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Biomedical subjects

T C Hodgman

Publications and source records attributed to T C Hodgman.

At least 19 recordsLinked to original sources
PubMed2004

Constructing an enzyme-centric view of metabolism.

MOTIVATION: The current paradigm for viewing metabolism, such as the Boehringer Chart or KEGG, takes a metabolite-centric view that is not ideal for genomics analysis because the same enzyme can appear in multiple places. Therefore an enzyme-centric view is also required. RESULTS: We have eliminated synonymous compound names taken from the ENZYME database ensuring that it is computationally parseable at all levels. Based on these results, we have written a software to create enzyme-centric graphs from reaction data, and we have created a second dataset with hub molecules removed, allowing a greater depth of information to be extracted from these graphs. We also present a detailed analysis of the various stages of the reconditioning process and the characteristics of the subgraphs resulting from the application of our software to the revised datasets. AVAILABILITY: Complete datasets and supplementary material may be downloaded from http://helix.ex.ac.uk/metabolism. The software for the creation of enzyme-centric graphs from reaction data is available on request from the authors.

Computer Simulation↗
PubMed2003

The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models.

MOTIVATION: Molecular biotechnology now makes it possible to build elaborate systems models, but the systems biology community needs information standards if models are to be shared, evaluated and developed cooperatively. RESULTS: We summarize the Systems Biology Markup Language (SBML) Level 1, a free, open, XML-based format for representing biochemical reaction networks. SBML is a software-independent language for describing models common to research in many areas of computational biology, including cell signaling pathways, metabolic pathways, gene regulation, and others. AVAILABILITY: The specification of SBML Level 1 is freely available from http://www.sbml.org/

Database Management Systems↗
PubMed2001

Simultaneous modelling of metabolic, genetic and product-interaction networks.

The creation of cell models from annotated genome information, as well as additional data from other databases, requires both a format and medium for its distribution. Standards are described for the representation of the data in the form of Document Type Definitions (DTDs) for XML files. Separate DTDs are detailed for genetic, metabolic and gene product-interaction networks, which can be used to hold information on individual subsystems, or which may be combined to create a whole cell DTD. In the execution of this work, a fifth DTD was also created for a metabolite thesaurus, which allows incorporation of metabolite synonyms and generic nomenclature data into the models. A gene-regulation classification scheme was also created, to facilitate incorporation of gene regulatory information in an efficient manner. The work is described with particular reference to the metabolic network of Escherichia coli, which contains 808 individual enzymes. The assignment of confidence levels to these data, through the use of Gene Ontology evidence codes, is highlighted. In silico investigations may now be performed using the mathematical simulation workbench, DBsolve, which incorporates the facility to introduce data directly from XML.

Computational Biology↗
PubMed2000

Comparison of functional annotation schemes for genomes.

In this paper we survey a number of functional classification schemes applicable to genomes. We present the concepts of depth, breadth and resolution as descriptors of the schemes' scope and architecture and compare selected classifications according to these criteria. We also generate a 'Combined Scheme' against which we map six classifications which we believe are representative of the range currently available. The mapping allows the generation of 'FuncWheels', which are graphical representations of hierarchical classification schemes. They are used to illustrate similarities and differences in functional space coverage. This survey highlights many issues related to the design and implementation of gene product functional classifications, which are discussed in the light of emerging 'second-generation' schemes.

Animals↗
PubMed2000

A historical perspective on gene/protein functional assignment.

Sequence determination and analysis began on proteins in the 1950s, with RNA starting about a decade later and DNA a similar period later still. Hence many of the concepts for function prediction were first developed by looking at amino acid sequences. Over time these methods have become much more sophisticated, allowing better discrimination of only weak similarities. The most recent developments concern an examination of contextual information, such as operon structure, metabolic reconstruction or co-expression profiles.

Genes↗
PubMed1999

Mathematical simulation and analysis of cellular metabolism and regulation.

MOTIVATION: A better understanding of the biological phenomena observed in cells requires the creation and analysis of mathematical models of cellular metabolism and physiology. The formulation and study of such models must also be simplified as far as possible to cope with the increasing complexity demanded and exponential accumulation of the metabolic reconstructions computed from sequenced genomes. RESULTS: A mathematical simulation workbench, DBsolve, has been developed to simplify the derivation and analysis of mathematical models. It combines: (i) derivation of large-scale mathematical models from metabolic reconstructions and other data sources; (ii) solving and parameter continuation of non-linear algebraic equations (NAEs), including metabolic control analysis; (iii) solving the non-linear stiff systems of ordinary differential equations (ODEs); (iv) bifurcation analysis of ODEs; (v) parameter fitting to experimental data or functional criteria based on constrained optimization. The workbench has been successfully used for dynamic metabolic modeling of some typical biochemical networks (Dolgacheva et al., Biochemistry (Moscow), 6, 1063-1068, 1996; Goldstein and Goryanin, Mol. Biol. (Moscow), 30, 976-983, 1996), including microbial glycolytic pathways, signal transduction pathways and receptor-ligand interactions. AVAILABILITY: DBsolve 5. 00 is freely available from http://websites.ntl.com/ approximately igor.goryanin. CONTACT: gzz78923@ggr.co.uk

Algorithms↗
PubMed1998

Nucleoprotein architecture and ColE1 dimer resolution: a hypothesis.

Dimers of plasmid ColE1 are converted to monomers by site-specific recombination, a process that requires 240 bp of DNA (cer) and four host-encoded proteins (XerC, XerD, ArgR and PepA). Here, we propose structures for nucleoprotein complexes involved in cer-Xer recombination based upon existing knowledge of the structures of component proteins and computational analyses of protein structure and DNA curvature. We propose that, in the nucleoprotein complex at a single cer site, a PepA hexamer acts as an adaptor, connecting the heterodimeric recombinase (XerCD) to an ArgR hexamer. This provides a protein core around which the cer site wraps, its exact path being defined by strong sequence-specific interactions with ArgR and XerCD, weak interactions with PepA and sequence-dependent flexibility of cer. The initial association of single-site complexes (pairing) is proposed to occur via an ArgR-PepA interaction. Pairing between sites in a plasmid dimer is stabilized by DNA supercoiling and is followed by a structural isomerization to form a recombination-proficient synaptic complex. We propose that paired structures formed between sites in trans are too short-lived to permit synaptic complex formation. There is thus an energetic barrier to inappropriate recombination reactions. Our proposals are consistent with a wide range of experimental observations.

Acetyltransferases↗
PubMed1998

Automated management of gene discovery projects.

UNLABELLED: The paper reports on programs, organization and Hypertext Mark-up Language (HTML) presentation provided by the Hierarchical Automated Gene Identification System (HAGIS) designed for managing sequencing projects. AVAILABILITY: On request from the authors. CONTACT: st23646@ggr.co.uk

Computational Biology↗
PubMed1997

Lewis X biosynthesis in Helicobacter pylori. Molecular cloning of an alpha(1,3)-fucosyltransferase gene.

The lipopolysaccharide of certain strains of Helicobacter pylori was recently shown to contain the Lewis X (Lex) trisaccharide (Galbeta-1, 4-(Fucalpha(1,3))-GlcNAc). Lex is an oncofetal antigen which appears on human gastric epithelium, and its mimicry by carbohydrate structures on the surface of H. pylori may play an important part in the interaction of this pathogen with its host. Potential roles for bacterial Lex in mucosal adhesion, immune evasion, and autoantibody induction have been proposed (Moran, A. P., Prendergast, M. M., and Appelmelk, B. J. (1996) FEMS Immunol. Med. Microbiol. 16, 105-115). In mammals, the final step of Lex biosynthesis is the alpha(1,3)-fucosylation of GlcNAc in a terminal Galbeta(1-->4)GlcNAc unit, and a corresponding GDP-fucose:N-acetylglucosaminyl alpha(1,3) fucosyltransferase (alpha(1,3)-Fuc-T) activity was recently discovered in H. pylori extracts. We used part of a human alpha(1, 3)-Fuc-T amino acid sequence to search an H. pylori genomic data base for related sequences. Using a probe based upon weakly matching data base sequences, we retrieved clones from a plasmid library of H. pylori DNA. DNA sequence analysis of the library clones revealed a gene which we have named fucT, encoding a protein with localized homology to the human alpha(1,3)-Fuc-Ts. We have demonstrated that fucT encodes an active Fuc-T enzyme by expressing the gene in Escherichia coli. The recombinant enzyme shows a strong preference for type 2 (e.g. LacNAc) over type 1 (e.g. lacto-N-biose) acceptors in vitro. Certain residues in a short segment of the H. pylori protein are completely conserved throughout the alpha(1,3)-Fuc-T family, defining an alpha(1,3)-Fuc-T motif which may be of use in identifying new fucosyltransferase genes.

Amino Acid Sequence↗
PubMed1997

A new dynamic tool to perform assembly of expressed sequence tags (ESTs).

MOTIVATION: Expressed Sequence Tags (ESTs) are short single-pass DNA sequences obtained from either ends of cDNA clones. To exploit these sequences efficiently, a dynamic Web-tool has been developed which uses these data to perform fast virtual cloning of cDNAs. RESULTS: Starting with a query sequence, the user is able to identify related ESTs and extend the sequence of interest step by step, possibly to a full-length transcript. Graphical views of the clustering are used to monitor the progress of a particular 'cloning' project. Potential open reading frames are detected by positional base preference, and hyperlinks to other Worldwide Web sites allows the user to retrieve information relevant to each EST in a cluster (e.g. sequence traces, clone size, plate position). Apart from cDNA cloning, this tool also provides a mechanism for collating gene families and polymorphism sites.

Algorithms↗
PubMed1997

Cloning and analysis of the first cry gene from Bacillus popilliae.

An 80-kDa parasporal crystal protein was detected in protein extracts of sporangia of Bacillus popilliae isolated from a diseased larva of the common cockchafer (Melolontha melolontha L.). Amino acid analysis of tryptic peptides revealed significant homology to the Cry2Aa endotoxins of Bacillus thuringiensis. The gene cryBP1 (cry18Aa1), which codes for the parasporal crystal protein, was found in a putative cry operon on the bacterial chromosome, which contains at least one further (smaller) open reading frame, orf1. The 706-amino-acid-long CryBP1 (Cry18Aa1) protein has a predicted molecular mass of 79 kDa and shows about 40% sequence identity to the Cry2 polypeptides of B. thuringiensis. In the light of published observations which suggest that the parasporal crystal proteins of B. popilliae are slightly toxic to their grub hosts, we propose the following survival strategy of B. popilliae. As an obligate pathogen of grubs, B. popilliae germinates in the gut of a grub and the parasporal crystal proteins are released and activated. The activated protein does not cause colloid osmotic lysis but instead damages the gut wall somehow to allow the vegetative cells to enter the hemolymph more easily. By becoming a parasite, B. popilliae can continue to proliferate efficiently while the living grub provides a food supply. This process is in contrast to that of B. thuringiensis, which rapidly kills the insect and is then limited to growth on the larval carcass.

Amino Acid Sequence↗
PubMed1993

Characterization of a Bacillus thuringiensis strain which is toxic to the housefly Musca domestica.

A Bacillus thuringiensis isolate has been discovered which is toxic to the common housefly (Musca domestica) as well as other Diptera and Lepidoptera. Crystal delta-endotoxins purified from this isolate killed 50% of Musca larvae at a concentration of 10.2 micrograms/ml, and beta-exotoxin was not detected. Sodium dodecyl polyacrylamide gel electrophoresis of the purified crystals revealed three protein species which were related to CryIA(b), CryIB and CryIIA toxins on the basis of immunoreactivity and amino-terminal sequence determination. Southern blot and DNA restriction analyses suggested that the strain has sequences related to one cryIA(b), one cryIIA, and two cryIIB genes.

Amino Acid Sequence↗
PubMed1993

Identification of a cryptic gene associated with an insertion sequence not previously identified in Bacillus thuringiensis.

After screening several Bt strains with a cryII toxin probe, clones from two strains were found to contain a cryptic cryIIB gene associated with an insertion sequence element belonging to the IS2/IS3 family. The lack of expression of this gene appears to result from mutation of the upstream orf2 gene which has been shown to be necessary for cryII expression.

Amino Acid Sequence↗
PubMed1992

Secondary structure analysis identifies a putative mouse protein demonstrating similarity to the repeat units found in CDC4, the G protein beta subunits and related proteins.

The predicted protein product of an anonymous clone isolated from a cDNA library prepared from 12 day post coitum (p.c) embryonic mouse heart tissue demonstrated the same segmental repeats previously identified in the cell division control protein, CDC4 and the G protein beta 1 subunit. A search of the protein database subsequently identified three other classes of protein containing the repeat. Secondary structure analyses performed on the repeat sequences revealed a high degree of conservation suggesting that the repeat motif performs a specific function in a diverse range of proteins.

Amino Acid Sequence↗
PubMed1990

The construction of Bacillus thuringiensis strains expressing novel entomocidal delta-endotoxin combinations.

Using our recently reported method of electroporation to transform Bacillus thuringiensis [Bone & Ellar (1989) FEMS Microbiol. Lett. 58, 171-178], cloned B. thuringiensis entomocidal delta-endotoxin genes have been introduced into several native B. thuringiensis strains. In many cases the resulting transformants expressed both their native toxins and the cloned toxin, producing strains with broader toxicity spectra. The introduction of the var. tenebrionis toxin gene into B. thuringiensis var. israelensis resulted in a strain with activity against Pieris brassicae (cabbage white butterfly), an activity which neither parent strain possesses. We discuss further the possibility of synergism and also the problems associated with introducing cloned DNA by this method.

Bacillus thuringiensis↗
PubMed1989

The elucidation of protein function by sequence motif analysis.

Protein sequence motifs are acquiring increasing prominence in the area of sequence analysis. This review describes the current methods of their construction and their use in the determination of protein function, and offers guidelines on interpreting data obtained. An appendix is attached which refers to 200 motifs of various kinds.

Amino Acid Sequence↗