A Microbial Biocatalysis Database

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Table of Contents

Cover [109k]
Symbolic Representation of the UM-BBD. The upper part of the figure symbolizes the worldwide distribution of information of interest to biotechnology, using the Kyoto University Ligand Chemical Database and the European Bioinformatics Institute EMBL Nucleic Acid Sequence Database to represent the many databases linked to the UM-BBD. The middle shows links to each of these two databases from one UM-BBD reaction, pentachlorophenol --> 2,3,5,6 tetrachlorohydroxyquinone. The lower part symbolizes a bacterium and its metabolism upon which the entire UM-BBD is based. The image was generated by Brian Beardsley, BioMedical Graphic Communications, University of Minnesota, Minneapolis, MN, 55455, USA.

Title Page


Microbial Biocatalytic Resources on the World Wide Web

The University of Minnesota Biocatalysis/Biodegradation Database

Acknowledgements and Biographical Sketches



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A Microbial Biocatalysis Database

November 3, 1995

Lynda B.M. Ellis* and Lawrence P. Wackett**

*Department of Laboratory Medicine and Pathology,
University of Minnesota, Minneapolis, MN 55455, and
**Department of Biochemistry,
University of Minnesota, St Paul, MN 55108.

Running Head: Biocatalysis Database

Soc. Ind. Microbiol. News (1995) 45(4):167-173.

Corresponding author:
Dr. Lawrence P. Wackett

SIM NEWS (ISSN 1043-4976), is published bi-monthly, one volume per year, by the Society for Industrial Microbiology and is mailed to all SIM members. Price of a single copy for non-members is US$6.00.

Kristien Mortelmans
SRI International
333 Ravenswood Avenue
Menlo Park, CA 94025-3493

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The Carbon Cycle
The recycling of organic matter on Earth is largely predicated on the enormous catalytic diversity of microbial enzymes. Eight million organic compounds are known. Many get into the environment and most do not accumulate there, instead they are chemically transformed by microbial enzymes. The organization of enzymes into well-regulated metabolic pathways provides for the release of energy that can be captured as ATP. Thus, microorganisms burn organic matter for their own metabolic benefit while serving to maintain the Earth's carbon cycle. This ensures that most of the eight million organic compounds do not become sequestered from the Earth's cycles and life is perpetuated.

Microbiologists have long recognized that the enormous diversity of microbial enzymes represents an invaluable resource for biosynthesizing desirable molecules. The fermentation of sugars to ethanol is one of the earliest applications, known in the first recordings of history, although its enzymatic basis was only revealed in 1897 using a microbial cell-free system (Buchner, 1897). In the century since Buchner, largely due to work on microbial systems, intermediary metabolism has been elucidated; antibiotics were discovered and are now biosynthesized; and enzymes are used for other synthetic purposes. An early example of this last application is the use of oxygenases in fungi to catalyze the stereospecific hydroxylation of progesterone to 11-alpha-hydroxyprogesterone (Peterson & Murray, 1952). More recently, molecular biological methods have extended the range of applications for microbial enzymes in biotechnology (Grund, 1995). For example, naphthalene dioxygenase genes, cloned and expressed in E. coli, provide the last enzymatic step for a fermentation process to make the blue jean dye indigo (Ensley et al., 1983).

Microbes have long been used to treat agricultural and industrial wastes. This process, sometimes called biodegradation or bioremediation, is simply microbial metabolism directed against compounds in the environment that are potentially hazardous to animals. The enzymatic basis of biodegradative metabolism, or catabolism, is of great interest. Some of the same enzymes studied for biocatalytic potential in specialty chemical synthesis are also important in the biotransformation of pollutants (Gibson, 1993). For example, naphthalene dioxygenases and related enzymes used in indigo biosynthesis, as mentioned above, also serve to initiate oxidative degradation of polycyclic aromatic hydrocarbons in biological pollution treatment processes.

Better Access to Information is Needed
Innovations in commercial biosynthesis and environmental biotechnology will come from better access to information on microbial biocatalysis. In the past, most applications of bioremediation have been empirically derived and do not use pure cultures or even well-defined microbial consortia. As microbial recombinant techniques become easier, more microbial degradation pathways are discovered, and recycling of wastes to usable chemicals becomes increasingly important, the rational design of organisms for bioremediation is not only desirable, but essential (Timmis et al., 1994).

What is meant by rational design? Consider an example: A company presently produces, as a by-product, a hazardous pollutant that must be disposed of, and wants instead to turn it into a marketable compound. Its staff must answer four fundamental question, summarized in Table 1. First, what are the pollutant's physical properties, toxicology, EPA regulations and other compound-specific data? Second, what metabolic pathways are known both for the biodegradation of the pollutant and the biosynthesis of one or more possible marketable compounds? Third, how can the information gathered in step 2 be used to create a complete metabolic pathway for the desired bioconversion which can be expressed in a host organism? This third step requires a knowledge of gene regulation and factors influencing enzyme expression. Fourth, which organism under which conditions will optimally carry out this bioconversion?

Though Table 1 arbitrarily segregates information on compounds, pathways, macromolecules and organisms, it is clear that all real-world microbial biotechnology problems, including education and training, will require information on most if not all of these. If only one class of information (such as a compound's physical properties) were needed, it might be obtained from traditional sources such as textbooks, catalogues or handbooks. As information needs grow, these traditional sources become increasingly less satisfactory. There is a clear need for a consolidated microbial biotechnology information source accessible to users with diverse backgrounds and interests. These users include workers in: biotechnology companies; companies dealing with organic hazardous waste; government agencies dealing with biotechnology and environmental regulation; and academic teaching and research laboratories.

The important information described above is voluminous and found in many different forms. For example, over 4,000 enzymes have been catalogued (Webb, 1984), many more have been identified, and there are 270,000 known gene sequences in the February, 1995 version of the GenBank nucleic acid sequence database (URL1, Table 2). The number of new GenBank sequences is growing exponentially, with a doubling time of 1.5 years, and is expected to be well over 1,000,000 by the end of the century. This growth is in part due to journals which make submission of novel sequences to a database a prepublication requirement. Besides GenBank, there are many other relevant databases. For example, general enzyme information is stored in the Kyoto Ligand Chemical database (URL2), and the Deutsche Sammlung von Mikroorganismen (DSM) has started a microbial strain database (URL3).

These databases meet some of the needs indicated in Table 1, but there is increasing demand for a consolidated microbial biotechnology information source. This article describes the University of Minnesota Biocatalysis/Biodegradation Database (UM-BBD, URL4), a World Wide Web resource designed to fill that niche. The UM-BBD is organized around metabolic pathways, similar to the Enzyme Metabolic Pathway (EMP) Database at Argonne National Laboratories (URL5). Unlike the EMP, the UM-BBD focuses on microbial enzymes and deals largely with non-intermediary metabolism. The UM-BBD links to the EMP database, where appropriate, to continue these metabolic pathways into intermediary metabolism. To put its information in context, we will first describe the nature and use of the World Wide Web and then continue with the special features of the UM-BBD.

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Microbial Biocatalytic Resources
on the World Wide Web

What is the World Wide Web?
Most industrial and academic scientists have Internet access through their company or institution or through personal or professional accounts with Internet service providers. While some Internet resources have been around for decades, the growth of the World Wide Web (WWW or Web) over the past two years provides a powerful tool to ease access to these resources. The Web is usually available to most persons with "full" Internet access, although its ability to display graphical information is best at higher-speed connections. The Web is based on so-called client/server architecture: clients (also called browsers), housed on individual personal computers or workstations, obtain information from servers on other, often distant, machines. Web client (and server) software exists for almost any computer platform, and is often available at little or no cost. Local system administrators can advise users on how to obtain and use appropriate client software.

URLs and Biotechnology
The Web permits one to assess a wide spectrum of information using convenient links to other databases that are accessed via their addresses, called Uniform Resource Locators (URLs). URLs for many relevant information sources are given in Table 2. The URL for the UM-BBD (URL4) links to its "home page" (Figure 1). Each of the fifteen underlined text words or phrases in Figure 1 is a link to further information. A user follows a link usually by moving a computer mouse to it, and clicking a mouse button. As shown on the cover photograph, and in more detailed form in Figure 2, the Web allows the UM-BBD to link to information on chemical properties, toxicology, enzymes, genes, and intermediary metabolism.

Sources for data on physicochemical properties include on-line Material Safety Data Sheets, such as those being collected at the University of Utah (URL6). For toxicology data, the EXtension TOXicology NETwork, EXTOXNET (URL7), housed at Oregon State University, provides excellent summaries, particularly for agricultural chemicals, and permits full-text searches. The fate of environmental chemicals is largely dependent on their reaction with microbial enzymes, and this is a major focus of the UM-BBD. A key link to the Kyoto University Ligand Chemical Database in Japan (URL2) permits one to access information on over 3,800 enzymes, many of them from microbial systems. From this, one can learn the enzyme class, reaction stoichiometry, and other enzymes that use the same substrate(s) or produce the same product(s). One can also link to nucleic acid sequences, Medline references, reaction graphics and other information directly from the UM-BBD (Figure 2). Features unique to the UM-BBD include graphic and textual reactions and pathway maps, including the organisms which initiate each branch of a pathway (Figure 3).

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The University of Minnesota
Biocatalysis/Biodegradation Database (UM-BBD)

Current Status and Limitations
At present the UM-BBD is in its infancy, and contains information on four representative catabolic pathways: toluene, a simple aromatic; naphthalene, a bicyclic aromatic; atrazine, a halogenated heterocyclic, and pentachlorophenol, a polyhalogenated aromatic compound. It already is being used instructionally, to teach information retrieval and Internet skills to students taking courses in Ecological Biochemistry and Applied & Microbial Biochemistry at the University of Minnesota. An example Internet exercise using the UM-BBD is available from L.W. upon request. Students at the University of Minnesota have evaluated the UM-BBD, commenting favorably on the ease and speed of access and depth of information provided and suggesting changes. This feedback has been used to improve database content and format.

Students and other users have encouraged graphics and even suggested a completely graphical interface to the UM-BBD. However users who may be accessing the database through a slower speed connection or through text-only Web browsers are best served with text. For these reasons, we make graphics supplemental and do not plan to eliminate text.

With all the information sources mentioned earlier, there remain some limitations, especially for information on chemical compounds. We currently transcribe information for some compounds from the CRC Handbook of Data on Organic Compounds (Weast & Grasselli, 1992), though that may change as more chemical manufacturers put their catalogs on line (for example, Fisher Scientific (URL8).

Future Directions
Additional metabolic pathways will be added. Because of the enormous range of microbial catabolism, users of the database are encouraged to contribute these pathways. Initially, much of the contributed information will be from the scientific literature. We will credit each contribution which becomes part of the database. Contributors to the UM-BBD need not be authors of the original work; the original authors will be cited in each reaction. Over time, we expect that contributions will be information not yet found in the published scientific literature. To maintain accuracy, an international external advisory board is being assembled to critically review new entries and guide the future of the UM-BBD. As the UM-BBD grows, its compounds, reactions and eventually even the pathways, will be indexed and made searchable. If we look further into the future, we can speculate that, as is now the case for protein and nucleic acid sequences, journals may require authors reporting novel microbial biocatalytic reactions to submit them to the UM-BBD as a precondition of publication.

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Acknowledgements and
Biographical Sketches

The authors thank Yuemo Zeng for programming assistance. Supported in part by University of Minnesota Bush Sabbatical Supplement Award and Department of Education Title II-D grant support to L.E. and University of Minnesota Biological Process Technology Institute and Genencor, Inc. awards to L.W.

Biographical Sketches
Dr. Lynda Ellis is Associate Professor of Laboratory Medicine and Pathology at the University of Minnesota, Minneapolis, MN. She also holds appointments in the Health Informatics and Pathobiology graduate programs. Dr. Ellis received her Ph.D. in Biochemistry with Robert Abeles at Brandeis University in 1971. She did postdoctoral work with Clare Woodward in the Departments of Laboratory Medicine and Biochemistry at the University of Minnesota until 1973, and that year started at Minnesota. In 1993-94, Dr. Ellis was a visiting Professor in the Department of Biochemistry, University of Minnesota, St Paul.

Dr. Larry Wackett is Associate Professor of Biochemistry and the Biological Process Technology Institute at the University of Minnesota, St. Paul, MN. He also holds appointments in the Microbiology, Microbial Ecology, and Toxicology graduate programs. Dr. Wackett received his Ph.D. in Microbiology with David Gibson at the University of Texas, Austin in 1984. He did postdoctoral research with Chris Walsh in the Chemistry Department at MIT until 1987, and that year started at Minnesota. In 1994, Dr. Wackett was a visiting Professor in the Microbiology Institute at the Swiss Federal Institute of Technology (ETH) in Zurich.

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Buchner, E. (1897). Alcoholische gärung ohne hefezellen. Ber. Dtsch. Chem. Ges. 30:117-124.

Ensley, B.D., Ratzkin, B.J., Osslund, T.D., Simon, M.J., Wackett, L.P. and Gibson, D.T. (1983). Expression of naphthalene oxidation genes in Escherichia coli results in the biosynthesis of indigo. Science 222:167-169.

Gibson, D.T. (1993). Biodegradation, biotransformation and the Belmont. J. Ind. Microbiol. 12:1-12.

Grund, A.D. (1995). Biocatalytic hydroxylation of aromatic hydrocarbons for chemical synthesis. Soc. Ind. Microbiol. News 45:59-63.

Peterson, D.H. and Murray, H.C. (1952). Microbiological oxygenation of steroids at carbon ll. J. Am. Chem. Soc. 74:1871-1872.

Timmis, K.N., Steffan, R.J. & Unterman, R. (1994). Designing microorganisms for the treatment of toxic wastes. Ann Rev. Microbiol. 48:525-557.

Webb, E.C. (1984). Enzyme nomenclature. Academic Press, New York.

Weast, R.C., and Grasselli, J.G. (1992). CRC Handbook of Data on Organic Compounds, 2nd Ed. CRC Press, Inc., Boca Raton, Florida.

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Table 1

Bioconverting a pollutant into a marketable compound: An application of microbial biotechnology and its information needs.

                                        Information Needed On

Questions to be Answered     Compounds  Metabolic  Genes &  Organisms
                                            Pathways   Enzymes

1. What is known of a 
   compound's physical               +        -        -       -
   properties, toxicology, 
   EPA regulations, etc.?   

2. How is a pollutant biodegraded? 
   How is a marketable compound      +        +        -       -

3. How to design or discover
   a bioconversion pathway?          +        +        +       -

4. What are optimal conditions   
   for the biological system?        +        +        +       +
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Table 2

Selected Internet Information Resources for Microbial Biotechnology and their Uniform Resource Locators (URLs)

URL1: GenBank at the National Center for Biotechnology Information

URL2: Kyoto University Ligand Chemical Database

URL3: Deutsche Sammlung von Mikroorganismen (DSM)

URL4: University of Minnesota Biocatalysis/Biodegradation Database

URL5: Enzyme Metabolic Pathways at Argonne National Laboratory

URL6: University of Utah Material Safety Data Sheets

URL7: Extension Toxicology Network at Oregon State University

URL8: Fisher Scientific http://www.fisher1.com/

These URLs were correct when the paper was published. Many have changed over time. To emphasize the transient nature of much on the Web today, we have decided NOT to update these URLs. However a list of these and many more Useful Internet Resources for Microbial Biotechnology is maintained as accurately as possible, as part of the UM-BBD.

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Page Author: Lynda Ellis
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