Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 20
Filter
2.
Br J Gen Pract ; 73(736): e798-e806, 2023 11.
Article in English | MEDLINE | ID: mdl-37722858

ABSTRACT

BACKGROUND: Hypertension is a key modifiable risk factor for cardiovascular disease - the leading cause of death in the UK. Good blood pressure (BP) control reduces mortality. However, health inequities may lead to variability in hypertension monitoring and control. AIM: To investigate health inequities related to ethnicity, sex, age, and socioeconomic status in the monitoring, treatment, and control of BP in a large cohort of adult patients with hypertension. DESIGN AND SETTING: A cross-sectional cohort study of adults with hypertension registered with general practices in North East London on 1 April 2019. METHOD: Multivariable logistic regression was used to estimate associations of demographics and treatment intensity for the following hypertension management indicators: a) BP recording in past 12 months; b) BP on age- adjusted target; and c) BP on age-adjusted target and BP recorded in past 12 months. RESULTS: In total, 156 296 adults were included. The Black ethnicity group was less likely to have controlled BP than the White ethnicity group (odds ratio [OR] 0.87, 95% [confidence interval] CI = 0.84 to 0.91). The Asian ethnicity group was more likely to have controlled BP (OR 1.28, 95% CI = 1.23 to 1.32). Ethnicity differences in control could not be explained by the likelihood of having a recent BP recording, nor by treatment intensity differences. Older adults (aged ≥50 years) were more likely to have controlled hypertension than younger patients. CONCLUSION: Individuals of Black ethnicity and younger people are less likely to have controlled hypertension and may warrant targeted interventions. Possible explanations for these findings are presented but further research is needed about reasons for ethnic differences.


Subject(s)
Cardiovascular Diseases , Hypertension , Aged , Humans , Cardiovascular Diseases/etiology , Cross-Sectional Studies , Electronic Health Records , Hypertension/drug therapy , Hypertension/epidemiology , Hypertension/complications , London/epidemiology , Middle Aged , Male , Female , Adult
3.
BJGP Open ; 6(4)2022 Dec.
Article in English | MEDLINE | ID: mdl-36028299

ABSTRACT

BACKGROUND: Patients with both atrial fibrillation (AF) and cardiovascular disease (CVD) may receive dual antithrombotic therapy (DAT) with both an anticoagulant and ≥1 antiplatelet agents. Avoiding prolonged duration of DAT and use of gastroprotective therapies reduces bleeding risk. AIM: To describe the extent and duration of DAT and use of gastroprotection in a primary care cohort of patients with AF. DESIGN & SETTING: Observational study in 1.2 million people registered with GPs across four east London clinical commissioning groups (CCGs), covering prescribing from January 2020-June 2021. METHOD: In patients with AF, factors associated with DAT prescription, prolonged DAT prescription (>12 months), and gastroprotective prescription were characterised using logistic regression. RESULTS: There were 8881 patients with AF, of whom 4.7% (n = 416) were on DAT. Of these, 65.9% (n = 274) were prescribed DAT for >12 months and 84.4% (n = 351) were prescribed concomitant gastroprotection. Independent of all other factors, females with AF were less likely to receive DAT than males (odds ratio [OR] 0.61, 95% confidence interval [CI] = 0.49 to 0.77). Similarly, older (aged ≥75 years) individuals (OR 0.79, 95% CI = 0.63 to 0.98) were less likely to receive DAT than younger patients. Among those with AF on DAT, pre-existing CVD (OR 3.33, 95% CI = 1.71 to 6.47) and South Asian ethnicity (OR 2.70, 95% CI = 1.15 to 6.32) were associated with increased gastroprotection prescriptions. Gastroprotection prescription (OR 1.80, 95% CI = 1.01 to 3.22) was associated with prolonged DAT prescription. CONCLUSION: Almost two-thirds of patients with AF on DAT were prescribed prolonged durations of therapy. Prescription of gastroprotection therapies was suboptimal in one in six patients. Treatment decisions varied by sex, age, ethnic group, and comorbidity. Duration of DAT and gastroprotection in patients with AF requires improvement.

5.
Heart ; 107(15): 1220-1225, 2021 Jul 12.
Article in English | MEDLINE | ID: mdl-34016698

ABSTRACT

OBJECTIVE: The Familial Hypercholesterolaemia Case Ascertainment Tool (FAMCAT) has been proposed to enhance case finding in primary care. In this study, we test application of the FAMCAT algorithm to describe risks of familial hypercholesterolaemia (FH) in a large unselected and ethnically diverse primary care cohort. METHOD: We studied patients aged 18-65 years from three contiguous areas in inner London. We retrospectively applied the FAMCAT algorithm to routine primary care data and estimated the numbers of possible cases of FH and the potential service implications of subsequent investigation and management. RESULTS: Of the 777 128 patients studied, the FAMCAT score estimated between 11 736 and 23 798 (1.5%-3.1%) individuals were likely to have FH, depending on an assumed FH prevalence of 1 in 250 or 1 in 500, respectively. There was over-representation of individuals of South Asian ethnicity among those likely to have FH, with this cohort making up 41.9%-45.1% of the total estimated cases, a proportion which significantly exceeded their 26% representation in the study population. CONCLUSIONS: We have demonstrated feasibility of application of the FAMCAT as an aid to case finding for FH using routinely recorded primary care data. Further research is needed on validity of the tool in different ethnic groups and more refined consideration of family history should be explored. While FAMCAT may aid case finding, implementation requires information on the cost-effectiveness of additional health services to investigate, diagnose and manage case ascertainment in those identified as likely to have FH.

6.
BMJ Open ; 11(12): e052884, 2021 12 30.
Article in English | MEDLINE | ID: mdl-35536740

ABSTRACT

OBJECTIVES: To characterise gaps in antihypertensive treatment in people with hypertension and statin treatment in people with cardiovascular diseases (CVD) in a large urban population and quantify the health and economic impacts of their optimisation. DESIGN: A cross-sectional population study and a long-term CVD decision model. SETTING: Primary care, UK. PARTICIPANTS: All adults with diagnosed hypertension or CVD in a population of about 1 million people, served by 123 primary care practices in London, UK in 2019. INTERVENTIONS: Following UK clinical guidelines, all adults with diagnosed hypertension were categorised into optimal, suboptimal and untreated groups with respect to their antihypertensive treatment, and all adults with diagnosed CVD were categorised in the same manner with respect to their statin treatment. OUTCOMES: Proportion of patients suboptimally treated or untreated. Projected cardiovascular events avoided, years and quality-adjusted life years (QALYs) gained and healthcare costs saved with optimised treatments. RESULTS: 21 954 of the 91 828 adults with hypertension (24%; mean age 59 years; 49% women) and 9062 of the 23 723 adults with CVD (38%; mean age 69 years; 43% women) were not optimally treated with antihypertensive or statin treatment, respectively. Per 1000 additional patients optimised over 5 years, hypertension treatment is projected to prevent 25 (95% CI 16 to 32) major vascular events (MVEs) and 7 (3 to 10) vascular deaths, statin treatment, 28 (22 to 33) MVEs and 6 (4 to 7) vascular deaths. Over their lifespan, a patient with uncontrolled hypertension aged 60-69 years is projected to gain 0.64 (95% CI 0.36 to 0.87) QALYs with optimised hypertension treatment, and a similarly aged patient with previous CVD not optimally treated with statin is projected to gain 0.3 (0.24 to 0.37) QALYs with optimised statin treatment. In both cases, the hospital cost savings minus extra medication costs were about £1100 per person over remaining lifespan. CONCLUSIONS: Optimising cardiovascular treatments can cost-effectively reduce cardiovascular risk and improve life expectancy.


Subject(s)
Cardiovascular Diseases , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Hypertension , Adult , Aged , Antihypertensive Agents/therapeutic use , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/prevention & control , Cost-Benefit Analysis , Cross-Sectional Studies , Female , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hypertension/drug therapy , Male , Middle Aged , United Kingdom/epidemiology , Urban Population
7.
Circ Cardiovasc Genet ; 7(6): 920-9, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25373139

ABSTRACT

BACKGROUND: Human variation in susceptibility to hypoxia-induced pulmonary hypertension is well recognized. High-altitude residents who do not develop pulmonary hypertension may host protective gene mutations. METHODS AND RESULTS: Exome sequencing was conducted on 24 unrelated Kyrgyz highlanders living 2400 to 3800 m above sea level, 12 (10 men; mean age, 54 years) with an elevated mean pulmonary artery pressure (mean±SD, 38.7±2.7 mm Hg) and 12 (11 men; mean age, 52 years) with a normal mean pulmonary artery pressure (19.2±0.6 mm Hg) to identify candidate genes that may influence the pulmonary vascular response to hypoxia. A total of 140 789 exomic variants were identified and 26 116 (18.5%) were classified as novel or rare. Thirty-three novel or rare potential pathogenic variants (frameshift, essential splice-site, and nonsynonymous) were found exclusively in either ≥3 subjects with high-altitude pulmonary hypertension or ≥3 highlanders with a normal mean pulmonary artery pressure. A novel missense mutation in GUCY1A3 in 3 subjects with a normal mean pulmonary artery pressure encodes an α1-A680T soluble guanylate cyclase (sGC) variant. Expression of the α1-A680T sGC variant in reporter cells resulted in higher cyclic guanosine monophosphate production compared with the wild-type enzyme and the purified α1-A680T sGC exhibited enhanced sensitivity to nitric oxide in vitro. CONCLUSIONS: The α1-A680T sGC variant may contribute to protection against high-altitude pulmonary hypertension and supports sGC as a pharmacological target for reducing pulmonary artery pressure in humans at altitude.


Subject(s)
Altitude Sickness/genetics , Guanylate Cyclase/genetics , Hypertension, Pulmonary/genetics , Receptors, Cytoplasmic and Nuclear/genetics , Alleles , Altitude Sickness/pathology , Amino Acid Sequence , Animals , Cyclic GMP/metabolism , Female , Genotype , Guanylate Cyclase/metabolism , HEK293 Cells , High-Throughput Nucleotide Sequencing , Humans , Hypertension, Pulmonary/pathology , Male , Middle Aged , Molecular Sequence Data , Nitric Oxide/metabolism , Phylogeny , Polymorphism, Single Nucleotide , Receptors, Cytoplasmic and Nuclear/metabolism , Sequence Alignment , Sequence Analysis, DNA , Signal Transduction , Soluble Guanylyl Cyclase
8.
J Nucl Med ; 55(7): 1112-8, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24904112

ABSTRACT

UNLABELLED: PET radioligand binding to the 18-kD translocator protein (TSPO) in the brains of patients with multiple sclerosis (MS) primarily reflects activated microglia and macrophages. We previously developed genetic stratification for accurate quantitative estimation of TSPO using second-generation PET radioligands. In this study, we used (18)F-PBR111 PET and MR imaging to measure relative binding in the lesional, perilesional, and surrounding normal-appearing white matter of MS patients, as an index of the innate immune response. METHODS: (18)F-PBR111 binding was quantified in 11 MS patients and 11 age-matched healthy volunteers, stratified according to the rs6971 TSPO gene polymorphism. Fluid-attenuated inversion recovery and magnetization transfer ratio (MTR) MR imaging were used to segment the white matter in MS patients as lesions, perilesional volumes, nonlesional white matter with reduced MTR, and nonlesional white matter with normal MTR. RESULTS: (18)F-PBR111 binding was higher in the white matter lesions and perilesional volumes of MS patients than in white matter of healthy controls (P < 0.05). Although there was substantial heterogeneity in binding between different lesions, a within-subject analysis showed higher (18)F-PBR111 binding in MS lesions (P < 0.05) and in perilesional (P < 0.05) and nonlesional white matter with reduced MTR (P < 0.005) than in nonlesional white matter with a normal MTR. A positive correlation was observed between the mean (18)F-PBR111 volume of distribution increase in lesions relative to nonlesional white matter with a normal MTR and the MS severity score (Spearman ρ = 0.62, P < 0.05). CONCLUSION: This study demonstrates that quantitative TSPO PET with a second-generation radioligand can be used to characterize innate immune responses in MS in vivo and provides further evidence supporting an association between the white matter TSPO PET signal in lesions and disease severity. Our approach is practical for extension to studies of the role of the innate immune response in MS for differentiation of antiinflammatory effects of new medicines and their longer term impact on clinical outcome.


Subject(s)
Multiple Sclerosis/diagnostic imaging , Positron-Emission Tomography , Pyridines , White Matter/diagnostic imaging , Adult , Aged , Case-Control Studies , Female , Humans , Inflammation/diagnostic imaging , Macrophages/immunology , Male , Microglia/pathology , Middle Aged , Multiple Sclerosis/immunology , Multiple Sclerosis/pathology , Reproducibility of Results , White Matter/immunology , White Matter/pathology
10.
Microbiology (Reading) ; 153(Pt 2): 521-528, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17259624

ABSTRACT

Identification of protein translation start sites is largely a bioinformatics exercise, with relatively few confirmed by N-terminal sequencing. Translation start site determination is critical for defining both the protein sequence and the upstream DNA which may contain regulatory motifs. It is demonstrated here that translation start sites can be determined during routine protein identification, using MALDI-MS and MS/MS data to select the correct N-terminal sequence from a list of alternatives generated in silico. Applying the method to 13 proteins from Mycobacterium tuberculosis, 11 predicted translational start sites were confirmed, and two reassigned. The authors suggest that these data (be they confirmation or reassignments) are important for the annotation of both this genome and those of organisms with related genes. It was also shown that N-acetylation, reported to be rare in prokaryotes, was present in three of the 13 proteins (23 %), suggesting that in the mycobacteria this modification may be common, and an important regulator of protein function, although more proteins need to be analysed. This method can be performed with little or no additional experimental work during proteomics investigations.


Subject(s)
Bacterial Proteins/chemistry , Mycobacterium tuberculosis/metabolism , Peptide Chain Initiation, Translational/genetics , Peptide Mapping/methods , Proteome , Tandem Mass Spectrometry/methods , Amino Acid Sequence , Bacterial Proteins/metabolism , Base Sequence , Codon, Initiator , Humans , Molecular Sequence Data , Mycobacterium tuberculosis/chemistry , Mycobacterium tuberculosis/genetics , Peptides/chemistry
11.
J Mol Biol ; 353(5): 929-36, 2005 Nov 11.
Article in English | MEDLINE | ID: mdl-16213520

ABSTRACT

The majority of the Mycobacterium tuberculosis response to hypoxia and nitric oxide is through the DosRS (DevRS) two-component regulatory system. The N-terminal input domain of the DosS sensor contains two GAF domains. We demonstrate here that the proximal GAF domain binds haem, and identified histidine 149 of DosS as critical to haem-binding; the location of this histidine residue is similar to the cGMP-binding site in a crystal structure of cyclic nucleotide phosphodiesterase 2A. GAF domains are frequently involved in binding cyclic nucleotides, but this is the first GAF domain to be identified that binds haem. In contrast, PAS domains (similar to GAF domains in structure but not primary sequence) frequently use haem cofactors, and these findings further illustrate how the functions of these domains overlap. We propose that the activation of the DosS sensor is controlled through the haem binding of molecular oxygen or nitric oxide.


Subject(s)
Heme/metabolism , Hypoxia , Mycobacterium tuberculosis/chemistry , Nitric Oxide/metabolism , Protamine Kinase/chemistry , Amino Acid Sequence , Bacterial Proteins/chemistry , Bacterial Proteins/metabolism , Bacterial Proteins/physiology , Cloning, Molecular , Histidine , Molecular Sequence Data , Mycobacterium tuberculosis/physiology , Oxygen/metabolism , Protamine Kinase/metabolism , Protamine Kinase/physiology , Protein Structure, Tertiary , Sequence Alignment
12.
Nucleic Acids Res ; 33(10): 3253-62, 2005.
Article in English | MEDLINE | ID: mdl-15942028

ABSTRACT

An important step in understanding the regulation of a prokaryotic genome is the generation of its transcription unit map. The current strongest operon predictor depends on the distributions of intergenic distances (IGD) separating adjacent genes within and between operons. Unfortunately, experimental data on these distance distributions are limited to Escherichia coli and Bacillus subtilis. We suggest a new graph algorithmic approach based on comparative genomics to identify clusters of conserved genes independent of IGD and conservation of gene order. As a consequence, distance distributions of operon pairs for any arbitrary prokaryotic genome can be inferred. For E.coli, the algorithm predicts 854 conserved adjacent pairs with a precision of 85%. The IGD distribution for these pairs is virtually identical to the E.coli operon pair distribution. Statistical analysis of the predicted pair IGD distribution allows estimation of a genome-specific operon IGD cut-off, obviating the requirement for a training set in IGD-based operon prediction. We apply the method to a representative set of eight genomes, and show that these genome-specific IGD distributions differ considerably from each other and from the distribution in E.coli.


Subject(s)
Chromosome Mapping/methods , Genomics/methods , Operon , Algorithms , Base Sequence , Conserved Sequence , Escherichia coli/genetics , Genome, Bacterial
13.
Trends Microbiol ; 12(12): 537-44, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15539113

ABSTRACT

Bacterial pathogens adapt to their host environments to a large extent through switching on complex transcriptional programmes, and whole-genome microarray experiments promise to reveal this complexity. There has been a recent burst of articles reporting transcriptome analyses of Mycobacterium tuberculosis, including for the first time studies in macrophages and mice. We review gene expression reports, and compare them with each other and with microarray-based gene essentiality studies, revealing at times a startling lack of correlation. Additionally, we suggest a standardization format for the submission of processed data for publication, to facilitate cross-experiment analyses.


Subject(s)
Gene Expression Profiling , Mycobacterium tuberculosis/genetics , Oligonucleotide Array Sequence Analysis/methods , Animals , Gene Expression Regulation, Bacterial , Mycobacterium tuberculosis/drug effects , RNA, Bacterial/analysis , RNA, Bacterial/isolation & purification
14.
Bioinformatics ; 20(14): 2288-95, 2004 Sep 22.
Article in English | MEDLINE | ID: mdl-15201178

ABSTRACT

MOTIVATION: Target selection strategies for structural genomic projects must be able to prioritize gene regions on the basis of significant sequence similarity with proteins that have already been structurally determined. With the rapid development of protein comparison software a robust prioritization scheme should be independent of the choice of algorithm and be able to incorporate different sequence similarity thresholds. RESULTS: A robust target selection strategy has been developed that can assign a priority level to all genes in any genome. Structural assignments to genome sequences are calculated at two thresholds and six levels (1-6) describe the prioritization of all whole genes and partial gene regions. This simple two-threshold approach can be implemented with any fold recognition or homology detection algorithms. The results for 10 genomes are presented using the SSEARCH and PSI-BLAST programs. AVAILABILITY: Programs are available on request from the authors.


Subject(s)
Algorithms , Chromosome Mapping/methods , Gene Targeting/methods , Genes/genetics , Genomics/methods , Sequence Alignment/methods , Sequence Analysis, Protein/methods , Protein Structure, Tertiary , Sequence Homology, Amino Acid , Structure-Activity Relationship
15.
Mol Microbiol ; 51(4): 1003-14, 2004 Feb.
Article in English | MEDLINE | ID: mdl-14763976

ABSTRACT

Inositol is utilized by Mycobacterium tuberculosis in the production of its major thiol and of essential cell wall lipoglycans. We have constructed a mutant lacking the gene encoding inositol-1-phosphate synthase (ino1), which catalyses the first committed step in inositol synthesis. This mutant is only viable in the presence of extremely high levels of inositol. Mutant bacteria cultured in inositol-free medium for four weeks showed a reduction in levels of mycothiol, but phosphatidylinositol mannoside, lipomannan and lipoarabinomannan levels were not altered. The ino1 mutant was attenuated in resting macrophages and in SCID mice. We used site-directed mutagenesis to alter four putative active site residues; all four alterations resulted in a loss of activity, and we demonstrated that a D310N mutation caused loss of the active site Zn2+ ion and a conformational change in the NAD+ cofactor.


Subject(s)
Genes, Essential , Mycobacterium tuberculosis/genetics , Myo-Inositol-1-Phosphate Synthase/genetics , Myo-Inositol-1-Phosphate Synthase/metabolism , Amino Acid Sequence , Animals , Binding Sites/genetics , Cysteine , DNA Mutational Analysis , Disaccharides/analysis , Gene Deletion , Genes, Bacterial , Glycopeptides , Inositol/biosynthesis , Lipopolysaccharides/analysis , Macrophages/microbiology , Mice , Mice, SCID , Models, Molecular , Molecular Sequence Data , Mutagenesis, Site-Directed , Mutation , Mycobacterium tuberculosis/enzymology , Mycobacterium tuberculosis/growth & development , Mycobacterium tuberculosis/pathogenicity , Myo-Inositol-1-Phosphate Synthase/chemistry , Phosphatidylinositols/analysis , Pyrazoles/analysis , Sulfhydryl Compounds/analysis , Tuberculosis/microbiology , Virulence/genetics
16.
Metab Eng ; 5(3): 211-9, 2003 Jul.
Article in English | MEDLINE | ID: mdl-12948755

ABSTRACT

The solution of the shortest path problem in biochemical systems constitutes an important step for studies of their evolution. In this paper, a linear programming (LP) algorithm for calculating minimal pathway distances in metabolic networks is studied. Minimal pathway distances are identified as the smallest number of metabolic steps separating two enzymes in metabolic pathways. The algorithm deals effectively with circularity and reaction directionality. The applicability of the algorithm is illustrated by calculating the minimal pathway distances for Escherichia coli small molecule metabolism enzymes, and then considering their correlations with genome distance (distance separating two genes on a chromosome) and enzyme function (as characterised by enzyme commission number). The results illustrate the effectiveness of the LP model. In addition, the data confirm that propinquity of genes on the genome implies similarity in function (as determined by co-involvement in the same region of the metabolic network), but suggest that no correlation exists between pathway distance and enzyme function. These findings offer insight into the probable mechanism of pathway evolution.


Subject(s)
Algorithms , Escherichia coli/genetics , Escherichia coli/metabolism , Metabolism/physiology , Models, Biological , Multienzyme Complexes/genetics , Multienzyme Complexes/metabolism , Programming, Linear , Computer Simulation , Evolution, Molecular , Gene Expression Regulation, Bacterial/physiology , Gene Expression Regulation, Enzymologic/genetics , Numerical Analysis, Computer-Assisted
17.
Nucleic Acids Res ; 31(1): 469-73, 2003 Jan 01.
Article in English | MEDLINE | ID: mdl-12520054

ABSTRACT

The Gene3D database (http://www.biochem.ucl.ac.uk/bsm/cath_new/Gene3D/) provides structural assignments for genes within complete genomes. These are available via the internet from either the World Wide Web or FTP. Assignments are made using PSI-BLAST and subsequently processed using the DRange protocol. The DRange protocol is an empirically benchmarked method for assessing the validity of structural assignments made using sequence searching methods where appropriate assignment statistics are collected and made available. Gene3D links assignments to their appropriate entries in relevent structural and classification resources (PDBsum, CATH database and the Dictionary of Homologous Superfamilies). Release 2.0 of Gene3D includes 62 genomes, 2 eukaryotes, 10 archaea and 40 bacteria. Currently, structural assignments can be made for between 30 and 40 percent of any given genome. In any genome, around half of those genes assigned a structural domain are assigned a single domain and the other half of the genes are assigned multiple structural domains. Gene3D is linked to the CATH database and is updated with each new update of CATH.


Subject(s)
Databases, Genetic , Genome , Protein Structure, Tertiary , Proteins/chemistry , Animals , Computational Biology , Genome, Archaeal , Genome, Bacterial , Imaging, Three-Dimensional , Internet , Proteins/physiology , Structural Homology, Protein
18.
Curr Opin Struct Biol ; 12(3): 374-82, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12127458

ABSTRACT

Small-molecule metabolism forms the core of the metabolic processes of all living organisms. As early as 1945, possible mechanisms for the evolution of such a complex metabolic system were considered. The problem is to explain the appearance and development of a highly regulated complex network of interacting proteins and substrates from a limited structural and functional repertoire. By permitting the co-analysis of phylogeny and metabolism, the combined exploitation of pathway and structural databases, as well as the use of multiple-sequence alignment search algorithms, sheds light on this problem. Much of the current research suggests a chemistry-driven 'patchwork' model of pathway evolution, but other mechanisms may play a role. In the future, as metabolic structure and sequence space are further explored, it should become easier to trace the finer details of pathway development and understand how complexity has evolved.


Subject(s)
Biological Evolution , Metabolism , Amino Acid Sequence , Enzymes/chemistry , Enzymes/metabolism , Escherichia coli/metabolism , Protein Structure, Tertiary , Sequence Homology
19.
J Mol Biol ; 318(3): 911-32, 2002 May 03.
Article in English | MEDLINE | ID: mdl-12054833

ABSTRACT

Here, we analyse Escherichia coli enzymes involved in small molecule metabolism (SMM). We introduce the concept of pathway distance as a measure of the number of distinct metabolic steps separating two SMM enzymes, and we consider protein homology (as determined by assigning enzymes to structural and sequence families) and gene interval (the number of genes separating two genes on the E. coli chromosome). The relationships between these three contexts (pathway distance, homology and chromosomal localisation) is investigated extensively. We make use of these relationships to suggest possible SMM evolution mechanisms. Homology between enzyme pairs close in the SMM was higher than expected by chance but was still rare. When observed, homologues usually conserved their reaction mechanism and/or co-factor binding rather than shared substrate binding. The correlation between pathway distance and gene intervals was clear. Enzymes catalysing nearby SMM reactions were usually encoded by genes close by on the E. coli chromosome. We found many co-regulated blocks of three to four genes (usually non-homologous) encoding enzymes occurring within four metabolic steps of one another; nearly all of these blocks formed part of known or predicted operons. The "inline reuse" of enzymes (i.e. the use of the same enzyme to catalyse two or more different steps of a metabolic pathway) is also discussed: of these enzymes, four were multifunctional (i.e. catalysed a different reaction in each instance), nine had multiple substrate specificity (i.e. catalysed the same reaction on different substrates in each instance) and one catalysed the same reaction on the same substrate but as part of two different complexes. We also identified 59 sets of isozymic proteins most commonly duplicated to function under different conditions, or with a different preferred substrate or minor substrate. In addition to transcriptional units, isozymes and inline reuse of enzymes provide mechanisms for controlling the SMM network. Our data suggest that several pathway evolution mechanisms may occur in concert, although chemistry-driven duplication/recruitment is favoured. SMM exploits regulatory strategies involving chromosomal location, isozymes and the reuse of enzymes.


Subject(s)
Escherichia coli/enzymology , Escherichia coli/genetics , Chromosomes, Bacterial/genetics , Evolution, Molecular , Genes, Bacterial , Genome, Bacterial , Glycolysis , Isoenzymes/genetics , Isoenzymes/metabolism , Operon
20.
Genome Res ; 12(3): 503-14, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11875040

ABSTRACT

We present a novel web-based resource, Gene3D, of precalculated structural assignments to gene sequences and whole genomes. This resource assigns structural domains from the CATH database to whole genes and links these to their curated functional and structural annotations within the CATH domain structure database, the functional Dictionary of Homologous Superfamilies (DHS) and PDBsum. Currently Gene3D provides annotation for 36 complete genomes (two eukaryotes, six archaea, and 28 bacteria). On average, between 30% and 40% of the genes of a given genome can be structurally annotated. Matches to structural domains are found using the profile-based method (PSI-BLAST). and a novel protocol, DRange, is used to resolve conflicts in matches involving different homologous superfamilies.


Subject(s)
Databases, Genetic , Genes/genetics , Genome , Software , Animals , Archaeal Proteins/genetics , Bacterial Proteins/genetics , Databases, Genetic/statistics & numerical data , Databases, Protein , Genes, Archaeal/genetics , Genes, Bacterial/genetics , Genome, Archaeal , Genome, Bacterial , Internet , Protein Structure, Tertiary , Proteins/genetics , Sequence Homology, Nucleic Acid , Software/statistics & numerical data
SELECTION OF CITATIONS
SEARCH DETAIL
...