (Fig. (Fig.11).Chang et al. (2) proposed an alternate biosynthetic scheme (Fig. (Fig.1B)1B) and reported the conversion of exogenously supplied APP to PRN in vivo. Similarly, Zhou et al. (25) reported the conversion of APP to APRN in a cell-free system. These workers concluded that APP is an intermediate in PRN biosynthesis and that ring rearrangement precedes chlorination (Fig. (Fig.1B).1B). In the present study, APP accumulated only in strains which overexpressed the prnB gene. Furthermore, APP was not detected in cultures of BL915ΔORF1, which contains functional prnBCD genes expressed from the native promoter, as would be expected if the ring rearrangement (catalyzed by the prnB gene product) occurs before the first chlorination step (catalyzed by the prnA gene product). Like Hamill et al. (8) and van Pée et al. (23), we demonstrated that exogenously supplied 7-CT is converted to PRN. These results, together with the finding that the gene product of prnA catalyzes the NADH-dependent chlorination of l-tryptophan to 7-CLT (11), support the biosynthetic pathway proposed by van Pée et al. (23) (Fig. (Fig.1A)1A) and suggest that APP is a side product or dead-end metabolite. Purification and kinetic characterization of the prnA and prnB gene products, including investigations of substrate specificity and regioselectivity, will further clarify the roles of 7-CLT and APP in the PRN biosynthetic pathway.If APP is indeed a dead-end metabolite, it would be advantageous to tightly regulate the amount of prnB gene product present in cells, thus minimizing the diversion of substrate into APP. The prnB gene begins with GTG (9), which is a two- to threefold-less-efficient initiation codon than ATG (18); however, the prnB open reading frame is apparently translationally coupled to the prnA open reading frame (9). Coupling increases translational efficiency and is thought to be a mechanism to ensure coordinate expression of the coupled genes (18). In PRN biosynthesis, translational coupling of prnA and prnB may be a mechanism to regulate the level of prnB gene product present in cells and minimize the diversion of tryptophan to APP. 相似文献
Bacterial strains and plasmids.
The bacterial strains and plasmids used in this study are described in Table Table1.1. Pseudomonas strains were cultured in Luria-Bertani medium at 28°C. Antibiotics, when used, were added at the following concentrations: tetracycline, 30 μg/ml; and kanamycin, 50 μg/ml. The expression vector pPEH14 consists of the Ptac promoter and rrnB ribosomal terminator from pKK223-3 (Pharmacia, Uppsala, Sweden) cloned into the BglII site of the broad-host-range plasmid pRK290 (4). Ptac is a strong constitutive promoter in Pseudomonas (unpublished data). The PRN biosynthetic genes are the coding regions described by Hammer et al. (9). Each coding region was cloned from the translation initiation codon to the stop codon by PCR with restriction sites added to the ends to facilitate cloning. For prnB, the native GTG initiation codon was changed to ATG. The clones were sequenced after PCR.TABLE 1
Bacterial strains and plasmids used in this study| P. fluorescens strain or plasmid | Characteristics | Source or reference |
|---|---|---|
| Strains | ||
| BL915 | Wild type | 10 |
| BL915ΔORF1 | Deletion in prnA of BL915, Prn−, Kmr | 9 |
| BL915ΔORF2 | Deletion in prnB of BL915, Prn−, Kmr | 9 |
| BL915ΔORF3 | Deletion in prnC of BL915, Prn−, Kmr | 9 |
| BL915ΔORF4 | Deletion in prnD of BL915, Prn−, Kmr | 9 |
| BL915ΔORF1–4 | Deletion in prnABCD of BL915, Prn−, Kmr | 9 |
| Plasmids | ||
| pPEH14(prnA) | pRK290 carrying Ptac functionally fused to the 1.6-kb prnA coding region | This study |
| pPEH14(prnB) | pRK290 carrying Ptac functionally fused to the 1.1-kb prnB coding region | This study |
| pPEH14(prnC) | pRK290 carrying Ptac functionally fused to the 1.7-kb prnC coding region | This study |
| pPEH14(prnD) | pRK290 carrying Ptac functionally fused to the 1.1-kb prnD coding region | This study |
Chemical standards.
7-Cl-d,l-tryptophan (7-CT) was synthesized as described by van Pée et al. (24). Monodechloroaminopyrrolnitrin (MDA) was extracted from cultures of P. aureofaciens and verified as described by van Pée et al. (23). Aminopyrrolnitrin (APRN) was prepared from PRN by reduction with sodium dithionite (22). PRN was synthesized according to the method of Gosteli (6).Western analysis.
To produce antigen, each prn gene was subcloned into a pET3 vector and transformed into E. coli BL21(De3) (Novagen, Inc., Madison, Wis.). Inclusion bodies were purified from induced cultures with protocols from Novagen. Inclusion body protein (100 μg) was run on a preparative Laemmli polyacrylamide electrophoresis gel, blotted to nitrocellulose filters, and stained with Ponceau S. The major band was excised, solubilized in dimethyl sulfoxide, and used by Duncroft, Inc. (Lovettsville, Va.), to immunize goats and produce antiserum against each PRN protein.Cultures of P. fluorescens BL915 were grown for 48 h in Luria-Bertani medium with the appropriate antibiotics. The cells were pelleted and resuspended in a small volume of Tris-EDTA. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western analysis were performed as described by Sambrook et al. (21). The primary antiserum (goat anti-PRN protein) was diluted 1/1,000, and the secondary antibody (rabbit anti-goat immunoglobulin G conjugated to peroxidase; Pierce, Rockford, Ill.) was diluted 1/3,000. Bands were visualized with an enhanced chemiluminescence kit (Amersham, Arlington Heights, Ill.). This Western analysis demonstrated that each antibody recognized a single protein band from wild-type BL915, and these bands were not present in BL915ΔORF1–4 (Fig. (Fig.2).2). The molecular weights of the recognized proteins were consistent with the sizes predicted from the gene sequences. Each prn gene was expressed on a plasmid in BL915ΔORF1–4. In each case, the protein product of the cloned gene reacted only with the expected antibody and was identical in size to the band detected by that antibody in wild-type BL915 (Fig. (Fig.2).2). Open in a separate windowFIG. 2Western blot analysis of the protein products of prn genes cloned from P. fluorescens BL915. Individual genes were expressed on plasmids in the host strain BL915ΔORF1–4. BL915 wild-type and BL915ΔORF1–4 controls are included on each blot. Blots A, B, C, and D were probed with antibodies raised against the products of prnA, prnB, prnC, and prnD, respectively. Arrows indicate the positions of the 60- and 42-kDa molecular mass markers.Intermediate analysis and feeding experiments.
To determine which biosynthetic intermediates were produced by the prn gene deletion mutants, 2-day-old cultures were extracted with an equal volume of ethyl acetate. The organic phase was dried under vacuum, and the residue was dissolved in a small volume of methanol. Thin-layer chromatography (TLC) was performed on silica-coated plates with toluene or hexane-ethyl acetate (2:1) as the mobile phase. PRN, APRN, MDA, and aminophenylpyrrole (APP) were visualized with van Urk’s reagent as described previously (22).To further clarify which biosynthetic step was blocked in each deletion mutant, intermediate feeding experiments were conducted. Cultures (10 ml) were incubated at 28°C for 48 h. Biosynthetic intermediates were dissolved in a small volume of methanol and added to 4 ml of culture at the following final concentrations: 7-CT, 2.5 μg/ml; MDA, 25 μg/ml; APRN, 12.5 μg/ml. The cultures were incubated for an additional 4 h at 28°C and then extracted with ethyl acetate and analyzed by TLC and liquid chromatography-mass spectrometry as described above.MDA, APRN, and PRN were not detected in cultures of BL915ΔORF1 (Fig. (Fig.3),3), indicating that this mutant is blocked at an early step in PRN biosynthesis. BL915ΔORF1 was able to produce PRN when 7-CT, MDA, or APRN was supplied exogenously (Table (Table2).2). When prnA was expressed in the absence of other prn genes (i.e., in BL915ΔORF1–4), 7-chloro-l-tryptophan (7-CLT) accumulated. The identity of 7-CLT was verified by comparison of results of high-performance liquid chromatography and mass spectra with chemically synthesized 7-CT. These results indicate that the prnA gene product catalyzes the chlorination of l-tryptophan. Open in a separate windowFIG. 3Accumulation of PRN biosynthetic intermediates in P. fluorescens BL915 and prn gene deletion mutants derived from it. Extracts from 2-day-old cultures were separated by TLC on silica plates with hexane-ethyl acetate (2:1 [vol/vol]) as the mobile phase. Metabolites were visualized with van Urk’s reagent. Arrows indicate the positions of MDA (olive green), APRN (reddish brown), and PRN (purple).TABLE 2
Production of PRN by deletion mutants when supplied with biosynthetic intermediates in the growth medium| Strain | Result with intermediate added to culturesa
| ||
|---|---|---|---|
| 7-CT | MDA | APRN | |
| BL915ΔORF1 | + | + | + |
| BL915ΔORF2 | − | + | + |
| BL915ΔORF3 | − | − | + |
| BL915ΔORF4 | − | − | − |
82.
Charlotte Lindqvist Lutz Bachmann Liselotte W Andersen Erik W Born Ulfur Arnason Kit M Kovacs Christian Lydersen Alexei V Abramov ØYstein Wiig 《Zoologica scripta》2009,38(2):113-127
The walrus ( Odobenus rosmarus ) is in some current systematic schemes divided into three subspecies: O. r. rosmarus in the North Atlantic, O. r. divergens in the North Pacific and O. r. laptevi in the Laptev Sea. These three subspecies have been described as differing in body size, but the taxonomic status of O. r. laptevi is disputed. The current study applies molecular and morphometric methods to assess the taxonomic status of O. r. laptevi and to analyse the systematic and phylogeographic relationships between the three purported walrus subspecies. Tusk length and tusk circumference were measured from the few skulls available of O. r. laptevi , and the obtained values were within the ranges reported for Pacific walruses. Thus, morphologically, subspecies status for O. r. laptevi is not supported according to the Amadon–Mayr '75% rule'. Phylogenetic analyses and haplotype networks based on mitochondrial nucleotide sequence data of NADH dehydrogenase 1, 16S rRNA, cytochrome oxidase I and the d -loop of the control region of the historic O. r. laptevi bone material and contemporary O. r. rosmarus and O. r. divergens showed that the Laptev Sea walrus groups with individuals from the North Pacific. Thus, the mitochondrial sequence data do not support the recognition of three walrus subspecies as reciprocally monophyletic evolutionary units with independent evolutionary histories. Only O. r. rosmarus and O. r. divergens meet this criterion with the present sampling. Accordingly, we recommend that Odobenus r. laptevi be abandoned and the Laptev walrus instead be recognized as the westernmost population of the Pacific walrus, Odobenus r. divergens. However, further research is recommended to assess whether the Laptev walrus could be considered as a significant unit in terms of conservation and management, since it is unique in several ecological parameters. 相似文献
83.
Giselle L. Saulnier Sholler Eugene W. Gerner Genevieve Bergendahl Robert B. MacArthur Alyssa VanderWerff Takamaru Ashikaga Jeffrey P. Bond William Ferguson William Roberts Randal K. Wada Don Eslin Jacqueline M. Kraveka Joel Kaplan Deanna Mitchell Nehal S. Parikh Kathleen Neville Leonard Sender Timothy Higgins Masao Kawakita Kyoko Hiramatsu Shun-suke Moriya André S. Bachmann 《PloS one》2015,10(5)
BackgroundNeuroblastoma (NB) is the most common cancer in infancy and most frequent cause of death from extracranial solid tumors in children. Ornithine decarboxylase (ODC) expression is an independent indicator of poor prognosis in NB patients. This study investigated safety, response, pharmacokinetics, genetic and metabolic factors associated with ODC in a clinical trial of the ODC inhibitor difluoromethylornithine (DFMO) ± etoposide for patients with relapsed or refractory NB.ConclusionsDFMO doses of 500-1500mg/m2/day are safe and well tolerated in children with relapsed NB. Children with the minor T allele at rs2302616 of the ODC gene with relapsed or refractory NB had higher levels of urinary polyamine markers and responded better to therapy containing DFMO, compared to those with the major G allele at this locus. These findings suggest that this patient subset may display dependence on polyamines and be uniquely susceptible to therapies targeting this pathway.
Trial Registration
Clinicaltrials.gov NCT#01059071 相似文献84.
85.
The centrosome is the principal microtubule organizing center in most animal cells. It consists of a pair of centrioles surrounded by pericentriolar material. The centrosome, like DNA, duplicates exactly once per cell cycle. During interphase duplicated centrosomes remain closely linked by a proteinaceous linker. This centrosomal linker is composed of rootletin filaments that are anchored to the centrioles via the protein C-Nap1. At the onset of mitosis the linker is dissolved by Nek2A kinase to support the formation of the bipolar mitotic spindle. The importance of the centrosomal linker for cell function during interphase awaits characterization. Here we assessed the phenotype of human RPE1 C-Nap1 knockout (KO) cells. The absence of the linker led to a modest increase in the average centrosome separation from 1 to 2.5 μm. This small impact on the degree of separation is indicative of a second level of spatial organization of centrosomes. Microtubule depolymerisation or stabilization in C-Nap1 KO cells dramatically increased the inter-centrosomal separation (> 8 μm). Thus, microtubules position centrosomes relatively close to one another in the absence of linker function. C-Nap1 KO cells had a Golgi organization defect with a two-fold expansion of the area occupied by the Golgi. When the centrosomes of C-Nap1 KO cells showed considerable separation, two spatially distinct Golgi stacks could be observed. Furthermore, migration of C-Nap1 KO cells was slower than their wild type RPE1 counterparts. These data show that the spatial organization of centrosomes is modulated by a combination of centrosomal cohesion and microtubule forces. Furthermore a modest increase in centrosome separation has major impact on Golgi organization and cell migration. 相似文献
86.
Elizabeth Peacock Sarah A. Sonsthagen Martyn E. Obbard Andrei Boltunov Eric V. Regehr Nikita Ovsyanikov Jon Aars Stephen N. Atkinson George K. Sage Andrew G. Hope Eve Zeyl Lutz Bachmann Dorothee Ehrich Kim T. Scribner Steven C. Amstrup Stanislav Belikov Erik W. Born Andrew E. Derocher Ian Stirling Mitchell K. Taylor ?ystein Wiig David Paetkau Sandra L. Talbo 《PloS one》2015,10(8)
87.
Zachary S. Templeton Michael H. Bachmann Rajiv V. Alluri William J. Maloney Christopher H. Contag Bonnie L. King 《Journal of visualized experiments : JoVE》2015,(97)
Bone is the most common site of breast cancer metastasis. Although it is widely accepted that the microenvironment influences cancer cell behavior, little is known about breast cancer cell properties and behaviors within the native microenvironment of human bone tissue.We have developed approaches to track, quantify and modulate human breast cancer cells within the microenvironment of cultured human bone tissue fragments isolated from discarded femoral heads following total hip replacement surgeries. Using breast cancer cells engineered for luciferase and enhanced green fluorescent protein (EGFP) expression, we are able to reproducibly quantitate migration and proliferation patterns using bioluminescence imaging (BLI), track cell interactions within the bone fragments using fluorescence microscopy, and evaluate breast cells after colonization with flow cytometry. The key advantages of this model include: 1) a native, architecturally intact tissue microenvironment that includes relevant human cell types, and 2) direct access to the microenvironment, which facilitates rapid quantitative and qualitative monitoring and perturbation of breast and bone cell properties, behaviors and interactions. A primary limitation, at present, is the finite viability of the tissue fragments, which confines the window of study to short-term culture. Applications of the model system include studying the basic biology of breast cancer and other bone-seeking malignancies within the metastatic niche, and developing therapeutic strategies to effectively target breast cancer cells in bone tissues. 相似文献
88.
Eva C. Schulte Maria Kousi Perciliz L. Tan Erik Tilch Franziska Knauf Peter Lichtner Claudia Trenkwalder Birgit Högl Birgit Frauscher Klaus Berger Ingo Fietze Magdolna Hornyak Wolfgang H. Oertel Cornelius G. Bachmann Alexander Zimprich Annette Peters Christian Gieger Thomas Meitinger Bertram Müller-Myhsok Nicholas Katsanis Juliane Winkelmann 《American journal of human genetics》2014
89.
Annett Mikolasch Veronika Hahn Katrin Manda Judith Pump Nicole Illas Dirk Gördes Michael Lalk Manuela Gesell Salazar Elke Hammer Wolf-Dieter Jülich Stephan Rawer Kerstin Thurow Ulrike Lindequist Frieder Schauer 《Amino acids》2010,39(3):671-683
In order to design potential biomaterials, we investigated the laccase-catalyzed cross-linking between l-lysine or lysine-containing peptides and dihydroxylated aromatics. l-Lysine is one of the major components of naturally occurring mussel adhesive proteins (MAPs). Dihydroxylated aromatics are structurally related to 3,4-dihydroxyphenyl-l-alanine, another main component of MAPs. Mass spectrometry and nuclear magnetic resonance analyses show that the ε-amino group of l-lysine is able to cross-link dihydroxylated aromatics. Additional oligomer and polymer cross-linked products were obtained from di- and oligopeptides containing l-lysine. Potential applications in medicine or industry for biomaterials synthesised via the three component system consisting of the oligopeptide [Tyr-Lys]10, dihydroxylated aromatics and laccase are discussed. 相似文献
90.
Mohd Akif Edward D. Sturrock Brian O. Bachmann 《Biochemical and biophysical research communications》2010,398(3):532-5980
Angiotensin-I converting enzyme (ACE, a zinc dependent dipeptidyl carboxypeptidase) is a major target of drugs due to its role in the modulation of blood pressure and cardiovascular disorders. Here we present a crystal structure of AnCE (an ACE homologue from Drosophila melanogaster with a single enzymatic domain) in complex with a natural product-phosphonotripeptide, K-26 at 1.96 Å resolution. The inhibitor binds exclusively in the S1 and S2 binding pockets of AnCE (coordinating the zinc ion) through ionic and hydrogen bond interactions. A detailed structural comparison of AnCE·K-26 complex with individual domains of human somatic ACE provides useful information for further exploration of ACE inhibitor pharmacophores involving phosphonic acids. 相似文献