SII-SWORD/CoKE huggingface dataset:
Amidase (Amidase)
Type: Family

Amidase signature (AS) enzymes are a large group of hydrolytic enzymes that contain a conserved stretch of approximately 130 amino acids known as the AS sequence. They are widespread, being found in both prokaryotes and eukaryotes. AS enzymes catalyse the hydrolysis of amide bonds (CO-NH2), although the family has diverged widely with regard to substrate specificity and function. Nonetheless, these enzymes maintain a core α/β/α structure, where the topologies of the N-and C-terminal halves are similar. AS enzymes characteristically have a highly conserved C-terminal region rich in serine and glycine residues, but devoid of aspartic acid and histidine residues, therefore they differ from classical serine hydrolases. These enzymes posses a unique, highly conserved Ser-Ser-Lys catalytic triad used for amide hydrolysis, although the catalytic mechanism for acyl-enzyme intermediate formation can differ between enzymes .

Examples of AS enzymes include:

Peptide amidase (Pam) , which catalyses the hydrolysis of the C-terminal amide bond of peptides.

Fatty acid amide hydrolases , which hydrolyse fatty acid amid substrates (e.g. cannabinoid anandamide and sleep-inducing oleamide), thereby controlling the level and duration of signalling induced by this diverse class of lipid transmitters.

Malonamidase E2 , which catalyses the hydrolysis of malonamate into malonate and ammonia, and which is involved in the transport of fixed nitrogen from bacteroids to plant cells in symbiotic nitrogen metabolism.

Subunit A of Glu-tRNA(Gln) amidotransferase ,a heterotrimeric enzyme that catalyses the formation of Gln-tRNA(Gln) by the transamidation of misacylated Glu-tRNA(Gln) via amidolysis of glutamine.
PEP-utilising enzyme, C-terminal (PEP_util_C)
Type: Domain

A number of enzymes that catalyze the transfer of a phosphoryl group from phosphoenolpyruvate (PEP) via a phospho-histidine intermediate have been shown to be structurally related . All these enzymes share the same catalytic mechanism: they bind PEP and transfer the phosphoryl group from it to a histidine residue. The sequence around that residue is highly conserved. This C-terminal domain has been shown to be the PEP-binding domain . It is often found associated with the pyruvate phosphate dikinase, AMP/ATP-binding domain (

) at its N terminus and the PEP-utilizing enzyme mobile domain.
RNA-directed DNA polymerase (reverse transcriptase), msDNA (Reverse_transcriptase_msDNA)
Type: Family

The use of an RNA template to produce DNA, for integration into the host genome and exploitation of a host cell, is a strategy employed in the replication of retroid elements, such as the retroviruses and bacterial retrons. The enzyme catalysing polymerisation is an RNA-directed DNA-polymerase, or reverse trancriptase (RT) (

). Reverse transcriptase occurs in a variety of mobile elements, including retrotransposons, retroviruses, group II introns, bacterial msDNAs, hepadnaviruses, and caulimoviruses. The enzymatic reaction leads to the production of a unique RNA-DNA complex called msDNA (multicopy single-stranded DNA) in which a single-stranded DNA branches out from an RNA molecule via a 2',5'-phosphodiester linkage .

Retroviral reverse transcriptase is synthesised as part of the POL polyprotein that contains; an aspartyl protease, a reverse transcriptase, RNase H and integrase. POL polyprotein undergoes specific enzymatic cleavage to yield the mature proteins. The discovery of retroelements in the prokaryotes raises intriguing questions concerning their roles in bacteria and the origin and evolution of reverse transcriptases and whether the bacterial reverse transcriptases are older than eukaryotic reverse transcriptases .

This protein family includes a number of bacterial reverse transcriptases, including Retron Ec73 reverse transcriptase from Escherichia coli and Trt from Bacillus stearothermophilus (

).
Spermadhesin (Spermadhesin)
Type: Family

A family of mammalian sperm proteins has been characterised . As shown in the following schematic representation these proteins, which have from 110 to 130 amino acid residues, contain four conserved cysteines involved in two disulphide bonds. Structurally, the spermadhesins consist of a CUB domain .

+---------+ +---------+
| | | |
xxxxCxxxxxxxxxCxxxxxxxxxxxCxxxxxxxxxCxxxxxxxxxxxxxxxxxx

'C': conserved cysteine involved in a disulphide bond.
Glycoside hydrolase, family 14A, bacterial (Glyco_hydro_14A_bac)
Type: Family

This entry represents glycoside hydrolase family 14 (

,

) which encompasses the beta-amylases. Beta-amylases, which are found in plants and bacteria, hydrolyse 1,4-alpha-glycosidic linkages in starch-type polysaccharide substrates, removing successive maltose units from the non-reducing ends of the chains. In potato plants, the enzyme has been found to work optimally at 40 degrees C, becoming unstable above this temperature. On the basis of sequence comparisons, plant and bacterial beta-amylases can be readily distinguished from each other.

The 3D structure of a complex of soybean beta-amylase with an inhibitor (alpha-cyclodextrin) has been determined to 3.0A resolution by X-ray diffraction . The enzyme folds into large and small domains: the large domain has a (β α)8 super-secondary structural core, while the smaller is formed from two long loops extending from the β3 and β4 strands of the (β α)8 fold . The interface of the two domains, together with shorter loops from the (β α)8 core, form a deep cleft, in which the inhibitor binds . Two maltose molecules also bind in the cleft, one sharing a binding site with alpha-cyclodextrin, and the other sitting more deeply in the cleft . Sequence alignments allow us to relate features of the bacterial beta-amylases to the soybean structure.

O-Glycosyl hydrolases (

) are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycosyl hydrolases, based on sequence similarity, has led to the definition of 85 different families . This classification is available on the CAZy (CArbohydrate-Active EnZymes) website.
Serine proteases, V8 family, serine active site (V8_ser_AS)
Type: Active_site

A number of prokaryotic proteases have been shown to be evolutionary related; their catalytic activity is provided by a charge relay system similar to that of the trypsin family of serine proteases but which probably evolved by independent convergent evolution. The sequence around the residues involved in the catalytic triad (aspartic acid, serine and histidine) are completely different from that of the analogous residues in the trypsin serine proteases and can be used as signatures specific to that category of proteases. The proteases which are known to belong to this family are listed below.

Staphylococcus aureus V8 proteinase, which preferentially cleaves peptide bonds on the carboxyl-terminal side of aspartate and glutamate and which is widely used in protein sequencing studies.

Bacillus licheniformis glutamate specific endopeptidase (GSE) , which like V8 cleaves on the carboxyl-terminal side of acidic residues, but with a strong preference for glutamate.

Bacillus subtilis extracellular "metalloprotease" (gene mpr) .

Staphylococcus aureus exfoliative (or epidermolytic) toxins A (gene eta) and B (gene etb). These toxins cause impetigous diseases commonly referred to as staphylococcal scalded skin syndrome (SSSS) and have been shown to possess proteolytic activity.

This entry represents the serine active site of serine proteases from the V8 family.
Progesterone receptor (Progest_rcpt)
Type: Family

Steroid or nuclear hormone receptors (NRs) constitute an important superfamily of transcription regulators that are involved in widely diverse physiological functions, including control of embryonic development, cell differentiation and homeostasis. Members of the superfamily include the steroid hormone receptors and receptors for thyroid hormone, retinoids, 1,25-dihydroxy-vitamin D3 and a variety of other ligands. The proteins function as dimeric molecules in nuclei to regulate the transcription of target genes in a ligand-responsive manner . In addition to C-terminal ligand-binding domains, these nuclear receptors contain a highly-conserved, N-terminal zinc-finger that mediates specific binding to target DNA sequences, termed ligand-responsive elements. In the absence of ligand, steroid hormone receptors are thought to be weakly associated with nuclear components; hormone binding greatly increases receptor affinity.

NRs are extremely important in medical research, a large number of them being implicated in diseases such as cancer, diabetes, hormone resistance syndromes, etc. While several NRs act as ligand-inducible transcription factors, many do not yet have a defined ligand and are accordingly termed "orphan" receptors. During the last decade, more than 300 NRs have been described, many of which are orphans, which cannot easily be named due to current nomenclature has recently been introduced in an attempt to rationalise the increasingly complex set of names used to describe superfamily members.

The progesterone receptor consists of 3 functional and structural domains: an N-terminal (modulatory) domain; a DNA binding domain that mediates specific binding to target DNA sequences (ligand-responsive elements); and a hormone binding domain. The N-terminal domain is unique to the progesterone receptors and spans approximately the first 500 residues; the highly-conserved DNA-binding domain is smaller (around 65 residues) and occupies the central portion of the protein; and the hormone binding domain lies at the receptor C terminus.
ATP synthase, F1 complex, gamma subunit (ATP_synth_F1_gsu)
Type: Family

The ATPase F1 complex gamma subunit forms the central shaft that connects the F0 rotary motor to the F1 catalytic core. The gamma subunit functions as a rotary motor inside the cylinder formed by the α(3)β(3) subunits in the F1 complex . The most conserved region of the gamma subunit is its C terminus, which seems to be essential for assembly and catalysis.

F-ATPases (also known as ATP synthases, F1F0-ATPase, or H(+)-transporting two-sector ATPase) (

) are composed of two linked complexes: the F1 ATPase complex is the catalytic core and is composed of 5 subunits (alpha, beta, gamma, delta, epsilon), while the F0 ATPase complex is the membrane-embedded proton channel that is composed of at least 3 subunits (A-C), with additional subunits in mitochondria. Both the F1 and F0 complexes are rotary motors that are coupled back-to-back. In the F1 complex, the central gamma subunit forms the rotor inside the cylinder made of the α(3)β(3) subunits, while in the F0 complex, the ring-shaped C subunits forms the rotor. The two rotors rotate in opposite directions, but the F0 rotor is usually stronger, using the force from the proton gradient to push the F1 rotor in reverse in order to drive ATP synthesis . These ATPases can also work in reverse in bacteria, hydrolysing ATP to create a proton gradient.

Transmembrane ATPases are membrane-bound enzyme complexes/ion transporters that use ATP hydrolysis to drive the transport of protons across a membrane. Some transmembrane ATPases also work in reverse, harnessing the energy from a proton gradient, using the flux of ions across the membrane via the ATPase proton channel to drive the synthesis of ATP.
Nitrilase/cyanide hydratase, conserved site (Nitrilase/CN_hydratase_CS)
Type: Conserved_site

This family includes both nitrilases and cyanide hydratase. Nitrilases (

) are enzymes that convert nitriles into their corresponding acids and ammonia. They are widespread in microbes as well as in plants where they convert indole-3-acetonitrile to the hormone indole-3- acetic acid. A conserved cysteine has been shown to be essential for enzyme activity; it seems to be involved in a nucleophilic attack on the nitrile carbon atom. Cyanide hydratase (

) converts HCN to formamide. In phytopathogenic fungi, it is used to avoid the toxic effect of cyanide released by wounded plants .
ER lumen protein retaining receptor (ER_ret_rcpt)
Type: Family

Proteins resident in the lumen of the endoplasmic reticulum (ER) contain a C-terminal tetrapeptide, commonly known as Lys-Asp-Glu-Leu (KDEL) in mammals and His-Asp-Glu-Leu (HDEL) in yeast (Saccharomyces cerevisiae) that acts as a signal for their retrieval from subsequent compartments of the secretory pathway. The receptor for this signal is a ~26kDa Golgi membrane protein, initially identified as the ERD2 gene product in S. cerevisiae. The receptor molecule, known variously as the ER lumen protein retaining receptor or the 'KDEL receptor', is believed to cycle between the cis side of the Golgi apparatus and the ER. It has also been characterised in a number of other species, including plants, Plasmodium, Drosophila and mammals. In mammals, 2 highly related forms of the receptor are known.
Oleosin (Oleosin)
Type: Family

Oleosins are the proteinaceous components of plants' lipid storage bodies called oil bodies. Oil bodies are small droplets (0.2 to 1.5 mu-m in diameter) containing mostly triacylglycerol that are surrounded by a phospholipid/ oleosin annulus. Oleosins may have a structural role in stabilising the lipid body during dessication of the seed, by preventing coalescence of the oil. They may also provide recognition signals for specific lipase anchorage in lipolysis during seedling growth. Oleosins are found in the monolayer lipid/ water interface of oil bodies and probably interact with both the lipid and phospholipid moieties. Oleosins are proteins of 16 Kd to 24 Kd and are composed of three domains: an N-terminal hydrophilic region of variable length (from 30 to 60 residues); a central hydrophobic domain of about 70 residues and a C-terminal amphipathic region of variable length (from 60 to 100 residues). The central hydrophobic domain is proposed to be made up of β-strand structure and to interact with the lipids . It is the only domain whose sequence is conserved.
Hydroxymethylglutaryl-CoA lyase, active site (HMG_CoA_lyase_AS)
Type: Active_site

Synonym(s): 3-hydroxy-3-methylglutaryl-coenzyme A synthase, HMG-CoA lyase.

HMG-CoA lyase catalyses the transformation of HMG-CoA into acetyl-CoA and acetoacetate. In vertebrates it is a mitochondrial enzyme that is involved in ketogenesis and in leucine catabolism . In some bacteria, such as Pseudomonas mevalonii, it is involved in mevalonate catabolism (gene mvaB). This signature contains the cysteine that has been shown , in mvaB, to be required for the activity of the enzyme.
Prostaglandin F receptor (PglndnF_rcpt)
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 .

Prostanoids (prostaglandins (PG) and thromboxanes (TX)) mediate a wide variety of actions and play important physiological roles in the cardiovascular and immune systems, and in pain sensation in peripheral systems. PGI2 and TXA2 have opposing actions, involving regulation of the interaction of platelets with the vascular endothelium, while PGE2, PGI2 and PGD2 are powerful vasodilators and potentiate the action of various autocoids to induce plasma extravasation and pain sensation. To date, evidence for at least 5 classes of prostanoid receptor has been obtained. However, identification of subtypes and their distribution is hampered by expression of more than one receptor within a tissue, coupled with poor selectivity of available agonists and antagonists.

FP receptors bind prostaglandin F2-alpha and mediate contraction in a wide range of smooth muscle, including intraocular, myometrial and bronchial tissues, and are potent stimulants of luteolysis. The receptors activate the phosphoinositide pathway through a pertussis-toxin-insensitive G-protein, probably of the Gq/G11 class.
P2Y purinoceptor 1 (P2Y1_rcpt)
Type: Family

There are three distinct families of extracellular receptors for purine and pyrimidine nucleotides , known as P1, P2X and P2Y purinoceptors . These receptors induce a wide variety of biological effects and are involved in many different cellular functions . P2X receptors are ligand-gated ion channels, whereas P1 and P2Y receptors are rhodopsin-like G protein-coupled receptors . The families also differ by their method of activation: P1 receptors are preferentially activated by adenosine , P2X via ATP , whereas the P2Y receptors, in addition to being activated by ATP, are activated by different adenine and/or uridine nucleoside di- and triphosphates (ADP, UDP, UTP, UDP and UDP-glucose) .

The P2Y purinoceptors currently consist of eleven subtypes: P2Y1, P2Y2, P2Y3 P2Y4, P2Y6, P2Y8, P2Y10, P2Y11, P2Y12, P2Y13 and P2Y14 . P2Y3 has, as yet, only been found in birds , whilst the rest have been cloned in humans. The gaps in P2Y receptor numbering are due to the reclassification of some receptors that were initially associated with to the P2Y family. These include P2Y5 (now known as lysophosphatidic acid receptor 6), P2Y7 (now leukotriene B4 receptor) and P2Y9 (lysophosphatidic acid receptor 4) .

This entry represents the P2Y1 receptor, it is activated by adenine nucleotides and not by uracil nucleotides. Avian P2Y1 receptors are activated by ATP and ADP , whereas mammalian P2Y1 receptors are potently activated mainly by ADP and related diphosphate analogues . The P2Y1 receptor couples mainly Gq/11, and is expressed in the heart, skeletal muscle, aortic endothelium, pancreas, spleen, brain and spinal cord . It mediates muscle relaxation and the release of endothelium-derived nitric oxide . P2Y1 is also expressed in blood platelets and plays a crucial role in ADP-induced platelet aggregation .
Geminivirus MSV 27Kd coat protein (Gemcoat_MSV)
Type: Family

Geminiviruses are characterised by a genome of circular single-stranded DNA encapsidated in twinned (geminate) quasi-isometric particles, from which the group derives its name . Most geminiviruses can be divided into two subgroups on the basis of host range and/or insect vector: i.e. those that infect dicotyledenous plants and are transmitted by the same whitefly species, and those that infect monocotyledenous plants and are transmitted by different leafhopper vectors. The genomes of the whitefly-transmitted African cassava mosaic virus, Tomato golden mosaic virus (TGMV) and Bean golden mosaic virus (BGMV) possess a bipartite genome. By contrast, only a single DNA component has been identified for the leafhopper-transmitted Maize streak virus (MSV) and Wheat dwarf virus (WDV) . Beet curly top virus (BCTV), and Tobacco yellow dwarf virus belong to a third possible subgroup. Like MSV and WDV, BCTV is transmitted by a specific leafhopper species, yet like the whitefly-transmitted geminiviruses it has a host range confined to dicotyledenous plants.

Sequence comparison of the whitefly-transmitted Squash leaf curl virus (SqLCV) and Tomato yellow leaf curl virus (TYLCV) with the genomic components of TGMV and BGMV reveals a close evolutionary relationship . Amino acid sequence alignments of Potato yellow mosaic virus (PYMV) proteins with those encoded by other geminiviruses show that PYMV is closely related to geminiviruses isolated from the New World, especially in the putative coat protein gene regions . Comparison of MSV DNA-encoded proteins with those of other geminiviruses infecting monocotyledonous plants, including Panicum streak virus and Miscanthus streak virus (MiSV) , reveal high levels of similarity.
Outer capsid protein VP5, Orbivirus (Capsid_VP5_Orbivir)
Type: Family

The orbivirus VP5 protein is one of the two proteins (with VP2) which make up the virus particle outer capsid. Cryoelectron microscopy indicates that VP5 is a trimer suggesting that there are 360 copies of VP5 per virion .
Fructose-1,6-bisphosphatase class 1 (FBPase_class-1)
Type: Family

This entry represents the fructose-1,6-bisphosphatase (FBPase) class 1 family. FBPase is a critical regulatory enzyme in gluconeogenesis that catalyses the removal of 1-phosphate from fructose 1,6-bis-phosphate to form fructose 6-phosphate . It is involved in many different metabolic pathways and found in most organisms. FBPase requires metal ions for catalysis (Mg
2+
and Mn
2+
being preferred) and the enzyme is potently inhibited by Li
+
. The fold of fructose-1,6-bisphosphatase was noted to be identical to that of inositol-1-phosphatase (IMPase) . Inositol polyphosphate 1-phosphatase (IPPase), IMPase and FBPase share a sequence motif (Asp-Pro-Ile/Leu-Asp-Gly/Ser-Thr/Ser) which has been shown to bind metal ions and participate in catalysis. This motif is also found in the distantly-related fungal, bacterial and yeast IMPase homologues. It has been suggested that these proteins define an ancient structurally conserved family involved in diverse metabolic pathways, including inositol signalling, gluconeogenesis, sulphate assimilation and possibly quinone metabolism .

This entry also includes sedoheptulose-1,7-bisphosphatase, which is a member of the FBPase class 1 family.