Sequencing in all areas of the tree of life has produced >300,000 cytochrome P450 (CYP) sequences that have been mined and collected. Nomenclature has been assigned to >41,000 CYP sequences and the ...majority of the remainder has been sorted by BLAST searches into clans, families and subfamilies in preparation for naming. The P450 sequence space is being systematically explored and filled in. Well-studied groups like vertebrates are covered in greater depth while new insights are being added into uncharted territories like horseshoe crab (Limulus polyphemus), tardigrades (Hypsibius dujardini), velvet worm (Euperipatoides_rowelli), and basal land plants like hornworts, liverworts and mosses. CYPs from the fungi, one of the most diverse groups, are being explored and organized as nearly 800 fungal species are now sequenced. The CYP clan structure in fungi is emerging with 805 CYP families sorting into 32 CYP clans. >3000 bacterial sequences are named, mostly from terrestrial or freshwater sources. Of 18,379 bacterial sequences downloaded from the CYPED database, all are >43% identical to named CYPs. Therefore, they fit in the 602 named P450 prokaryotic families. Diversity in this group is becoming saturated, however 25% of 3305 seawater bacterial P450s did not match known P450 families, indicating marine bacterial CYPs are not as well sampled as land/freshwater based bacterial CYPs. Future sequencing plans of the Genome 10K project, i5k and GIGA (Global Invertebrate Genomics Alliance) are expected to produce more than one million cytochrome P450 sequences by 2020. This article is part of a Special Issue entitled: Cytochrome P450 biodiversity and biotechnology, edited by Erika Plettner, Gianfranco Gilardi, Luet Wong, Vlada Urlacher, Jared Goldstone.
•~350,000 cytochrome P450 sequences are collected from public and private sources.•P450s from panarthropods horseshoe crab, velvet worm and a tardigrade are analyzed.•The P450s from a first spider genome are named.•Progress is presented on naming P450 clans in fungi.•Methods are described for finding all P450 families in any taxa (gymnosperms, etc.).
Current challenges exist to widespread clinical implementation of genomic medicine and pharmacogenetics. The University of Florida (UF) Health Personalized Medicine Program (PMP) is a pharmacist-led, ...multidisciplinary initiative created in 2011 within the UF Clinical Translational Science Institute. Initial efforts focused on pharmacogenetics, with long-term goals to include expansion to disease-risk prediction and disease stratification. Herein we describe the processes for development of the program, the challenges that were encountered and the clinical acceptance by clinicians of the genomic medicine implementation. The initial clinical implementation of the UF PMP began in June 2012 and targeted clopidogrel use and the CYP2C19 genotype in patients undergoing left heart catheterization and percutaneous-coronary intervention (PCI). After 1 year, 1,097 patients undergoing left heart catheterization were genotyped preemptively, and 291 of those underwent subsequent PCI. Genotype results were reported to the medical record for 100% of genotyped patients. Eighty patients who underwent PCI had an actionable genotype, with drug therapy changes implemented in 56 individuals. Average turnaround time from blood draw to genotype result entry in the medical record was 3.5 business days. Seven different third party payors, including Medicare, reimbursed for the test during the first month of billing, with an 85% reimbursement rate for outpatient claims that were submitted in the first month. These data highlight multiple levels of success in clinical implementation of genomic medicine.
The state of cytochrome P450 sequence accumulation in different phyla is summarized. 12,456 P450s are currently named, with about 6000 more that are known, but not yet named. As the number of genomes ...sequenced moves from a few dozen to an inevitable few thousand, issues of nomenclature are discussed. Orthology will be the guiding principle for naming across related genomes such as vertebrates. Even if 1000 vertebrate genomes are sequenced there will still be only 19 CYP families in vertebrates. The variable clusters of genes in families CYP2, CYP3 and CYP4 may pose challenges for naming as 1:1 orthologs do not necessarily exist. The value of synteny across genomes is emphasized as a tool for deep time evolutionary studies of P450s in animals. There is evidence that macrosynteny may be useful in tracing the origin of animal CYP clans. The concept of saturation of sequence space is described and used to estimate how complete our knowledge is of P450s in different phyla. The special niche of filamentous fungal P450s acting in secondary metabolite gene clusters is discussed. From one quarter to one third of P450s in these fungi may be dedicated to these roles.
The Cytochrome P450 Homepage is a universal resource for nomenclature and sequence information on cytochrome P450 ( CYP ) genes. The site has been in continuous operation since February 1995. ...Currently, naming information for 11,512 CYPs are available on the web pages. The P450 sequences are manually curated by David Nelson, and the nomenclature system conforms to an evolutionary scheme such that members of CYP families and subfamilies share common ancestors. The organisation and content of the Homepage are described.
We explore the spectra and localization properties of the N-site banded one-dimensional non-Hermitian random matrices that arise naturally in sparse neural networks. Approximately equal numbers of ...random excitatory and inhibitory connections lead to spatially localized eigenfunctions and an intricate eigenvalue spectrum in the complex plane that controls the spontaneous activity and induced response. A finite fraction of the eigenvalues condense onto the real or imaginary axes. For large N, the spectrum has remarkable symmetries not only with respect to reflections across the real and imaginary axes but also with respect to 90^{∘} rotations, with an unusual anisotropic divergence in the localization length near the origin. When chains with periodic boundary conditions become directed, with a systematic directional bias superimposed on the randomness, a hole centered on the origin opens up in the density-of-states in the complex plane. All states are extended on the rim of this hole, while the localized eigenvalues outside the hole are unchanged. The bias-dependent shape of this hole tracks the bias-independent contours of constant localization length. We treat the large-N limit by a combination of direct numerical diagonalization and using transfer matrices, an approach that allows us to exploit an electrostatic analogy connecting the "charges" embodied in the eigenvalue distribution with the contours of constant localization length. We show that similar results are obtained for more realistic neural networks that obey "Dale's law" (each site is purely excitatory or inhibitory) and conclude with perturbation theory results that describe the limit of large directional bias, when all states are extended. Related problems arise in random ecological networks and in chains of artificial cells with randomly coupled gene expression patterns.
A world of cytochrome P450s Nelson, David R.
Philosophical transactions of the Royal Society of London. Series B. Biological sciences,
02/2013, Letnik:
368, Številka:
1612
Journal Article
Recenzirano
Odprti dostop
The world we live in is a biosphere influenced by all organisms who inhabit it. It is also an ecology of genes, with some having rather startling effects. The premise put forth in this issue is ...cytochrome P450 is a significant player in the world around us. Life and the Earth itself would be visibly different and diminished without cytochrome P450s. The contributions to this issue range from evolution on the billion year scale to the colour of roses, from Darwin to Rachel Carson; all as seen through the lens of cytochrome P450.
Although the effects of kinetics on crystal growth are well understood, the role of substrate curvature is not yet established. We studied rigid, two-dimensional colloidal crystals growing on ...spherical droplets to understand how the elastic stress induced by Gaussian curvature affects the growth pathway. In contrast to crystals grown on flat surfaces or compliant crystals on droplets, these crystals formed branched, ribbon-like domains with large voids and no topological defects. We show that this morphology minimizes the curvature-induced elastic energy. Our results illustrate the effects of curvature on the ubiquitous process of crystallization, with practical implications for nanoscale disorder-order transitions on curved manifolds, including the assembly of viral capsids, phase separation on vesicles, and crystallization of tetrahedra in three dimensions.
The superfamily of cytochrome P450 (CYP) enzymes plays key roles in plant evolution and metabolic diversification. This review provides a status on the CYP landscape within green algae and land ...plants. The 11 conserved CYP clans known from vascular plants are all present in green algae and several green algae-specific clans are recognized. Clan 71, 72, and 85 remain the largest CYP clans and include many taxa-specific CYP (sub)families reflecting emergence of linage-specific pathways. Molecular features and dynamics of CYP plasticity and evolution are discussed and exemplified by selected biosynthetic pathways. High substrate promiscuity is commonly observed for CYPs from large families, favoring retention of gene duplicates and neofunctionalization, thus seeding acquisition of new functions. Elucidation of biosynthetic pathways producing metabolites with sporadic distribution across plant phylogeny reveals multiple examples of convergent evolution where CYPs have been independently recruited from the same or different CYP families, to adapt to similar environmental challenges or ecological niches. Sometimes only a single or a few mutations are required for functional interconversion. A compilation of functionally characterized plant CYPs is provided online through the Plant P450 Database (erda.dk/public/vgrid/PlantP450/).
Cytochrome P450 enzymes play critical roles in regulation and diversification of plant metabolism. This review article provides an updated annotation of the plant cytochrome P450 families within the plant lineage, and discusses molecular features and dynamics of cytochrome P450 plasticity and evolution. This is presented along with specific examples from various biosynthetic pathways.
Abstract Objective As a negative regulator of T cells, Programmed Death Ligand 1 (PD-L1) is both an indicator and inhibitor of anti -tumor immune responses, which has led to confusion about its ...prognostic significance. We investigated the primary source of PD-L1 expression in epithelial ovarian cancer and its relationship to tumor-infiltrating lymphocytes (TIL) and associated gene products. Methods Tissue microarrays containing high-grade serous carcinomas (HGSC) and endometrioid, clear cell and mucinous ovarian cancers from optimally debulked patients were assessed by immunohistochemistry for expression of PD-L1 and other markers (CD68, CD3, CD8, PD-1, CD103, FoxP3 and CD25). The Cancer Genome Atlas was interrogated for associations between PD-L1 expression and immune-related transcriptional and genomic features of HGSC. Results PD-L1 was primarily expressed by tumor-associated CD68+ macrophages rather than tumor cells. PD-L1+ cells frequently co-localized with CD8, CD4 and PD-1+ TIL, CD25+ FoxP3+ Tregs, and other TIL subsets. PD-L1+ cells were prognostically favorable in HGSC. Moreover, the presence of both PD-L1+ cells and CD8 TIL was associated with better prognosis than CD8 TIL alone. PD-L1 gene expression was independent of BRCA status. At the transcriptional level, PD-L1 was associated with both cytolytic (granzyme B, T-bet and IFN-γ) and suppressive (PD-1, CTLA-4, LAG3 and IDO-1) gene products. Conclusions PD-L1 is primarily expressed by macrophages in ovarian cancer and is strongly associated with both cytolytic and regulatory TIL subsets, resulting in a net positive association with survival. Tumors containing PD-L1+ macrophages appear caught in an immunological stalemate that may require multi-pronged immunotherapy to alleviate.
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