Biomedical subjects

Christine Orengo

Publications and source records attributed to Christine Orengo.

5 recordsLinked to original sources

PubMed2003

Trimethylaminuria and a human FMO3 mutation database.

Trimethylaminuria (TMAuria), or fish-odor syndrome, is due to defective flavin-containing monooxygenase 3 (FMO3). In the liver, this protein catalyzes the NADPH-dependent oxidative metabolism of odorous trimethylamine (TMA), derived in the gut from dietary sources, to nonodorous trimethylamine N-oxide (TMA N-oxide). Affected individuals are unable to carry out this reaction and consequently exude a fishy body odor, due to the secretion of TMA in their breath and sweat and its excretion in their urine. This leads to a variety of psychosocial problems, including disruption of schooling, clinical depression, and attempted suicide. Twelve missense, three nonsense, and one gross deletion mutation are known to cause TMAuria. FMO3 is also a drug-metabolizing enzyme and compromised activity is expected to have implications for the efficacy of drug treatment and the possibility of adverse drug reactions both in TMAuric patients and in the general population. To date eight polymorphic variants, not associated with TMAuria, have been reported. A human FMO3 mutation database was created using MuStar, a locus-specific database system for maintaining data about allelic variants and distributing these via the World Wide Web. The database currently contains 24 entries and is accessible on the World Wide Web via the URL http://human-fmo3.biochem.ucl.ac.uk/Human_FMO3. Additional entries can be submitted via the curator of the database or via a web-based form.

Alleles↗

PubMed2003

A structural perspective on genome evolution.

Protein translations of over 100 complete genomes are now available. About half of these sequences can be provided with structural annotation, thereby enabling some profound insights into protein and pathway evolution. Whereas the major domain structure families are common to all kingdoms of life, these are combined in different ways in multidomain proteins to give various domain architectures that are specific to kingdoms or individual genomes, and contribute to the diverse phenotypes observed. These data argue for more targets in structural genomics initiatives and particularly for the selection of different domain architectures to gain better insights into protein functions.

Evolution, Molecular↗

PubMed2002

Quantifying the similarities within fold space.

We have used GRATH, a graph-based structure comparison algorithm, to map the similarities between the different folds observed in the CATH domain structure database. Statistical analysis of the distributions of the fold similarities has allowed us to assess the significance for any similarity. Therefore we have examined whether it is best to represent folds as discrete entities or whether, in fact, a more accurate model would be a continuum wherein folds overlap via common motifs. To do this we have introduced a new statistical measure of fold similarity, termed gregariousness. For a particular fold, gregariousness measures how many other folds have a significant structural overlap with that fold, typically comprising 40% or more of the larger structure. Gregarious folds often contain commonly occurring super-secondary structural motifs, such as beta-meanders, greek keys, alpha-beta plait motifs or alpha-hairpins, which are matching similar motifs in other folds. Apart from one example, all the most gregarious folds matching 20% or more of the other folds in the database, are alpha-beta proteins. They also occur in highly populated architectural regions of fold space, adopting sandwich-like arrangements containing two or more layers of alpha-helices and beta-strands.Domains that exhibit a low gregariousness, are those that have very distinctive folds, with few common motifs or motifs that are packed in unusual arrangements. Most of the superhelices exhibit low gregariousness despite containing some commonly occurring super-secondary structural motifs. In these folds, these common motifs are combined in an unusual way and represent a small proportion of the fold (<10%). Our results suggest that fold space may be considered as continuous for some architectural arrangements (e.g. alpha-beta sandwiches), in that super-secondary motifs can be used to link neighbouring fold groups. However, in other regions of fold space much more discrete topologies are observed with little similarity between folds.

Algorithms↗

PubMed2002

Use of structure comparison methods for the refinement of protein structure predictions. I. Identifying the structural family of a protein from low-resolution models.

Predicting the three-dimensional structure of proteins is still one of the most challenging problems in molecular biology. Despite its difficulty, several investigators have started to produce consistently low-resolution predictions for small proteins. However, in most of these cases, the prediction accuracy is still too low to make them useful. In the present article, we address the problem of obtaining better-quality predictions, starting from low-resolution models. To this end, we have devised a new procedure that uses these models, together with structure comparison methods, to identify the structural family of the target protein. This would allow, in a second step not described in the present work, to refine the predictions using conserved features of the identified family. In our approach, the structure database is investigated using predictions, at different accuracy levels, for a given protein. As query structures, we used both low-resolution versions of the native structures, as well as different sets of low accuracy predictions. In general, we found that for predictions with a resolution of > or =5-7 A, structure comparison methods were able to identify the fold of a protein in the top positions.

Databases, Protein↗

PubMed2002

Identification of new herpesvirus gene homologs in the human genome.

Viruses are intracellular parasites that use many cellular pathways during their replication. Large DNA viruses, such as herpesviruses, have captured a repertoire of cellular genes to block or mimic host immune responses, apoptosis regulation, and cell-cycle control mechanisms. We have conducted a systematic search for all homologs of herpesvirus proteins in the human genome using position-specific scoring matrices representing herpesvirus protein sequence domains, and pair-wise sequence comparisons. The analysis shows that approximately 13% of the herpesvirus proteins have clear sequence similarity to products of the human genome. Different human herpesviruses vary in their numbers of human homologs, indicating distinct rates of gene acquisition in different lineages. Our analysis has identified new families of herpesvirus/human homologs from viruses including human herpesvirus 5 (human cytomegalovirus; HCMV) and human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus; KSHV), which may play important roles in host-virus interactions.

Amino Acid Sequence↗