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Biomedical subjects

Charles C Lee

Publications and source records attributed to Charles C Lee.

13 recordsLinked to original sources

Cloning and characterization of a cold-active xylanase enzyme from an environmental DNA library.

There is a great interest in xylanases due to the wide variety of industrial applications for these enzymes. We cloned a xylanase gene (xyn8) from an environmental genomic DNA library. The encoded enzyme was predicted to be 399 amino acids with a molecular weight of 45.9 kD. The enzyme was categorized as a glycosyl hydrolase family 8 member based on sequence analysis of the putative catalytic domain. The purified enzyme was thermolabile, had an activity temperature optimum of 20 degrees C on native xylan substrate, and retained significant activity at lower temperatures. At 4 degrees C, the apparent K (m) was 3.7 mg/ml, and the apparent k (cat) was 123/s.

Agriculture↗

Isolation and characterization of a cold-active xylanase enzyme from Flavobacterium sp.

Xylan is the major component of hemicellulose, and xylan should be fully utilized to improve the efficiencies of a biobased economy. There are a variety of industrial reaction conditions in which an active xylanase enzyme would be desired. As a result, xylanase enzymes with different activity profiles are of great interest. We isolated a xylanase gene (xyn10) from a Flavobacterium sp. whose sequence suggests that it is a glycosyl hydrolase family 10 member. The enzyme has a temperature optimum of 30 degrees C, is active at cold temperatures, and is thermolabile. The enzyme has an apparent Km of 1.8 mg/ml and kcat of 100 sec-1 for beechwood xylan, attacks highly branched native xylan substrates, and does not have activity against glucans.

Amino Acid Sequence↗

Native or raw starch digestion: a key step in energy efficient biorefining of grain.

Improved molecular disassembly and depolymerization of grain starch to glucose are key to reducing energy use in the bioconversion of glucose to chemicals, ingredients, and fuels. In fuel ethanol production, these biorefining steps use 10-20% of the energy content of the fuel ethanol. The need to minimize energy use and to raise the net yield of energy can be met by replacing high-temperature, liquid-phase, enzymatic digestion with low temperature, solid-phase, enzymatic digestion. Also called cold hydrolysis, the approach is a step toward a "green" method for the production of fuel ethanol. There has been substantial prior and increased recent interest in this approach that is presented in this first review of the subject. We include incentives, developmental research, fundamental factors of raw starch digestion, and novel approaches in enzymology and processing. The discussion draws on resources found in enzymology, engineering, plant physiology, cereal chemistry, and kinetics.

Amylases↗

Principles governing auditory cortex connections.

Topographic maps are common constituents of the primary auditory, visual, and somatic sensory cortex. However, in most cortical areas, no such maps have yet been identified, posing a conceptual problem for theories of cortical function centered on topography. What principle guides the organization of these other areas? We investigated this issue in cat auditory cortex. The connectional topography of five tonotopic areas and eight non-tonotopic areas was assessed using retrograde tract tracing and quantified by three metrics: clustering, dispersion, and separation. Clustering measures the spatial density of labeled neurons, dispersion provides an index of their spread, and separation serves as a scaling metric. These parameters each show that all auditory cortical regions receive precise and equally topographic connections from thalamic, corticocortical, and commissural sources. This isotropic principle suggests a common substrate for coordinating communication across the cortex and may reflect common mechanisms related to the developmental patterning of connections. This unifying principle extends to auditory and prefrontal cortex, and perhaps to other neocortical areas.

Animals↗

An episomal expression vector for screening mutant gene libraries in Pichia pastoris.

Screening mutant gene libraries for isolating improved enzyme variants is a powerful technique that benefits from effective and reliable biological expression systems. Pichia pastoris is a very useful organism to express proteins that are inactive in other hosts such as Escherichia coli and Saccharomyces cerevisiae. However, most P. pastoris expression plasmids are designed to integrate into the host chromosome and hence are not as amenable to high-throughput screening projects. We have designed a P. pastoris expression vector, pBGP1, incorporating an autonomous replication sequence that allows the plasmid to exist as an episomal element. This vector contains the alpha-factor signal sequence to direct secretion of the mutant enzymes. Expression of the genes is driven by the constitutive GAP promoter, thus eliminating the need for timed or cell density-specific inductions. The pBGP1 plasmid was used to screen a xylanase gene library to isolate higher activity mutants.

Bleomycin↗

Cloning and characterization of the xyn11A gene from Lentinula edodes.

Hemicellulose represents a rich source of biomass that can be converted into useful chemical feedstocks. One of the main components of hemicellulose is xylan, a polymer of xylose residues. Xylanase enzymes that hydrolyze xylan are therefore of great commercial interest. We have cloned a gene (xyn11A) that encodes a 283-amino acid xylanase enzyme from the fungus Lentinula edodes. The enzyme has a pI of 4.6 and belongs to the highly conserved glycosyl hydrolase family 11. The xylanase gene was cloned into a Pichia pastoris expression vector that secretes active enzyme into both solid and liquid media. The optimal reaction conditions were at pH 4.5 and 50 degrees C. The enzyme had a Km of 1.5 mg/ml and a Vmax of 2.1 mmol/min/mg. Xyn11A produced primarily xylobiose, xylotriose, and xylotetraose from a birchwood xylan substrate. This is the first report on the cloning of a hemicellulase gene from L. edodes.

Amino Acid Sequence↗

Characterization of active Lentinula edodes glucoamylase expressed and secreted by Saccharomyces cerevisiae.

The gene encoding Lentinula edodes glucoamylase (GLA) was cloned into Saccharomyces cerevisiae, expressed constitutively and secreted in an active form. The enzyme was purified to homogeneity by (NH4)2SO4 fractionation, anion exchange and affinity chromatography. The protein had a correct N-terminal sequence of WAQSSVIDAYVAS, indicating that the signal peptide was efficiently cleaved. The recombinant enzyme was glycosylated with a 2.4% carbohydrate content. It had a pH optimum of 4.6 and a pH 3.4-6.4 stability range. The temperature optimum was 50 degrees C with stability <or=50 degrees C. The enzyme showed considerable loss of activity when incubated with glucose (44%), glucosamine (68%), galactose (22%), and xylose (64%). The addition of Mn++ activated the enzyme by 45%, while Li+, Zn++, Mg++, Cu+, Ca++, and EDTA had no effect. The enzyme hydrolyzed amylopectin at rates 1.5 and 8.0 times that of soluble starch and amylose, respectively. Soluble starch was hydrolyzed 16 and 29 times faster than wheat and corn starch granules, respectively, with the hydrolysis of starch granules using 10x the amount of GLA. Apparent Km and Vmax for soluble starch were estimated to be 3.0 mg/ml and 0.13 mg/ml/min (40 degrees C, pH 5.3), with an apparent kcat of 2.9 x 10(5) min(-1).

Amino Acid Sequence↗

Auditory thalamocortical transformation: structure and function.

Communicative, predatory, and reproductive behaviors rely on the auditory thalamocortical system, a key nexus that combines, transforms, and distributes virtually all acoustic information relevant to survival. The rules of connectivity for this complex network, both anatomically and functionally, are only beginning to be uncovered. Although the auditory thalamocortical system shares many features with other modalities, its connectivity and information processing principles differ from those of other modalities in many ways. Some physiological and anatomical bases for these differences are the subject of this review.

Animals↗

Enzyme-coupled assay for beta-xylosidase hydrolysis of natural substrates.

We describe here a new enzyme-coupled assay for the quantitation of d-xylose using readily available enzymes that allows kinetic evaluation of hemicellulolytic enzymes using natural xylooligosaccharide substrates. Hydrogen peroxide is generated as an intermediary analyte, which allows flexibility in the choice of the chromophore or fluorophore used as the final reporter. Thus, we present d-xylose quantitation results for solution-phase assays performed with both the fluorescent reporter resorufin, generated from N-acetyl-3,7-dihydroxyphenoxazine (Amplex Red), and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonate) (ABTS), whose corresponding radical cation has an absorbance maximum at approximately 400 nm. We also describe a useful solid-phase variation of the assay performed with the peroxidase substrate 3,3'-diaminobenzidine tetrahydrochloride, which produces an insoluble brown precipitate. In addition, kinetic parameters for hydrolysis of the natural substrates xylobiose and xylotriose were obtained using this assay for a glycosyl hydrolase family 39 beta-xylosidase from Thermoanaerobacterium sp. strain JW/SL YS485 (Swiss-Prot accession no. O30360). At higher xylobiose substrate concentrations the enzyme showed an increase in the rate indicative of transglycosylation, while for xylotriose marked substrate inhibition was observed. At lower xylobiose concentrations k(cat) was 2.7 +/- 0.4 s(-1), K(m) was 3.3 +/- 0.7 mM, and k(cat)/K(m) was 0.82 +/- 0.21 mM(-1) . s(-1). Nonlinear curve fitting to a substrate inhibition model showed that for xylotriose K(i) was 1.7 +/- 0.1 mM, k(cat) was 2.0 +/- 0.1 s(-1), K(m) was 0.144 +/- 0.011 mM, and k(cat)/K(m) was 14 +/- 1.3 mM(-1) . s(-1).

Benzothiazoles↗

High-activity barley alpha-amylase by directed evolution.

Barley alpha-amylase isozyme 2 was cloned into and constitutively secreted by Saccharomyces cervisiae. The gene coding for the wild-type enzyme was subjected to directed evolution. Libraries of mutants were screened by halo formation on starch agar plates, followed by high-throughput liquid assay using dye-labeled starch as the substrate. The concentration of recombinant enzyme in the culture supernatant was determined by immunodetection, and used for the calculation of specific activity. After three rounds of directed evolution, one mutant (Mu322) showed 1000 times the total activity and 20 times the specific activity of the wild-type enzyme produced by the same yeast expression system. Comparison of the amino acid sequence of this mutant with the wild type revealed five substitutions: Q44H, R303K and F325Y in domain A, and T94A and R128Q in domain B. Two of these mutations. Q44H and R303K, result in amino acids highly conserved in cereal alpha-amylases. R303K and F325Y are located in the raw starch-binding fragment of the enzyme molecule.

Amino Acid Sequence↗

Concurrent tonotopic processing streams in auditory cortex.

The basis for multiple representations of equivalent frequency ranges in auditory cortex was studied with physiological and anatomical methods. Our goal was to trace the convergence of thalamic, commissural, and corticocortical information upon two tonotopic fields in the cat, the primary auditory cortex (AI) and the anterior auditory field (AAF). Both fields are among the first cortical levels of processing. After neurophysiological mapping of characteristic frequency, we injected different retrograde tracers at separate, frequency-matched loci in AI and AAF. We found differences in their projections that support the notion of largely segregated parallel processing streams in the auditory thalamus and cerebral cortex. In each field, ipsilateral cortical input amounts to approximately 70% of the number of cells projecting to an isofrequency domain, while commissural and thalamic sources are each approximately 15%. Labeled thalamic and cortical neurons were concentrated in tonotopically predicted regions and in smaller loci far from their spectrally predicted positions. The few double-labeled thalamic neurons (<2%) are consistent with the hypothesis that information to AI and AAF travels along independent processing streams despite widespread regional overlap of thalamic input sources. Double labeling is also sparse in both the corticocortical and commissural systems ( approximately 1%), confirming their independence. The segregation of frequency-specific channels within thalamic and cortical systems is consistent with a model of parallel processing in auditory cortex. The global convergence of cells outside the targeted frequency domain in AI and AAF could contribute to context-dependent processing and to intracortical plasticity and reorganization.

Acoustic Stimulation↗

Direct screening of libraries of yeast clones for alpha-amylase activity on raw starch hydrolysis.

High-throughput screening for high-activity barley alpha-amylase mutants expressed in Saccharomyces cerevisiae is hampered by the interference of reducing agents, particularly the glucose used in yeast growth media. The present investigation employed colorimetric and chemiluminescent detection systems that enable direct and rapid screening of activities on raw starch substrate. Active clones could be separated into two groups, based on high total activity or high specific activity.

Base Sequence↗

Increased expression and secretion of recombinant alpha-amylase in Saccharomyces cerevisiae by using glycerol as the carbon source.

Saccharomyces cerevisiae transformed with plasmids containing the barley alpha-amylase gene was cultured, and enzyme activity and cell density were monitored at various time intervals. Proteins in yeast extract and culture medium were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Western blots of intra- and extracellular proteins were sequentially probed with anti-amylase antibody and anti-rabbit horseradish peroxidase conjugate, followed by chemiluminescent detection. The enzyme activity of recombinant barley alpha-amylase secreted by the yeast clone DY150[pYEX-Amyl] showed a significant increase when the culture medium included glycerol as the carbon source. The enhancement reached a 4.5-fold increase at 120 hr, and the effect was strain-nonspecific. Intra- and extracellular proteins increased significantly with time in both the yeast clone and the control grown in YEPG (2% yeast extract, 1% bacto-peptone, 2% glycerol). Proteins in YEPD (2% yeast extract,1% bacto-peptone, 2% glucose) and YEPG cultures showed very different band patterns, indicating that the metabolic pathway was altered. Western blot analysis indicated that the recombinant amylase accumulated inside yeast cells, at a relatively low level, compared with that in the culture medium. The transcript level of the alpha-amylase gene was significantly increased in the clone cultured in YEPG. This investigation demonstrates that the use of glycerol as a carbon source for S. cerevisiae enhances the synthesis and secretion of the recombinant enzyme while suppressing cell growth.

Blotting, Western↗