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PubMed2006

Do orphan G-protein-coupled receptors have ligand-independent functions? New insights from receptor heterodimers.

G-protein-coupled receptors (GPCRs) are important drug targets and are involved in virtually every biological process. However, there are still more than 140 orphan GPCRs, and deciphering their function remains a priority for fundamental and clinical research. Research on orphan GPCRs has concentrated mainly on the identification of their natural ligands, whereas recent data suggest additional ligand-independent functions for these receptors. This emerging concept is connected with the observation that orphan GPCRs can heterodimerize with GPCRs that have identified ligands, and by so doing regulate the function of the latter. Pairing orphan GPCRs with their potential heterodimerization partners will have a major impact on our understanding of the extraordinary diversity offered by GPCR heterodimerization and, in addition, will constitute a novel strategy to elucidate the function of orphan receptors that needs to be added to the repertoire of 'deorphanization' strategies.

Cell Line↗
PubMed1995

Suppression of gene expression on the simian virus 40 major late promoter by human TR4 orphan receptor. A member of the steroid receptor superfamily.

The key expression of the simian virus 40 (SV40) major late promoter could be repressed by the human TR4 orphan receptor via the +55 region of the SV40 major late promoter (nucleotide numbers 368-389, 5' -GTTA-AGGTTCGTAGGTCATGGA-3'). Using the coupled in vitro transcribed and translated TR4 orphan receptor with a molecular mass of 67.3 kilodaltons, electrophoretic mobility shift assay showed specific binding with a dissociation constant of 1.09 nM between the TR4 orphan receptor and the SV40 +55 oligonucleotides. In addition, chloramphenicol acetyltransferase assay demonstrated that this SV40 +55 region can function as a repressor via the TR4 orphan receptor, suppressing the transcriptional activities of both SV40 early and late promoters. Together, our data suggest that the TR4 orphan receptor may play an important role for the suppression of the SV40 gene expression.

Base Sequence↗
PubMed1996

Nuclear orphan receptor as a repressor of glucocorticoid receptor transcriptional activity.

Nuclear orphan receptors belong to the superfamily of ligand-activated transcription factors that show a close structural relationship and sequence homology. Ligands and functions of most of the orphan receptors have not yet been identified. The first nuclear orphan receptors that were cloned displayed a high degree of amino acid identity with the human estrogen receptor and were termed estrogen receptor-related (ERR) 1 and 2. In the present study, we show that ERR2 functions as a potent repressor of transcriptional activity mediated by the glucocorticoid receptor (GR). Transient transfection of different cell lines with a steroid-responsive reporter plasmid and receptor expression plasmids revealed that transcriptional activity mediated by GR in response to agonists was strongly suppressed by coexpression of ERR2. The orphan receptor displayed no promoter activity when expressed without GR. The inhibitory activity of ERR2 is cell-specific and also receptor-specific because transactivation mediated by the progesterone receptor is unaffected by ERR2. Our observations provide evidence that the nuclear orphan receptor ERR2 acts as an endogenous modulator of GR transcriptional activity.

Animals↗
PubMed2004

Orphan G protein-coupled receptors: targets for new therapeutic interventions.

With the completion of the human genome, many genes will be uncovered with unknown functions. The 'orphan' G protein coupled receptors (GPCRs) are examples of genes without known functions. These are genes that exhibit the seven helical conformation hallmark of the GPCRs but that are called 'orphans' because they are activated by none of the primary messengers known to activate GPCRs in vivo. They are the targets of undiscovered transmitters and this lack of knowledge precludes understanding their function. Yet, because they belong to the supergene family that has the widest regulatory role in the organism, the orphan GPCRs have generated much excitement in academia and industry. They hold much hope for revealing new intercellular interactions that will open new areas of basic research which ultimately will lead to new therapeutic applications. However, the first step in understanding the function of orphan GPCRs is to 'deorphanize' them, to identify their natural transmitters. Here we review the search for the natural primary messengers of orphan GPCRs and focus on two recently deorphanized GPCR systems, the melanin-concentrating hormone (MCH) and prolactin-releasing peptide (PrRP) systems, to illustrate the strategies applied to solve their function and to exemplify the therapeutic potentials that such systems hold.

Animals↗
PubMed2025

DeepES: deep learning-based enzyme screening to identify orphan enzyme genes.

MOTIVATION: Progress in sequencing technology has led to determination of large numbers of protein sequences, and large enzyme databases are now available. Although many computational tools for enzyme annotation were developed, sequence information is unavailable for many enzymes, known as orphan enzymes. These orphan enzymes hinder sequence similarity-based functional annotation, leading gaps in understanding the association between sequences and enzymatic reactions. RESULTS: Therefore, we developed DeepES, a deep learning-based tool for enzyme screening to identify orphan enzyme genes, focusing on biosynthetic gene clusters and reaction class. DeepES uses protein sequences as inputs and evaluates whether the input genes contain biosynthetic gene clusters of interest by integrating the outputs of the binary classifier for each reaction class. The validation results suggested that DeepES can capture functional similarity between protein sequences, and it can be implemented to explore orphan enzyme genes. By applying DeepES to 4744 metagenome-assembled genomes, we identified candidate genes for 236 orphan enzymes, including those involved in short-chain fatty acid production as a characteristic pathway in human gut bacteria. AVAILABILITY AND IMPLEMENTATION: DeepES is available at https://github.com/yamada-lab/DeepES. Model weights and the candidate genes are available at Zenodo (https://doi.org/10.5281/zenodo.11123900).

Deep Learning↗
PubMed2000

Activation of orphan receptor-mediated transcription by Ca(2+)/calmodulin-dependent protein kinase IV.

Retinoid-related receptor alpha (RORalpha) is an orphan nuclear receptor that constitutively activates transcription from its cognate response element. We show that RORalpha is Ca(2+ )responsive, and a Ca(2+)/calmodulin-independent form of Ca(2+)/calmodulin-dependent protein kinase IV (CaMKIV) potentiates RORalpha-dependent transcription 20- to 30-fold. Other orphan receptors including RORalpha2, RORgamma and COUP-TFI are also potentiated by CaMKIV. Transcriptional activation by CaMKIV is orphan receptor selective and does not occur with either the thyroid hormone or estrogen receptor. CaMKIV does not phosphorylate RORalpha or its ligand-binding domain (LBD) in vitro, although the LBD is essential for transactivation. Therefore, the RORalpha LBD was used in the mammalian two-hybrid assay to identify a single class of small peptide molecules containing LXXLL motifs that interacted with greater affinity in the presence of CaMKIV. This class of peptides antagonized activation of orphan receptor-mediated transcription by CaMKIV. These studies demonstrate a pivotal role for CaMKIV in the regulation of orphan receptor-mediated transcription.

Amino Acid Motifs↗
PubMed1975

Nutrition of orphan marsupials.

Marsupial milk has been found to be high in fats, protein and ash compared to eutherian milk. The generally low lactose content of marsupial milk and the corresponding low intestinal lactase activity of pouch young marsupials, when considered with the incidence of diarrhoea and the occasional formation of cataracts in orphan kangaroos fed on cow's milk (which has a high lactose content), suggests that a lactose-free milk be fed to orphan marsupials. Of the lactose-free milk substitutes for children now available, it is recommended that Pregestimil, Glucose Nutramigen and particularly CFI be used for very young orphan marsupial herbivores (especially kangaroos), as these are both lactose- and sucrose-free. Isomil, Prosobee and Triglyde, containing sucrose, may be suitable for older kangaroos which are also ingesting solids and brush-tailed possums of all ages. The appropriate natural diet of the orphan marsupial should be available at the time when initial solid food ingestion would occur in the natural state. It is suggested that milk substitute continue to be given until the orphan animal reaches the age where, in the natural state, it would be full independent.

Animal Feed↗
PubMed1980

Social interactions of orphans observed in a free-ranging troop of Japanese monkeys.

During 4 years of observations of a troop of free-ranging Japanese monkeys, more than 40 'orphans', young monkeys who lost their mothers, were found. Most infants who lost their mothers before the weaning period could not survive, while young animals over 1 year old could survive their mothers' deaths. Adult males of the troop and immature close relatives were observed to become the caretaker of these orphans. With a few exceptions, adult females were indifferent to orphans. Grooming behavior, rank, solitariness of males, and maternal behavior of females are compared between orphans and non-orphans.

Animals↗
PubMed2005

Cross genome phylogenetic analysis of human and Drosophila G protein-coupled receptors: application to functional annotation of orphan receptors.

BACKGROUND: The cell-membrane G-protein coupled receptors (GPCRs) are one of the largest known superfamilies and are the main focus of intense pharmaceutical research due to their key role in cell physiology and disease. A large number of putative GPCRs are 'orphans' with no identified natural ligands. The first step in understanding the function of orphan GPCRs is to identify their ligands. Phylogenetic clustering methods were used to elucidate the chemical nature of receptor ligands, which led to the identification of natural ligands for many orphan receptors. We have clustered human and Drosophila receptors with known ligands and orphans through cross genome phylogenetic analysis and hypothesized higher relationship of co-clustered members that would ease ligand identification, as related receptors share ligands with similar structure or class. RESULTS: Cross-genome phylogenetic analyses were performed to identify eight major groups of GPCRs dividing them into 32 clusters of 371 human and 113 Drosophila proteins (excluding olfactory, taste and gustatory receptors) and reveal unexpected levels of evolutionary conservation across human and Drosophila GPCRs. We also observe that members of human chemokine receptors, involved in immune response, and most of nucleotide-lipid receptors (except opsins) do not have counterparts in Drosophila. Similarly, a group of Drosophila GPCRs (methuselah receptors), associated in aging, is not present in humans. CONCLUSION: Our analysis suggests ligand class association to 52 unknown Drosophila receptors and 95 unknown human GPCRs. A higher level of phylogenetic organization was revealed in which clusters with common domain architecture or cellular localization or ligand structure or chemistry or a shared function are evident across human and Drosophila genomes. Such analyses will prove valuable for identifying the natural ligands of Drosophila and human orphan receptors that can lead to a better understanding of physiological and pathological roles of these receptors.

Amino Acid Sequence↗
PubMed1995

The isolation and characterization of MINOR, a novel mitogen-inducible nuclear orphan receptor.

The nuclear (steroid/thyroid/retinoid) receptor superfamily is a set of evolutionarily related ligand-inducible regulators of transcription. One subgroup within this family has been termed the orphan receptors because the potential ligands required for their activity have not been identified. We have cloned a novel orphan receptor, MINOR, which is mitogen inducible in a variety of cell types. Unlike NGFI-B/Nur77, another mitogen-inducible orphan receptor, MINOR gene expression is inhibited in Jurkat cells by the immunosuppressant cyclosporin A, suggesting that it is regulated by distinct second messenger pathways. The conservation of the DNA-binding domain between MINOR and other orphan receptors is reflected in the fact that they are able to bind to the same sequence, AAAG-GTCA [termed the NBRE (NGFI-B response element)]. The marked divergence in other domains, particularly the N-terminal putative transactivation domain, may result in qualitative or quantitative differences in other functions among these proteins. One of these differences may be the apparent squelching of peak levels of MINOR-mediated transcription by supraoptimal levels of MINOR expression, an effect not obtained with NGFI-B/Nur77. When MINOR i coexpressed with submaximal levels of NGFI-B/Nur77, synergistic or additive levels of reporter gene expression are obtained. However, at maximal levels of NGFI-B/Nur77 expression, MINOR antagonizes the level of reporter gene expression in a dose-dependent fashion. These cooperative/competitive interactions, together with the nonidentical expression patterns of MINOR and NGFI-B/Nur77, suggest complexity in the regulation of genes responsive to orphan receptors which bind to the NBRE.

Amino Acid Sequence↗
PubMed2000

Proposed initiatives for healthy children orphaned by AIDS.

The epidemiology of AIDS has changed greatly in recent years and increasing numbers of poor, minority women with children now contract HIV/AIDS. As infected women succumb to AIDS, many of their children become orphans. The paper explores the ability and appropriateness of the current child welfare system to care for healthy children orphaned by AIDS, and the likelihood of adoption for this population. The study includes a wide-ranging literature review of information about children orphaned by AIDS, and relevant information about the child welfare system, including racial bias. To determine current support for children orphaned by AIDS, the author surveyed social service departments and private agencies in eight major cities about programs available. Based on this information, the author proposes a series of policy initiatives aimed at alleviating the flight of children orphaned because of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1999

The orphans of Eritrea: a five-year follow-up study.

A group of 4-7-year-old war orphans were examined for the first time while living in an institution (the Solomuna Orphanage) during a protracted war between Eritrea and Ethiopia. At that time, they were compared to a group of refugee children living in a nearby camp with one or both parents. The orphans exhibited significantly more behavioral symptoms than the refugee children, but performed the cognitive tests at a more advanced level. Five years later, the orphans were re-examined; and they were compared to unaccompanied 9-12-year-children living in one of two residential settings that differed qualitatively in their social climate, principles of child care, and patterns of staff-child interactions. Although the severity of their behavioral symptoms had diminished, the orphans still exhibited many symptoms of emotional distress. On the other hand, they performed the cognitive measures as well as, or better than, unaccompanied children who had been protected from the terrors of war. The cross-sectional comparisons indicated that a residential setting that respects the individuality of children and promotes their close personal ties with at least one staff member can ameliorate many of the more serious psychological sequelae of having lost both parents and being exposed to the physical dangers of the war. The implications for war orphans in other Third World countries are discussed.

Affective Symptoms↗
PubMed2002

Functional assays for identifying ligands at orphan G protein-coupled receptors.

The superfamily of G protein-coupled receptors (GPCRs; 7TMs) is one of the largest families of genes identified in humans, and has a proven history of being an excellent source of drug targets. The near completion of the human genome sequencing project has allowed the identification of a plethora of sequences encoding "orphan" GPCRs--putative receptors whose natural ligand(s) remain to be discovered. In many cases, the level of sequence homology with known receptors is insufficient to be able to predict the natural ligand for these orphan receptors, although it is usually possible to determine the likely nature of the cognate ligand e.g. peptide, lipid, nucleotide etc. Deorphanizing these novel GPCRs and evaluating their biological function has become a major target of many of the major pharmaceutical companies as well as several academic groups. Since 1995 more than 50 ligands for orphan GPCRs have been discovered by using the orphan receptor as a biosensor and screening candidate compounds looking for a biological response (the so-called "reverse pharmacology" approach). Identification of the natural ligands for these receptors marks the beginning of the process of understanding the biology of these newly discovered signalling systems and the development of novel therapies targeted at them. This article will focus on the functional assays which have been used to discover ligands for orphan GPCRs.

Animals↗
PubMed2001

Fomepizole (orphan medical).

Orphan Medical has developed fomepizole as a potential treatment for both ethylene glycol and methanol poisoning. The drug was launched as Antizol in January 1998 for the treatment of ethylene glycol poisoning [273949] after US marketing approval was grantedin December 1997 [271563]. It has also received US approval for methanol poisoning [393217] and UK approval for ethylene glycol poisoning [329495]. In 1999, Orphan Medical's partner, Cambridge Laboratories, intended to pursue European approval under the mutual recognition procedure [329495]. However, by September 2000, Cambridge Laboratories had discontinued their involvement with fomepizole and IDIS World Medicines had licensed the rights to distribute the drug in the UK [412142]. In February 2000, the Canadian Therapeutic Products Programme (TPP) granted fomepizole Priority Review, provided that an NDA was submitted by March 14, 2000 [354665]. In August 2000, the TPP accepted this NDA and set a target date for approval in the fourth quarter of 2000 [379474]. The TPP granted fomepizole a Notice of Compliance permitting the sale of fomepizole in Canada in December 2000. The company's marketing partner in Canada, Paladin Labs had launched fomepizole by January 2001 [396953]. In June 2000, Tucker Anthony Cleary Gull stated that the Orphan Drug status which Orphan Medical had obtained for fomepizole would provide marketing exclusivity through December 2004. The analysts also stated that fomepizole had accounted for 40% of Orphan Medical's revenue in financial year 1999, although +/- 30% of sales were estimated to be due to stockpiling [409606].

Journal Article↗
PubMed1996

The two orphan Na+/Cl(-)-dependent transporters Rxt1 and V-7-3-2 have an overlapping expression pattern in the rat central nervous system.

The messenger RNA expression patterns of two orphan Na+/Cl(-)-dependent transporters, Rxt1 and V-7-3-2, were compared in the adult rat CNS by in situ hybridization histochemistry. The sites of synthesis of both orphan transporters were found to largely overlap. The highest concentrations of Rxt1 and V-7-3-2 mRNAs were present in the olfactory bulb, cerebral cortex, hippocampus, habenular and pontine nuclei, and cerebellum. Low levels of orphan transporters mRNAs were observed in the basal ganglia (caudate-putamen, nucleus accumbens, globus pallidus), septum nuclei, substantia nigra, colliculi and brainstem. Only few regions were found to express only one of these two orphan transporters: Rxt1 mRNA in the thalamic area and the hilus of the dentate gyrus. V-7-3-2 mRNA in motoneurons of the most ventral zone of the spinal cord. Rxt1 mRNA was generally more abundant than V-7-3-2 mRNA, except in few areas (piriform cortex, horizontal limb of the diagonal band, medial habenular nucleus, pyramidal and granular cell layers in the hippocampus) where the levels of both mRNAs were similar. The overall parallelism between both distributions was further confirmed at the cellular level on emulsion-coated sections, especially in the hippocampus where pyramidal and granular neurons very probably synthesize both Rxt1 and V-7-3-2. These data provide a further demonstration of the synthesis of the orphan transporters Rxt1 and V-7-3-2 exclusively in neurons whose locations suggest that they might correspond to glutamatergic neurons and subsets of GABAergic neurons.

Amino Acid Sequence↗
PubMed1997

Caregiver issues and AIDS orphans: perspectives from a social worker focus group.

This study examines social workers' perceptions of the needs of families coping with acquired immunodeficiency syndrome (AIDS). This research investigates the problems of family caregivers of children orphaned by human immunodeficiency virus (HIV)-related death of their parents. A qualitative semistructured interview format was used in a focus group of 18 social workers. Four questions were designed to assess family needs and resources, as well as to evaluate the social workers' perspectives of governmental policies affecting these families. A list of four problems and two recommendations for change evolved from the focus group. Inadequate finances to house and care for the children was the primary cause for distress in these families. The major governmental policy that hindered the social workers' ability to assist families pertained to the low financial entitlement for caregivers who are related to the orphaned child. It was noted that unrelated caregivers receive substantially more money for the care of these children than family caregivers receive. Recommendations were made to change this policy and to develop guardianship laws that facilitate families' abilities to provide care to AIDS orphans. Family caregivers of AIDS orphans are bombarded with great demands and limited resources. This analysis of their situation from the social workers' perspective is a positive step toward the improvement of support services for these families. Further research should include individual qualitative interviews assessing the needs of the caregivers and AIDS orphans.

Acquired Immunodeficiency Syndrome↗
PubMed2007

Therapeutic profile of orphan medicines.

PURPOSE: To characterise the therapeutic profile of orphan medicines. MATERIALS AND METHODS: A cross-sectional study was performed during 2 months in a convenience sample of seven hospital pharmacy services, in the region of Lisbon. Data were collected, from pharmaceutical service's records. RESULTS: A total of 18 orphan medicines, were dispensed to 355 patients with rare diseases. Most patients were adults (76.4%). Premature and neonates accounted with 50.0% of the paediatric patients. Differences were not found between the proportion of male and female patients across age groups (p = 0.762). Only 18.3% were inpatients. A high proportion of paediatric inpatients (58.3%) were seen in relation to adult inpatients (5.9%) (p = 0.001). In general, anti-neoplastic and immunomodulating agents for rare cancers were the most frequent dispensed medicines (51.3%). In relation to paediatrics, Caffeine Citrate for primary apnoea of premature newborns had the higher frequency distribution (57.1%). Five (71.4%) medicines dispensed for paediatrics, do not have market authorisation and the remaining (28.6%) were used off-label. For pulmonary arterial hypertension 19 of 27 patients (70.3%) were treated with Bosentan. According to evidence-based clinical practice guidelines, Bosentan has a good level of evidence and substantial benefit: grade of recommendation A. CONCLUSIONS: Most orphan medicines dispensed to paediatrics and adults were not licensed.A special pharmacovigilance program and a risk management plan through the entire life cycle should be implemented, towards effectiveness and safety of orphan medicines.

Adolescent↗
PubMed2000

A proposal to improve the supply of orphan drugs.

Industrial medicinal products are not always available for the treatment of some specific patients or diseases. Appropriate research on orphan drugs, neglected doses or administration routes and patients' sensitivity to excipients, as an example, might lead to interesting results in this respect. In the United States, a specific legislation on orphan drugs dates back to 1983; in the European Union, regulations are currently being studied. The industrial production of orphan drugs might be improved following the adoption of adequate incentives. New regulations should also take care of neglected doses, and stimulate the preparation of galenic products, as an example by including a number of monographs on orphan drugs in Pharmacopoeias and National Formularies. As a matter of fact, magistral and officinal preparations made in community and hospital pharmacies in accordance with a medical prescription or with the prescription of a Pharmacopoeia or an Official Formulary, can represent an effective alternative. In this paper, the regulations enforced in the USA and Japan, the European situation, possible incentives to the industry and the role of galenic products will be discussed.

Drug and Narcotic Control↗