SII-SWORD/CoKE huggingface dataset:
Flavin monooxygenase (FMO) 5 (Flavin_mOase_5)
Type: Family

Flavin-containing monooxygenases (FMOs) constitute a family of xenobiotic-metabolising enzymes . Using an NADPH cofactor and FAD prosthetic group, these microsomal proteins catalyse the oxygenation of nucleophilic nitrogen, sulphur, phosphorous and selenium atoms in a range of structurally diverse compounds. Five mammalian forms of FMO are now known and have been designated FMO1-FMO5 .

The deduced amino acid sequence of human FM05 includes the putative FAD-(GxGxxG) and NADP
+
pyrophosphate-binding (GxGxxA) sites characteristic of mammalian FMOs , a 'FATGY' motif that has also been observed in a range of siderphore biosynthetic enzymes , and a C-terminal hydrophobic segment that is believed to anchor the monooxygenase to the microsomal membrane . Human and guinea pig FMO5, like other FMOs, are encoded by multiple transcripts. FMO5 has been identified in livers of adult humans, rabbits and guinea pigs, and foetal livers of humans . Neither the human nor guinea pig enzyme effectively catalyse the metabolism of methimazole, a general FMO substrate; however, both are active with n-octylamine . The responses to detergent, ions and elevated temperature are all similar to those observed in rabbit FMO5, suggesting that these properties are species- independent and that this form of FMO is not readily classified as a drug- metabolising enzyme .
Chemerin-like receptor 1 (CML1)
Type: Family

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups . The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence . The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) . GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice . Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs .

The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices .

Chemerin-like receptor 1 (CML1, also known as ChemR23 and DEZ), is a GPCR for the chemoattractant adipokine chemerin, and for the omega-3 fatty acid derived molecule resolvin E1 , mainly found in chordates. Interaction with chemerin induces activation of the MAPK and PI3K signaling pathways leading to downstream functional effects, such as a decrease in immune responses, stimulation of adipogenesis, and angiogenesis . Resolvin E1 decreases pro-inflammatory cytokine expression and enhances macrophage phagocytic activity by regulation of the NFkB pathway . This protein is prominently expressed in dendritic cells and macrophages .
Equilibrative nucleoside transporter (Eqnu_transpt)
Type: Family

Nucleosides are hydrophilic molecules and require specialised transport proteins for permeation of cell membranes. There are two types of nucleoside transport processes: equilibrative bidirectional processes driven by chemical gradients and inwardly directed concentrative processes driven by an electrochemical gradient . The two types of nucleoside transporters are classified into two families: the solute carrier (SLC) 29 and SLC28 families, corresponding to equilibrative and concentrative nucleoside transporters, respectively .

Equilibrative nucleoside transporters (ENTs) are integral membrane proteins which enable the movement of hydrophilic nucleosides and nucleoside analogues down their concentration gradients across cell membranes. ENT family members have been identified in humans, mice, fish, tunicates, slime molds, and bacteria . This entry also includes ENT from Plasmodium falciparum, which shares low sequence identity with the human ENT1 (hENT1) and is unsusceptible to hENT1 inhibitor, therefore, it is a good candidate to design inhibitors to disrupt the transport activity of PfENT1 and prevent the proliferation of parasites .
Gap junction alpha-3 protein (Cx46) (Connexin46)
Type: Family

Gap junction alpha-3 protein (also called connexin46, or Cx46) is a connexin of ~415 amino acid residues. The bovine form is slightly shorter (401 residues) and is hence known as Cx44, having a molecular mass of ~44 kD. Cx46 (together with Cx50) is a connexin isoform expressed in the lens fibres of the eye. Here, gap junctions join the cells into a functional syncytium, and also couple the fibres to the epithelial cells on the anterior surface of the lens. The lens fibres depend on this epithelium for their metabolic support, since they lose their intra-cellular organelles, and accumulate high concentrations of crystallins, in order to produce their optical transparency. Genetically-engineered mice deficient in Cx46 demonstrate the importance of Cx46 in forming lens fibre gap junctions; these mice develop normal lenses, but subsequently develop early onset senile-type cataracts that resemble human nuclear cataracts. Aberrant proteolysis of crystallin proteins was observed in the lenses of Cx46-null mice . A Cx46 mutant in a highly conserved threonine has been linked to autosomal dominant cataracts. This mutation causes loss of gap junction function and alters hemi-channel gating .
Follicle stimulating hormone receptor (FSH_rcpt)
Type: Family

Glycoprotein hormone receptors are members the rhodopsin-like G-protein coupled receptor (GPCR) family. They function as receptors for the pituitary hormones thyrotropin (TSH receptor), follitropin (FSH receptor) and lutropin (LH receptor). In mammals the LH receptor is also the receptor for the placental hormone, human chorionic gonadotropin (hCG), so is denominated as a lutropin-choriogonadotropic hormone receptor (LHCG receptor). The receptors share close sequence similarity, and are characterised by large extracellular domains believed to be involved in hormone binding via leucine-rich repeats (LRR) .

In females, the follicle-stimulating hormone acts on the ovaries, promoting development of follicles and is the principal hormone regulating secretion of oestrogens . In males, it is responsible for the integrity of the seminiferous tubules and acts on Sertoli cells to support gametogenesis . FSH is used clinically to treat infertility in females and for some types of spermatogenesis in males .

The follicle-stimulating hormone receptor (FSH receptor or FSHR), which this entry represents, is a transmembrane receptor that interacts with the follicle-stimulating hormone. The activation of the FSH receptor is necessary for the hormonal functioning of FSH . The receptor is found in ovary and testis , and its predominant effector pathway being via activation of adenylyl cyclase through G proteins .
Lutropin-choriogonadotropic hormone receptor (LSH_rcpt)
Type: Family

Glycoprotein hormone receptors are members the rhodopsin-like G-protein coupled receptor (GPCR) family. They function as receptors for the pituitary hormones thyrotropin (TSH receptor), follitropin (FSH receptor) and lutropin (LH receptor). In mammals the LH receptor is also the receptor for the placental hormone, human chorionic gonadotropin (hCG), so is denominated as a lutropin-choriogonadotropic hormone receptor (LHCG receptor). The receptors share close sequence similarity, and are characterised by large extracellular domains believed to be involved in hormone binding via leucine-rich repeats (LRR) .

The beta subunits of the luteinizing hormone and human chorionic gonadotropin are closely related in sequence and elicit their biological actions via the same receptor. LH is released from the anterior pituitary under the influence of gonadotrophin-releasing hormone and progesterones. hCG is released by the placenta during pregnancy. In females, LH stimulates ovulation and is the major hormone involved in the regulation of progesterone secretion by the corpus luteum. In males, it stimulates Leydig cells to secrete androgens, particularly testosterone.

This entry represents lutropin-choriogonadotropic hormone receptor (LCGR), also known as luteinizing hormone-choriogonadotropin receptor (LHCGR), or luteinizing hormone receptor (LH receptor). It is a transmembrane receptor found predominantly in organs invloved in reproductive biology such as the ovary and testis . The receptor interacts with both luteinizing hormone and human chorionic gonadotropins and represents a G protein-coupled receptor, rhodopsin-type (GPCRA). Its activation is necessary for the hormonal functioning during reproduction and activates adenylyl cyclase through G proteins .
Thyrotropin receptor (TSH_rcpt)
Type: Family

Glycoprotein hormone receptors are members the rhodopsin-like G-protein coupled receptor (GPCR) family. They function as receptors for the pituitary hormones thyrotropin (TSH receptor), follitropin (FSH receptor) and lutropin (LH receptor). In mammals the LH receptor is also the receptor for the placental hormone, human chorionic gonadotropin (hCG), so is denominated as a lutropin-choriogonadotropic hormone receptor (LHCG receptor). The receptors share close sequence similarity, and are characterised by large extracellular domains believed to be involved in hormone binding via leucine-rich repeats (LRR) .

This entry represents the thyrotropin receptor, also known as thyroid-stimulating hormone receptor (TSHR) is synthesised in the thyrotroph cells of the anterior pituitary under the influence of TSH and thyroid hormones . Upon binding circulating thyrotropin, a G-protein signal cascade activates adenylyl cyclase and intercellular levels of cAMP rise. cAMP activates all functional aspects of the thyroid cell, including iodine pumping; thyroglobulin synthesis, iodination, endocytosis and proteolysis; thyroid peroxidase activity; and hormone release . Graves disease is caused by stimulatory anti-TSH receptor antibodies .
Chemerin-like receptor 2 (CML2)
Type: Family

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups . The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence . The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) . GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice . Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs .

The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices .

Chemerin-like receptor 2 (CML2, also known as GPCR1), is a receptor for chemoattractant adipokine chemerin/RARRES2 that may have a role for in the regulation of inflammation and energy homeostasis . This protein also acts also as a receptor for TAFA1, mediates its effects on neuronal stem-cell proliferation and differentiation via the activation of ROCK/ERK and ROCK/STAT3 signaling pathway . In humans, GPR1 is expressed in the human hippocampus . By contrast, the rat GPR1 gene is not expressed in hippocampus, demonstrating a functional variation for this receptor in these species .
G protein-coupled receptor 4 orphan (GPR4_orph)
Type: Family

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups . The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence . The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) . GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice . Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs .

The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices .

Several 7TM receptors have been cloned but their endogenous ligands are unknown; these have been termed orphan receptors. A novel GPCR (GPR4) from the critical myotonic dystrophy (DM) region on chromosome 19q13.3 has been sequenced . The gene is intronless and contain an open reading frame encoding a protein of 362 amino acids. Two isoforms of GPR4 are expressed in humans, differing in their 3' untranslated region as a result of the use of alternate polyadenylation signals. GPR4 is widely expressed, with higher levels in kidney, heart, and especially lung . Sequence analysis suggests that GPR4 is a peptide receptor; it shares strongest similarity with purinergic receptors and receptors for angiotensin II, platelet activating factor, thrombin and bradykinin .
Melatonin receptor 1A/1B (Mel_1A/1B_rcpt)
Type: Family

Melatonin is a naturally occurring compound found in animals, plants, and microbes . In animals melatonin is secreted by the pineal gland during darkness . It regulates a variety of neuroendocrine functions and is thought to play an essential role in circadian rhythms . Drugs that modify the action of melatonin, and hence influence circadian cycles, are of clinical interest for example, in the treatment of jet-lag .

Many of the biological effects of melatonin are produced through the activation of melatonin receptors , which are members of rhodopsin-like G protein-coupled receptor family. There are three melatonin receptor subtypes. Melatonin receptor type 1A and melatonin receptor type 1B are present in humans and other mammals while melatonin receptor type 1C has been identified in amphibia and birds . There is also a closely-related orphan receptor, termed melatonin-related receptor type 1X (also known as GPR50) , is yet to achieve receptor status from the International Union of Basic and Clinical Pharmacology (IUPHAR), since a robust response mediated via the protein has not been reported in the literature. Melatonin receptor type 1C receptors are 80% identical and are distinct from 1A and 1B subtypes. Similar ligand binding and functional characteristics are observed in expressed 1A and 1C receptors. The melatonin receptors inhibit adenylyl cyclase via a pertussis-toxin-sensitive G-protein, probably of the Gi/Go class.

Melatonin receptor 1A, also known as MT1 melatonin receptor , mediates the circadian and reproductive effects of the hormone melatonin. Melatonin receptor 1A is expressed in the hypothalamic suprachiasmatic nuclei and hypophyseal pars tuberalis .

Melatonin receptor type 1B is found primarily in the retina, selected brain regions and some arterial beds . Activation of human recombinant melatonin receptor 1B inhibits the adenylyl cyclase pathway and cyclic guanosine monophosphate formation . It is thought to participate in the circadian timing system , inhibition of dopamine release in the retina , and in vasodilation of the caudal artery .
Melatonin receptor type 1C (Mel_rcpt_1C)
Type: Family

Melatonin is a naturally occurring compound found in animals, plants, and microbes . In animals melatonin is secreted by the pineal gland during darkness . It regulates a variety of neuroendocrine functions and is thought to play an essential role in circadian rhythms . Drugs that modify the action of melatonin, and hence influence circadian cycles, are of clinical interest for example, in the treatment of jet-lag .

Many of the biological effects of melatonin are produced through the activation of melatonin receptors , which are members of rhodopsin-like G protein-coupled receptor family. There are three melatonin receptor subtypes. Melatonin receptor type 1A and melatonin receptor type 1B are present in humans and other mammals while melatonin receptor type 1C has been identified in amphibia and birds . There is also a closely-related orphan receptor, termed melatonin-related receptor type 1X (also known as GPR50) , is yet to achieve receptor status from the International Union of Basic and Clinical Pharmacology (IUPHAR), since a robust response mediated via the protein has not been reported in the literature. Melatonin receptor type 1C receptors are 80% identical and are distinct from 1A and 1B subtypes. Similar ligand binding and functional characteristics are observed in expressed 1A and 1C receptors. The melatonin receptors inhibit adenylyl cyclase via a pertussis-toxin-sensitive G-protein, probably of the Gi/Go class.

This entry represents melatonin receptor 1C, which is found in birds, fish and amphibians, but not in humans . It has been shown that the widespread distribution of 1C in brain provides a molecular substrate for the profound actions of melatonin in birds . Also, in amphibians, very low concentrations of melatonin activate the 1C receptor subtype, triggering movement of granules toward the cell centre, thus lightening skin colour. 1C receptor activation reduces intracellular cAMP via a pertussis toxin-sensitive inhibitory G-protein (Gi) .
Melatonin-related receptor 1X (Mel_rcpt_1X)
Type: Family

Melatonin is a naturally occurring compound found in animals, plants, and microbes . In animals melatonin is secreted by the pineal gland during darkness . It regulates a variety of neuroendocrine functions and is thought to play an essential role in circadian rhythms . Drugs that modify the action of melatonin, and hence influence circadian cycles, are of clinical interest for example, in the treatment of jet-lag .

Many of the biological effects of melatonin are produced through the activation of melatonin receptors , which are members of rhodopsin-like G protein-coupled receptor family. There are three melatonin receptor subtypes. Melatonin receptor type 1A and melatonin receptor type 1B are present in humans and other mammals while melatonin receptor type 1C has been identified in amphibia and birds . There is also a closely-related orphan receptor, termed melatonin-related receptor type 1X (also known as GPR50) , is yet to achieve receptor status from the International Union of Basic and Clinical Pharmacology (IUPHAR), since a robust response mediated via the protein has not been reported in the literature. Melatonin receptor type 1C receptors are 80% identical and are distinct from 1A and 1B subtypes. Similar ligand binding and functional characteristics are observed in expressed 1A and 1C receptors. The melatonin receptors inhibit adenylyl cyclase via a pertussis-toxin-sensitive G-protein, probably of the Gi/Go class.

This entry represents melatonin-related receptor 1X from human pituitary, also known as G protein-coupled receptor 50 (GPR50). It is the mammalian orthologue of melatonin receptor 1C described in non-mammalian vertebrates . It is closely related to the other melatonin subtypes as it is 45% identical to human 1A and 1B receptors , However, it lacks N-linked glycosylation sites and bears a >300 residue C-terminal tail. 1X receptor is expressed in hypothalamus and pituitary, suggesting that the receptor and its natural ligand are involved in neuroendocrine function .