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At least 253 records · Page 14Linked to original sources

The use of the luxA gene of the bacterial luciferase operon as a reporter gene.

Bacterial luciferase can be assayed rapidly and with high sensitivity both in vivo and in vitro. Here we demonstrate that the N-terminal hydrophobic domain of the alpha catalytic subunit of the luciferase enzyme is indispensable for enzyme activity, although N-terminal translational fusions with full luciferase activity can be obtained. Bacterial luciferase is therefore ideally suited as a reporter enzyme for gene fusion experiments. A list of vectors for the convenient use of the luciferase marker genes to monitor gene expression in vivo are presented.

Base Sequence↗

Assay of ATP in intact cells of the facultative phototroph Rhodobacter capsulatus expressing recombinant firefly luciferase.

This study reports on the construction, calibration and use of recombinant cells of Rhodobacter capsulatus expressing the luciferase gene of the North American firefly Photinus pyralis to detect, by bioluminescence, variations of endogenous ATP levels under various physiological conditions. We show that the antibiotic polymyxin B allows luciferin to rapidly move into cell cytosol, but does not make external ATP freely accessible to intracellular luciferase. Notably, in toluene:ethanol-permeabilized cells, the apparent K(mATP) for luciferase (50 microM) is similar to that measured in soluble cell fractions. This finding limits the applicability of the firefly luciferase for monitoring intracellular maximal ATP concentration because dark/aerobic-grown recombinant cells of Rba. capsulatus contain approximately 1.3-2.6+/-0.5 mM ATP. Therefore, the effects of chemical and physical factors such as oxygen, light, carbonyl cyanide m-chlorophenyl hydrazone and antimycin A on ATP synthesis were examined in cells subjected to different starvation periods to reduce the endogenous ATP pool below the luciferase ATP saturation level (< or =0.2 mM). We conclude that the amount of endogenous ATP generated by light is maximal in the presence of oxygen, which is required to optimize the membrane redox poise.

Adenosine Triphosphate↗

Renilla luciferase- Aequorea GFP (Ruc-GFP) fusion protein, a novel dual reporter for real-time imaging of gene expression in cell cultures and in live animals.

Light-emitting reporter proteins play an increasing role in the study of gene expression in vitro and in vivo. Here we present a ruc-gfp fusion gene construct generated by fusing a cDNA for Renilla luciferase (ruc) in-frame with a cDNA encoding the "humanized" GFP (gfp) from Aequorea. A plasmid containing the fusion gene construct was successfully transformed into, and expressed in, mammalian cells. The transformed cells exhibited both Renilla luciferase activity in the presence of coelenterazine and GFP fluorescence upon excitation with UV light. Spectrofluorometry of cells containing the Ruc-GFP fusion protein, in the absence of wavelengths capable of exciting GFP fluorescence but in the presence of the luciferase substrate, coelenterazine, showed an emission spectrum with two peaks at 475 nm and 508 nm. These two peaks correspond to the emission maximum of Renilla luciferase at 475 nm and that of GFP at 508 nm. The peak at 508 nm generated in the presence of coelenterazine alone (without UV excitation) is the result of intramolecular energy transfer from Renilla luciferase to Aequorea GFP. Southern analysis of genomic DNA purified from transformed Chinese hamster ovary (CHO) cells and fluorescence in situ hybridization (FISH) to metaphase chromosomes confirmed the integration of the ruc-gfp fusion gene on a single chromosome. The bifunctional Ruc-GFP fusion protein allows the detection of gene expression at the single-cell level based on green fluorescence, and in a group of cells based on luminescence emission. Furthermore, animal experiments revealed that light emission from the Ruc-GFP fusion protein can be detected externally in the organs or tissues of live animals bearing the gene construct.

Animals↗

Bacterial luciferase activity and the intracellular redox pool in Escherichia coli.

In this study, we analyzed the activity of a bacterial luciferase (LuxAB of Vibrio fischeri) expressed under the control of a consensus-type promoter, lacUV5, in Escherichia coli, and found that activity declines abruptly upon entry into the stationary growth phase. Since this decline was reproducibly observed in strains cultured in various growth media, we refer to this phenomenon as ADLA (Abrupt Decline of Luciferase Activity) and define the time point when activity begins to decline as T (0). Because the levels of luciferase proteins (LuxA and LuxB) remained constant before and after T (0), ADLA cannot be due to the repression of luciferase gene expression. Further analyses suggested that a decline in the supply of intracellular reducing power for luciferase was responsible for ADLA. We also found that ADLA was alleviated or did not occur in several mutants deficient in nucleoid proteins, suggesting that ADLA is a genetically controlled process involved in intracellular redox flow.

Aliivibrio fischeri↗

A study of protein-protein interactions in living cells using luminescence resonance energy transfer (LRET) from Renilla luciferase to Aequorea GFP.

We have previously reported that Escherichia coli and mammalian cells containing a fusion protein consisting of the Renilla luciferase linked to Aequorea GFP exhibited luminescence resonance energy transfer (LRET) from luciferase to GFP in the presence of coelenterazine. In this paper, we describe the construction of two gene fusions in which the cDNA for insulin-like growth factor II (IGF-II) is connected to the cDNA for a "humanized" GFP, and the cDNA for insulin-like growth factor binding protein 6 (IGFBP-6) is linked to a cDNA encoding the Renilla luciferase (RUC). The expression of the fusion gene constructs in CHO cells resulted in single polypeptides with the molecular weights expected for IGF-II-GFP and IGFBP-6-RUC, respectively, based on the use of antibodies against GFP and Renilla luciferase. The secretion of IGF-II-GFP from CHO cells was verified by fluorescence microscopy and the presence of IGFBP-6-RUC in the culture medium was confirmed by luminometry. The interaction between the two known binding partners, IGF-II and IGFBP-6, was monitored by measuring LRET from the IGFBP-6-RUC protein to IGF-II-GFP in the presence of coelenterazine, using a low-light imaging system and spectrofluorometry. Based on these data, luciferase-to-GFP LRET holds great promise for the study of protein-protein interactions in eukaryotic cells in real time.

Animals↗

Bioluminescent enzyme immunoassay for estriol. Use of reversibly inactivated bacterial luciferase as label.

A bioluminescent enzyme immunoassay using estriol labeled with reversibly inactivated bacterial luciferase is described. An estriol derivative bearing an alkylthiolsulfonate is linked to the cysteinyl thiols of luciferase by formation of mixed disulfide linkages; thus, luciferase becomes inactive. After immunoassay, the inactive luciferase of the label bound to the immunoprecipitate is reactivated by incubation with dithiothreitol and the luciferase activity then is quantitated by a 20-s reaction performed with an automated luminometer (LKB 1251). Under the defined conditions, the labels are stable for at least 14 days as tested at 4 degrees C. A standard curve with a wide linear range from 50 to 6000 pg is demonstrated. This unique technology discussed here, therefore, offers exciting possibilities as a sensitive and rapid enzyme immunoassay for estriol.

Estradiol↗

Firefly luciferase luminescence assays using scintillation counters for quantitation in transfected mammalian cells.

The firefly enzyme luciferase catalyzes the luminescent reaction of luciferin with ATP and oxygen. The luciferase gene has recently been cloned and proposed as a reporter gene in procaryotic and eucaryotic cells. We present here a luciferase activity assay which relies on luminescence detection using a standard scintillation counter. This technique is simple, fast, inexpensive, and still very sensitive: as little as 0.02 pg (250,000 molecules) of enzyme is readily detected. The technique is optimized for the luciferase assay in mammalian cell lysates. Thus, the luciferase gene may become a very useful tool for gene regulation studies.

Animals↗

Interaction between luciferases from various species of bioluminescent bacteria and the yellow fluorescent protein of Vibrio fischeri strain Y-1.

The interaction of the Yellow Fluorescent Protein (YFP) from Vibrio fischeri strain Y-1 with luciferases from other bioluminescent bacterial strains have been studied. Addition of purified YFP to a Y-1 luciferase assay results in enhancement of the intensity of blue (484 nm) bioluminescence and a new peak in the emission spectrum at about 540 nm. The bimodal spectrum also resulted when the luciferase used in the reaction was isolated from the species V. fischeri ATCC 7744, V. fischeri Y-1, Photobacterium phosphoreum, and P. leiognathi, but not when the luciferase was from V. harveyi. Analysis of the degree of enhancement versus the amount of YFP added yielded a binding constant for YFP to luciferase (V. fischeri Y-1 and V. harveyi) of about 2.4-4.0 microM.

Bacterial Proteins↗

The nucleotide sequence of the luxA and luxB genes of Xenorhabdus luminescens HM and a comparison of the amino acid sequences of luciferases from four species of bioluminescent bacteria.

The luxA and luxB genes of bioluminescent bacteria encode the alpha and beta subunits of luciferase, respectively. Sequences of the luxA and luxB genes of Xenorhabdus luminescens, the only terrestrial bioluminescent bacterium known, were determined and the amino acid sequence of luciferase deduced. The alpha subunit was found to contain 360 amino acids and has a calculated molecular weight of 41,005 Da, while the beta subunit contains 327 amino acids and has a calculated molecular weight of 37,684 Da. Alignment of this luciferase with the luciferases of three marine bacteria showed 196 (or 55%) conserved residues in the alpha subunit and 114 (or 35%) conserved residues in the beta subunit. The highest degree of homology between any two species was between the luciferases of X. luminescens and Vibrio harveyi with 84% identity in the alpha subunits and 59% identity in the beta subunits.

Amino Acid Sequence↗

The structural origin of the color differences in the bioluminescence of firefly luciferase.

Six chimeric mutants between Hotaria parvula (lambda max = 568 nm) and Pyrocoelia miyako (lambda max = 550 nm) luciferases were reconstructed to determine the structural origin of the color differences in firefly luciferase. Based on light-emitting color, five chimeric luciferases could be divided into two groups: the three green-emitting mutants, classified as P. miyako luciferase, and the two yellow-emitting mutants, classified as H. parvula luciferase. Their common fragments between Val-209 and Ala-318 within each group contain the active site for the color differences.

Amino Acid Sequence↗

Cloning, sequencing and expression of dinoflagellate luciferase DNA from a marine alga, Gonyaulax polyedra.

The marine dinoflagellate, Gonyaulax polyedra emits light in a reaction involving the enzymatic oxidation of its tetrapyrrole luciferin by molecular oxygen; its luciferase (LCF) single chain has an estimated molecular mass of 130 kDa, and exhibits a circadian rhythm in its activity. A cDNA expression library in the lambda ZAPII vector was constructed from the polyadenylated RNA isolated from the Gonyaulax cells during the early night phase, the time at which LCF synthesis is believed to be greatest. Of the approx. 1.2 . 10(5) phages from the library screened with antibody against Gonyaulax LCF, 13 positive plaques were obtained. The nucleotide sequences of two of the larger inserts (2.4 kb and 1.6 kb in length), both carrying the poly(A) tail, were determined and found to be identical in the overlapping region. When expressed in Escherichia coli, both cDNA clones produced active luciferase. A Northern hybridization using the cDNA as a probe showed that the length of the lcf mRNA is approx. 4.1 kb, sufficiently long to encode the 130 kDa LCF. Analyses of polymerase chain reaction products, prepared using both the cloned cDNA and Gonyaulax chromosomal DNA as templates, indicated that the cloned region of the luciferase gene does not carry any introns. This represents the first dinoflagellate luciferase to be cloned and sequenced; its deduced amino acid sequence bears no significant homologies with that of any other luciferase, or any other sequence in the data base.

Amino Acid Sequence↗

Stepwise removal of the C-terminal 12 amino acids of firefly luciferase results in graded loss of activity.

The C-terminus of the firefly luciferase (550 amino acids) was engineered using PCR followed by in vitro transcription-translation in order to investigate the role of the last 12 amino acids in the bioluminescence. Coding sequences were removed stepwise and the decapeptide MRSAMSGLHL, a putative AMP-activated protein kinase phosphorylation site, was used to replace the last 8-12 amino acids in order to test for amino acid specificity at the C-terminus. Removal of up to seven of the C-terminal amino acids resulted in no detectable loss of bioluminescent activity. However, the luciferase activity decreased stepwise from 50 to 0.1% when 8-12 amino acids were removed. Replacement of amino acids 539-550 and 543-550 by MRSAMSGLHL generated luciferases that retained 22 and 35% of catalytic activity respectively. These results have important implications for the further development of engineered luciferases as intracellular indicators and the understanding of the active centre of beetle luciferases.

Amino Acid Sequence↗

Synthesis and pathway of Luciola mingrelica firefly luciferase in Xenopus laevis frog oocytes and in cell-free systems.

Poly (A+)RNA was isolated from the lanterns of adult fireflies of L. mingrelica. The poly (A+)RNA was translated in a cell-free translation mixture from rabbit reticulocyte and from Krebs II mouse ascites cells and in Xenopus laevis frog oocytes. The synthesis of the enzymatically active firefly luciferase was demonstrated in all systems. In the cell-free systems a maximal quantity of luciferase is synthesized during the first 1-2 h, then the decreasing activity of luciferase is observed. The optimal concentration of mRNA for translation in the mouse ascites cell extract was found. The kinetics of the synthesis of the luciferase, its pathway and stability in X. laevis oocytes was studied. It was observed that luciferase is secreted from oocytes into the incubation medium.

Animals↗

Ethanol unfolds firefly luciferase while competitive inhibitors antagonize unfolding: DSC and FTIR analyses.

Firefly luciferase has gained popularity as a protein model in elucidating anaesthesia mechanism because the bioluminescence of the purified enzyme system is extremely sensitive to volatile anaesthetics. This study analysed the thermal unfolding of firefly luciferase by differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR). DSC showed that the transition of firefly luciferase from the folded (N) to unfolded (D) state occurred at 41.7 degrees C with the excess heat flow of 1.6 cal g-1 protein. Ethanol decreased the transition temperature dose dependently. In contrast, luciferin competitors, anilinonaphthalenesulphonate (ANS), toluidinonaphthalenesulphonate (TNS), and myristic acid increased the transition temperature. The competitive inhibitors antagonized unfolding and stabilized the N-state. Ethanol promoted unfolding and stabilized the D-state. Temperature scan by FTIR agreed with the DSC data. The intensities of amide-I' and amide-II' bands started to increase at 20-25 degrees C. This temperature coincides with the temperature where the bioluminescence of firefly luciferase is maximal. The unfolding effect of ethanol was evident even at 5 degrees C. ANS, TNS, and myristic acid completely protected the enzyme from the thermal unfolding. This is the first demonstration that the noncompetitive inhibitors induce the isothermal first-order phase transition in a functional protein, whereas competitive inhibitors protect the enzyme from thermal unfolding. The action mode of competitive inhibitors on firefly luciferase is completely different from that of noncompetitive inhibitors.

Calorimetry, Differential Scanning↗

Red- and green-emitting firefly luciferase mutants for bioluminescent reporter applications.

Light emission from the North American firefly Photinus pyralis, which emits yellow-green (557-nm) light, is widely believed to be the most efficient bioluminescence system known, making this luciferase an excellent tool for monitoring gene expression. Here, we present studies leading to the production of a set of red- and green-emitting luciferase mutants with bioluminescent properties suitable for expanding the use of the P. pyralis system to dual-color reporter assays, biosensor measurements with internal controls, and imaging techniques. Using a combination of mutagenesis methods, we determined that the Ser284Thr mutation was sufficient to create an excellent red-emitting luciferase with a bioluminescence maximum of 615 nm, a narrow emission bandwidth, and favorable kinetic properties. Also, we developed a luciferase, containing the changes Val241Ile, Gly246Ala, and Phe250Ser, whose emission maximum was blue-shifted to 549 nm, providing a set of enzymes whose bioluminescence maxima were separated by 66 nm. Model studies demonstrated that in assays using a set of optical filters, the luciferases could be detected at the attomole level and seven orders of magnitude higher. In addition, in the presence of the Ser284Thr enzyme serving as a control, green light emission could be measured over a 10,000-fold range. The results presented here with the P. pyralis mutants provide evidence that simultaneous multiple analyte assay development is feasible with these novel proteins that require only a single substrate.

Amino Acid Substitution↗

Synthesis of an N-acyl sulfamate analog of luciferyl-AMP: a stable and potent inhibitor of firefly luciferase.

In the first of two half-reactions resulting in the emission of visible light, firefly luciferase forms luciferyl-adenylate from its natural substrates beetle luciferin and Mg-ATP. The acyl-adenylate is subsequently oxidized producing the light emitter oxyluciferin in an electronically excited state. In vitro, under mild conditions of temperature and pH, the acyl-adenylate intermediate is readily hydrolyzed and susceptible to oxidation. We report here the multi-step synthesis and physical and enzymatic characterization of an N-acyl sulfamate analog of luciferyl-adenylate, 5'-O-[(N-dehydroluciferyl)-sulfamoyl]-adenosine (compound 5). This represents the first example of a stable and potent (Ki = 340 nM) reversible inhibitor of firefly luciferase activity based on the structure of the natural acyl-adenylate intermediate. Additionally, we present the results of limited proteolysis studies that demonstrate that the binding of the novel acyl-adenylate analog protects luciferase from proteolysis. The findings presented here are interpreted in the context of the hypothesis that luciferase and the other enzymes in a large superfamily of adenylate-forming proteins adopt two conformations to catalyze two different partial reactions. We anticipate that the novel N-acyl sulfamate analog will be a valuable reagent in future studies designed to elucidate the role of conformational changes in firefly luciferase catalyzed bioluminescence.

Adenosine Monophosphate↗

Implication of a critical residue (Glu175) in structure and function of bacterial luciferase.

Structural properties of a bacterial luciferase mutant, evolved by random mutagenesis, have been investigated. Bacterial luciferases (LuxAB) can be readily classed as slow or fast decay luciferases based on their rates of luminescence decay in a single turnover assay. By random mutagenesis, one of the mutants generated by a single mutation on LuxA at position 175 (E175G) resulted in the "slow decay" Xenorhabdus luminescens luciferase was converted into a luciferase with a significantly more rapid decay rate [Hosseinkhani, S., Szittner, R. and Meighen, E.A. (2005) Biochemical Journal 385, 575-580]. A single mutation (E175G), in a loop that connects alpha helix 5 and beta sheet 5 brought about changes in the kinetic and structural properties of the enzyme. Enhancement of tryptophan fluorescence was observed with a lower degree of fluorescence quenching by acrylamide upon mutation. Near- and far-UV circular dichroism spectra of the native and mutant forms suggested formation of an intermediate structure, further supported by 8-anilino-1-naphthalene-sulphonic acid (ANS) fluorescence which indicated lower exposure of hydrophobic residues as a result of mutation. Fluorescence quenching studies utilizing acrylamide indicated a more accessible fluor for the native form. Thus, the E175G point mutation appears to change the enzymatic decay rate by inducing a substantial tertiary structural change, without a large effect on secondary structural elements, as revealed by Fourier transform IR spectroscopy. Overall, the mutation caused structural changes that go beyond the simple change in orientation of Glu175.

Animals↗

A luciferase-based budding assay for Ebola virus.

The VP40 matrix protein of Ebola virus (EBOV) is capable of budding from mammalian cells as a virus-like particle (VLP) and is the major protein involved in virus egress. A functional budding assay has been developed based upon this characteristic of VP40 to assess the contributions of VP40 sequences as well as host proteins to the budding process. This well-defined assay has been modified for potential use in a high-throughput format in which the detection and quantification of firefly luciferase protein in VLPs represents a direct measure of VP40 budding efficiency. Luciferase was found to be incorporated into budding VP40 VLPs. Furthermore, co-expression of EBOV glycoprotein (GP) enhances release of VLPs containing VP40 and luciferase. In contrast, when luciferase is co-expressed with a budding deficient mutant of VP40, luciferase levels in the VLP fraction decrease significantly. This assay represents a promising high-throughput approach to identify inhibitors of EBOV budding.

Cell Line↗