Biomedical subjects

Bissan Al-Lazikani

Publications and source records attributed to Bissan Al-Lazikani.

6 recordsLinked to original sources

PubMed2006

Defective acute inflammation in Crohn's disease: a clinical investigation.

BACKGROUND: The cause of Crohn's disease has not been mechanistically proven. We tested the hypothesis that the disease is a form of immunodeficiency caused by impaired innate immunity. METHODS: We investigated inflammatory responses in patients and controls by quantifying neutrophil recruitment and cytokine production after acute trauma, interleukin 8 secretion by cultured monocyte-derived macrophages after exposure to inflammatory mediators, and local inflammatory and vascular changes in response to subcutaneous injection of heat-killed Escherichia coli. FINDINGS: In patients with Crohn's disease, trauma to rectum, ileum, or skin led to abnormally low neutrophil accumulation (differences from healthy individuals of 79%, n=8, p=0.0003; 57%, n=3, p=0.05; 50%, n=13, p<0.0001, respectively) and lower production of proinflammatory interleukin 8 (63%, n=7, p=0.003; 63%, n=3, p=0.05; 45%, n=8, p<0.0001) and interleukin 1beta (50%, n=8, p=0.0005). Interleukin 8 secretion by cultured macrophages was reduced after exposure to acute wound fluid (38%, n=50, p<0.0001), C5a (48%, n=41, p=0.0005), or tumour necrosis factor alpha (52%, n=27, p<0.0001). Local inflammatory reaction to inoculation with E coli was attenuated, as quantified by changes in bloodflow (ileal disease 50%, n=6, p=0.01; colonic disease 77%, n=6, p=0.0003). This response was mediated by nitric oxide in controls, was increased by sildenafil in patients, and was not related to CARD15 genotype. INTERPRETATION: In Crohn's disease, a constitutionally weak immune response predisposes to accumulation of intestinal contents that breach the mucosal barrier of the bowel wall, resulting in granuloma formation and chronic inflammation. Polymorphisms in CARD15 do not underlie this phenotype, but incapacitate the NOD2 pathway that can compensate for impairment of innate inflammation. Current treatment of secondary chronic inflammation might exaggerate the underlying lesion and promote chronic disease.

Case-Control Studies↗

PubMed2006

How many drug targets are there?

For the past decade, the number of molecular targets for approved drugs has been debated. Here, we reconcile apparently contradictory previous reports into a comprehensive survey, and propose a consensus number of current drug targets for all classes of approved therapeutic drugs. One striking feature is the relatively constant historical rate of target innovation (the rate at which drugs against new targets are launched); however, the rate of developing drugs against new families is significantly lower. The recent approval of drugs that target protein kinases highlights two additional trends: an emerging realization of the importance of polypharmacology, and also the power of a gene-family-led approach in generating novel and important therapies.

Drug Approval↗

PubMed2005

Effective function annotation through catalytic residue conservation.

Because of the extreme impact of genome sequencing projects, protein sequences without accompanying experimental data now dominate public databases. Homology searches, by providing an opportunity to transfer functional information between related proteins, have become the de facto way to address this. Although a single, well annotated, close relationship will often facilitate sufficient annotation, this situation is not always the case, particularly if mutations are present in important functional residues. When only distant relationships are available, the transfer of function information is more tenuous, and the likelihood of encountering several well annotated proteins with different functions is increased. The consequence for a researcher is a range of candidate functions with little way of knowing which, if any, are correct. Here, we address the problem directly by introducing a computational approach to accurately identify and segregate related proteins into those with a functional similarity and those where function differs. This approach should find a wide range of applications, including the interpretation of genomics/proteomics data and the prioritization of targets for high-throughput structure determination. The method is generic, but here we concentrate on enzymes and apply high-quality catalytic site data. In addition to providing a series of comprehensive benchmarks to show the overall performance of our approach, we illustrate its utility with specific examples that include the correct identification of haptoglobin as a nonenzymatic relative of trypsin, discrimination of acid-d-amino acid ligases from a much larger ligase pool, and the successful annotation of BioH, a structural genomics target.

Amino Acid Sequence↗

PubMed2005

The complement of enzymatic sets in different species.

We present here a comprehensive analysis of the complement of enzymes in a large variety of species. As enzymes are a relatively conserved group there are several classification systems available that are common to all species and link a protein sequence to an enzymatic function. Enzymes are therefore an ideal functional group to study the relationship between sequence expansion, functional divergence and phenotypic changes. By using information retrieved from the well annotated SWISS-PROT database together with sequence information from a variety of fully sequenced genomes and information from the EC functional scheme we have aimed here to estimate the fraction of enzymes in genomes, to determine the extent of their functional redundancy in different domains of life and to identify functional innovations and lineage specific expansions in the metazoa lineage. We found that prokaryote and eukaryote species differ both in the fraction of enzymes in their genomes and in the pattern of expansion of their enzymatic sets. We observe an increase in functional redundancy accompanying an increase in species complexity. A quantitative assessment was performed in order to determine the degree of functional redundancy in different species. Finally, we report a massive expansion in the number of mammalian enzymes involved in signalling and degradation.

Animals↗

PubMed2004

SCOPEC: a database of protein catalytic domains.

MOTIVATION: Domains are the units of protein structure, function and evolution. It is therefore essential to utilize knowledge of domains when studying the evolution of function, or when assigning function to genome sequence data. For this purpose, we have developed a database of catalytic domains, SCOPEC, by combining structural domain information from SCOP, full-length sequence information from Swiss-Prot, and verified functional information from the Enzyme Classification (EC) database. Two major problems need to be overcome to create a database of domain-function relationships; (1) for sequences, EC numbers are typically assigned to whole sequences rather than the functional unit, and (2) The Protein Data Bank (PDB) structures elucidated from a larger multi-domain protein will often have EC annotation although the relevant catalytic domain may lie elsewhere. RESULTS: SCOPEC entries have high quality enzyme assignments; having passed both computational and manual checks. SCOPEC currently contains entries for 75% of all EC annotations in the PDB. Overall, EC number is fairly well conserved within a superfamily, even when the proteins are distantly related. Initial analysis is encouraging; suggesting that there is a 50:50 chance of conserved function in distant homologues first detected by a third iteration PSI-BLAST search. Therefore, we envisage that a knowledge-based approach to function assignment using the domain-EC relationships in SCOPEC will gain a marked improvement over this base line. AVAILABILITY: The SCOPEC database is a valuable resource in the analysis and prediction of protein structure and function. It can be obtained or queried at our website http://www.enzome.com

Catalysis↗

PubMed2003

Sequence, structure and energetic determinants of phosphopeptide selectivity of SH2 domains.

Here, we present an approach for the prediction of binding preferences of members of a large protein family for which structural information for a number of family members bound to a substrate is available. The approach involves a number of steps. First, an accurate multiple alignment of sequences of all members of a protein family is constructed on the basis of a multiple structural superposition of family members with known structure. Second, the methods of continuum electrostatics are used to characterize the energetic contribution of each residue in a protein to the binding of its substrate. Residues that make a significant contribution are mapped onto the protein sequence and are used to define a "binding site signature" for the complex being considered. Third, sequences whose structures have not been determined are checked to see if they have binding-site signatures similar to one of the known complexes. Predictions of binding affinity to a given substrate are based on similarities in binding-site signature. An important component of the approach is the introduction of a context-specific substitution matrix suitable for comparison of binding-site residues. The methods are applied to the prediction of phosphopeptide selectivity of SH2 domains. To this end, the energetic roles of all protein residues in 17 different complexes of SH2 domains with their cognate targets are analyzed. The total number of residues that make significant contributions to binding is found to vary from nine to 19 in different complexes. These energetically important residues are found to contribute to binding through a variety of mechanisms, involving both electrostatic and hydrophobic interactions. Binding-site signatures are found to involve residues in different positions in SH2 sequences, some of them as far as 9A away from a bound peptide. Surprisingly, similarities in the signatures of different domains do not correlate with whole-domain sequence identities unless the latter is greater than 50%. An extensive comparison with the optimal binding motifs determined by peptide library experiments, as well as other experimental data indicate that the similarity in binding preferences of different SH2 domains can be deduced on the basis of their binding-site signatures. The analysis provides a rationale for the empirically derived classification of SH2 domains described by Songyang & Cantley, in that proteins in the same group are found to have similar residues at positions important for binding. Confident predictions of binding preference can be made for about 85% of SH2 domain sequences found in SWISSPROT. The approach described in this work is quite general and can, in principle, be used to analyze binding preferences of members of large protein families for which structural information for a number of family members is available. It also offers a strategy for predicting cross-reactivity of compounds designed to bind to a particular target, for example in structure-based drug design.

Amino Acid Sequence↗