SII-SWORD/CoKE huggingface dataset:
Haem peroxidase, animal-type (Haem_peroxidase_animal)
Type: Family

Peroxidases are haem-containing enzymes that use hydrogen peroxide as the electron acceptor to catalyse a number of oxidative reactions.

Peroxidases are found in bacteria, fungi, plants and animals. On the basis of sequence similarity, a number of animal haem peroxidases can be categorised as members of a superfamily: myeloperoxidase (MPO); eosinophil peroxidase (EPO); lactoperoxidase (LPO); thyroid peroxidase (TPO); prostaglandin H synthase (PGHS); and peroxidasin .
Gonadoliberin (Gonadoliberin)
Type: Family

The gonadotropin-releasing hormones (GnRH) (gonadoliberin) are a family of peptides that play a pivotal role in reproduction. The main function of GnRH is to act on the pituitary to stimulate the synthesis and secretion of luteinizing and follicle-stimulating hormones, but GnRH also acts on the brain, retina, sympathetic nervous system, gonads and placenta in certain species. There seems to be at least three forms of GnRH . The second form is expressed in midbrain and seems to be widespread. The third form has only been found so far in fish. GnRH is a C-terminal amidated decapeptide processed from a larger precursor protein. Four of the ten residues are perfectly conserved in all species where GnRH has been sequenced.
Glucose-6-phosphate dehydrogenase, active site (G6P_DH_AS)
Type: Active_site

Glucose-6-phosphate dehydrogenase (G6PD) catalyses the first step in the pentose pathway, the reduction of glucose-6-phosphate to gluconolactone 6-phosphate. A lysine residue has been identified as a reactive nucleophile associated with the activity of the enzyme . The sequence around this lysine is totally conserved from bacterial to mammalian G6PD's and is used as the pattern to identify the proteins associated with this entry.
Glutamate 5-kinase, conserved site (Glutamate_5-kinase_CS)
Type: Conserved_site

Glutamate 5-kinase (

) (gamma-glutamyl kinase) (GK) is the enzyme that catalyzes the first step in the biosynthesis of proline from glutamate, the ATP-dependent phosphorylation of L-glutamate into L-glutamate 5-phosphate.

In eubacteria (gene proB) and yeast (gene PRO1), GK is a monofunctional protein, while in plants and mammals, it is a bifunctional enzyme (P5CS) that consists of two domains: a N-terminal GK domain and a C-terminal gamma- glutamyl phosphate reductase domain (

).

This entry represents a highly conserved glycine-and alanine- rich region located in the central section of these enzymes.
Glycoside hydrolase family 22 domain (Glyco_hydro_22_CS)
Type: Domain

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.

Glycoside hydrolase family 22

comprises enzymes with two known activities; lysozyme type C (

) and alpha-lactalbumins. Asp and/or the carbonyl oxygen of the C-2 acetamido group of the substrate acts as the catalytic nucleophile/base.

Alpha-lactalbumin is a milk protein that acts as the regulatory subunit of lactose synthetase, acting to promote the conversion of galactosyltransferase to lactose synthase, which is essential for milk production. In the mammary gland, alpha-lactalbumin changes the substrate specificity of galactosyltransferase from N-acetylglucosamine to glucose.

Lysozymes (

) act as bacteriolytic enzymes by hydrolyzing the beta(1->4) bonds between N-acetylglucosamine and N-acetylmuramic acid in the peptidoglycan of prokaryotic cell walls. It has also been recruited for a digestive role in certain ruminants and colobine monkeys . There are at least five different classes of lysozymes : C (chicken type), G (goose type), phage-type (T4), fungi (Chalaropsis), and bacterial (Bacillus subtilis). There are few similarities in the sequences of the different types of lysozymes.

Lysozyme type C and alpha-lactalbumin are similar both in terms of primary sequence and structure, and probably evolved from a common ancestral protein . Around 35 to 40% of the residues are conserved in both proteins as well as the positions of the four disulphide bonds. There is, however, no similarity in function. Another significant difference between the two enzymes is that all lactalbumins have the ability to bind calcium , while this property is restricted to only a few lysozymes .

The binding site was deduced using high resolution X-ray structure analysis and was shown to consist of three aspartic acid residues. It was first suggested that calcium bound to lactalbumin stabilised the structure, but recently it has been claimed that calcium controls the release of lactalbumin from the golgi membrane and that the pattern of ion binding may also affect the catalytic properties of the lactose synthetase complex.

This domain includes three cysteines which are involved in two of the disulphide bonds found in these proteins.
Glycoside hydrolase, family 35, conserved site (Glyco_hydro_35_CS)
Type: Conserved_site

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.

Glycoside hydrolase family 35

comprises enzymes with only one known activity; beta-galactosidase (

).

Mammalian beta-galactosidase is a lysosomal enzyme (gene GLB1) which cleaves the terminal galactose from gangliosides, glycoproteins, and glycosaminoglycans and whose deficiency is the cause of the genetic disease Gm(1) gangliosidosis (Morquio disease type B).

One of the best conserved regions in these enzymes contains a glutamic acid residue which, on the basis of similarities with other families of glycosyl hydrolases, probably acts as the proton donor in the catalytic mechanism. This signature spans the region contain the putative active site glutamic acid residue, it is the second glutamic acid residue of the two in the pattern .
Glycoside hydrolase, family 4, conserved site (GlycHydrolase_4_CS)
Type: Conserved_site

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.

Glycoside hydrolase family 4

comprises enzymes with several known activities; 6-phospho-beta-glucosidase (

); 6-phospho-alpha-glucosidase (

); alpha-galactosidase (

).

These enzymes require NAD and a divalent ion for their activity and are proteins of about 50kDa; e.g. 6-phospho-alpha-glucosidase requires both NAD(H) and divalent metal (Mn2+, Fe2+, Co2+, or Ni2+) for activity . The signature pattern is located to a conserved region located in the central section. This region does not contain residues directly shown to be important for the catalytic activity.
Glypican, conserved site (Glypican_CS)
Type: Conserved_site

Glypicans are a family of heparan sulphate proteoglycans which are anchored to cell membranes by a glycosylphosphatidylinositol (GPI) linkage. Six members (GPC1-6) are known in vertebrates . Structurally, these proteins consist of three separate domains:

A signal sequence;

An extracellular domain of about 500 residues that contains 12 conserved cysteines probably involved in disulphide bonds and which also contains the sites of attachment of the heparan sulphate glycosaminoglycan side chains;

A C-terminal hydrophobic region which is post-translationally removed after formation of the GPI-anchor.

The signature pattern in this entry is located in the central section of the extracellular domain and contains five of the conserved cysteines.
Ras guanine-nucleotide exchange factor, conserved site (Ras_G-nucl-exch_fac_CS)
Type: Conserved_site

Ras proteins are membrane-associated molecular switches that bind GTP and GDP and slowly hydrolyse GTP to GDP . The balance between the GTP bound (active) and GDP bound (inactive) states is regulated by the opposite action of proteins activating the GTPase activity and that of proteins which promote the loss of bound GDP and the uptake of fresh GTP . The latter proteins are known as guanine-nucleotide dissociation stimulators (GDSs) (or also as guanine-nucleotide releasing (or exchange) factors (GRFs)). Proteins that act as GDS can be classified into at least two families, on the basis of sequence similarities, the CDC24 family (see

) and the CDC25 family.

The size of the proteins of the CDC25 family range from 309 residues (LTE1) to 1596 residues (sos). The sequence similarity shared by all these proteins is limited to a region of about 250 amino acids generally located in their C-terminal section (currently the only exceptions are sos and ralGDS where this domain makes up the central part of the protein). This domain has been shown, in CDC25 an SCD25, to be essential for the activity of these proteins.

The crystal structure of the GEF region of human Sos1 complexes with Ras has been solved . The structure consists of two distinct α helical structural domains: the N-terminal domain which seems to have a purely structural role and the C-terminal domain which is sufficient for catalytic activity and contains all residues that interact with Ras. A main feature of the catalytic domain is the protrusion of a helical hairpin important for the nucleotide-exchange mechanism. The N-terminal domain is likely to be important for the stability and correct placement of the hairpin structure. The signature pattern for this entry spans the helical hairpin.
Heat shock protein Hsp90, conserved site (Heat_shock_protein_90_CS)
Type: Conserved_site

Prokaryotes and eukaryotes respond to heat shock and other forms of environmental stress by inducing synthesis of heat-shock proteins (hsp) . The 90kDa heat shock protein, Hsp90, is one of the most abundant proteins in eukaryotic cells, comprising 1-2% of cellular proteins under non-stress conditions . Its contribution to various cellular processes including signal transduction, protein folding, protein degradation and morphological evolution has been extensively studied . The full functional activity of Hsp90 is gained in concert with other co-chaperones, playing an important role in the folding of newly synthesised proteins and stabilisation and refolding of denatured proteins after stress. Apart from its co-chaperones, Hsp90 binds to an array of client proteins, where the co-chaperone requirement varies and depends on the actual client.

The sequences of hsp90s show a distinctive domain structure, with a highly-conserved N-terminal domain separated from a conserved, acidic C-terminal domain by a highly-acidic, flexible linker region.

The signature pattern for the hsp90 family of proteins is located in a highly conserved region found in the N-terminal part of these proteins.
Heat-stable enterotoxin, conserved site (Heat-stable_enterotox_CS)
Type: Conserved_site

This entry represents a group of heat-stable enterotoxins, such as STa from Escherichia coli, which are an important cause of acute diarrhoea in infants and travellers in developing countries. The mature STa protein is a 19-residue peptide containing three disulphide bridges that are functionally important. STa contains an N-terminal signal peptide composed of two domains, Pre and Pro, involved in extracellular toxin release, and a core enterotoxigenic domain . STa binds to and activates the guanylate cyclase C intestinal receptor, causing an increase in the intracellular levels of cyclic guanosine monophosphate (cGMP) .

The signature pattern used in this entry contains the 6 cysteines that are involved in disulphide bridges and the three conserved residues of the mature enterotoxin.
Hexokinase, binding site (Hexokinase_BS)
Type: Binding_site

Hexokinase (

) is an important glycolytic enzyme that catalyses the phosphorylation of keto- and aldohexoses (e.g. glucose, mannose and fructose) using MgATP as the phosphoryl donor.

In vertebrates there are four major isoenzymes, commonly referred as types I, II, III and IV. Type IV hexokinase, which is often incorrectly designated glucokinase , is only expressed in liver and pancreatic beta-cells and plays an important role in modulating insulin secretion; it is a protein of a molecular mass of about 50 Kd. Hexokinases of types I to III, which have low Km values for glucose, have a molecular mass of about 100 Kd. Structurally they consist of a very small N-terminal hydrophobic membrane-binding domain followed by two highly similar domains of 450 residues. The first domain has lost its catalytic activity and has evolved into a regulatory domain.

In yeast there are three different isoenzymes: hexokinase PI (gene HXK1), PII (gene HXKB), and glucokinase (gene GLK1). All three proteins have a molecular mass of about 50 Kd.

The hexokinase domain has an α/β fold and is distinctly folded in two subdomains of unequal size: the large and small subdomains. The large subdomain comprises a six-stranded mixed β-sheet and a number of additional α-helices. On one side, the sheet packs against the small subdomain, and on the other side it is shielded by several α-helices. The dominant feature of the small subdomain is a five stranded mixed β-sheet. The sheet is flanked by two helices on one side and by one helix on the other. The subdomain also has an additional β-sheet formed by two antiparallel strands .

All these enzymes contain one (or two in the case of types I to III isozymes) strongly conserved region which has been shown to be involved in substrate binding . This entry represents the conserved region involved in substrate binding.
Histidine triad, conserved site (Histidine_triad_CS)
Type: Conserved_site

The Histidine Triad (HIT) motif, His-x-His-x-His-x-x (x, a hydrophobic amino acid) was identified as being highly conserved in a variety of organisms . Crystal structure of rabbit Hint, purified as an adenosine and AMP-binding protein, showed that proteins in the HIT superfamily are conserved as nucleotide-binding proteins and that Hint homologues, which are found in all forms of life, are structurally related to Fhit homologues and GalT-related enzymes, which have more restricted phylogenetic profiles . Hint homologues including rabbit Hint and yeast Hnt1 hydrolyse adenosine 5' monophosphoramide substrates such as AMP-NH2 and AMP-lysine to AMP plus the amine product and function as positive regulators of Cdk7/Kin28 in vivo . Fhit homologues are diadenosine polyphosphate hydrolases and function as tumour suppressors in human and mouse though the tumour suppressing function of Fhit does not depend on ApppA hydrolysis . The third branch of the HIT superfamily, which includes GalT homologues, contains a related His-X-His-X-Gln motif and transfers nucleoside monophosphate moieties to phosphorylated second substrates rather than hydrolysing them .

The bovine protein kinase C inhibitor, PKCI-1, is an inhibitor protein that binds zinc without the use of zinc-finger motifs . Each protein molecule binds one zinc ion via a novel binding site containing 3 closely-spaced histidine residues . This region, referred to as the histidine triad (HIT) , has been identified in various prokaryotic and eukaryotic proteins of uncertain function .

The signature pattern used in this entry contains the region of the histidine triad and includes the three conserved histidine residues which are thought to bind the zinc ion.
Histone H4, conserved site (Histone_H4_CS)
Type: Conserved_site

Histone H4 is one of the four histones, along with H2A, H2B and H3, which form the eukaryotic nucleosome core. The sequence of histone H4 has remained almost invariant in more then 2 billion years of evolution . The signature pattern for this entry is a pentapeptide found in positions 14 to 18 of all H4 sequences. It contains a lysine residue which is often acetylated and a histidine residue which is implicated in DNA-binding .
Citrate synthase active site (Citrate_synthase_AS)
Type: Active_site

Citrate synthase

is a member of a small family of enzymes that can directly form a carbon-carbon bond without the presence of metal ion cofactors. It catalyses the first reaction in the Krebs' cycle, namely the conversion of oxaloacetate and acetyl-coenzyme A into citrate and coenzyme A. This reaction is important for energy generation and for carbon assimilation. The reaction proceeds via a non-covalently bound citryl-coenzyme A intermediate in a 2-step process (aldol-Claisen condensation followed by the hydrolysis of citryl-CoA).

This entry represents types I and II citrate synthase enzymes, as well as the related enzymes 2-methylcitrate synthase and ATP citrate synthase. 2-methylcitrate (

) synthase catalyses the conversion of oxaloacetate and propanoyl-CoA into (2R,3S)-2-hydroxybutane-1,2,3-tricarboxylate and coenzyme A. This enzyme is induced during bacterial and fungal growth on propionate , while type II hexameric citrate synthase is constitutive . ATP citrate synthase (

) (also known as ATP citrate lyase) catalyses the MgATP-dependent, CoA-dependent cleavage of citrate into oxaloacetate and acetyl-CoA, a key step in the reductive tricarboxylic acid pathway of CO2 assimilation used by a variety of autotrophic bacteria and archaea to fix carbon dioxide . ATP citrate synthase is composed of two distinct subunits. In eukaryotes, ATP citrate synthase is a homotetramer of a single large polypeptide, and is used to produce cytosolic acetyl-CoA from mitochondrial produced citrate . This entry includes citrate synthase from Thermosulfidibacter takaii, which catalyses both citrate generation and citrate cleavage as it is part of a reversible tricarboxylic acid (TCA) cycle that can fix carbon dioxide autotrophically and may represent an ancestral mode of the conventional reductive TCA (rTCA) cycle .

There are a number of regions of sequence similarity between prokaryotic and eukaryotic citrate synthases. One of the best conserved contains a histidine which is one of three residues shown to be involved in the catalytic mechanism of the vertebrate mitochondrial enzyme . This entry represents this region.
Homoserine dehydrogenase, conserved site (HDH_CS)
Type: Conserved_site

Bacteria, plants and fungi metabolise aspartic acid to produce four amino acids -lysine, threonine, methionine and isoleucine -in a series of reactions known as the aspartate pathway. Additionally, several important metabolic intermediates are produced by these reactions, such as diaminopimelic acid, an essential component of bacterial cell wall biosynthesis, and dipicolinic acid, which is involved in sporulation in Gram-positive bacteria. Members of the animal kingdom do not posses this pathway and must therefore acquire these essential amino acids through their diet. Research into improving the metabolic flux through this pathway has the potential to increase the yield of the essential amino acids in important crops, thus improving their nutritional value. Additionally, since the enzymes are not present in animals, inhibitors of them are promising targets for the development of novel antibiotics and herbicides. For more information see .

Homoserine dehydrogenase (

) catalyses the third step in the aspartate pathway; the NAD(P)-dependent reduction of aspartate beta-semialdehyde into homoserine . Homoserine is an intermediate in the biosynthesis of threonine, isoleucine, and methionine. The enzyme can be found in a monofunctional form, in some bacteria and yeast, or a bifunctional form consisting of an N-terminal aspartokinase domain and a C-terminal homoserine dehydrogenase domain, as found in bacteria such as Escherichia coli and in plants. Structural analysis of the yeast monofunctional enzyme (

) indicates that the enzyme is a dimer composed of three distinct regions; an N-terminal nucleotide-binding domain, a short central dimerisation region, and a C-terminal catalytic domain . The N-terminal domain forms a modified Rossman fold, while the catalytic domain forms a novel α-β mixed sheet.

The signature pattern of this entry is 23 to 24 residues in length, is located in the central region and contains two conserved aspartate residues.
Hydrogenase assembly chaperone, conserved site (Hydgase_assmbl_chp_CS)
Type: Conserved_site

The large subunit of [NiFe]-hydrogenase, as well as other nickel metalloenzymes, is synthesised as a precursor devoid of the metalloenzyme active site. This precursor then undergoes a complex post-translational maturation process that requires a number of accessory proteins. The hydrogenase expression/formation proteins (HupF/HypC) form a family of small proteins that are hydrogenase precursor-specific chaperones required for this maturation process . They are believed to keep the hydrogenase precursor in a conformation accessible for metal incorporation .

The signature pattern for this entry is 9 residues in length, located at the N terminus; all the proteins matched by this pattern start with a conserved Met-Cys dipeptide.
Translation initiation factor 3, conserved site (Translation_initiation_fac3_CS)
Type: Conserved_site

Initiation factor 3 (IF-3) (gene infC) is one of the three factors required for the initiation of protein biosynthesis in bacteria. IF-3 is thought to function as a fidelity factor during the assembly of the ternary initiation complex which consist of the 30S ribosomal subunit, the initiator tRNA and the messenger RNA. IF-3 is a basic protein that binds to the 30S ribosomal subunit . The chloroplast initiation factor IF-3(chl) is a protein that enhances the poly(A,U,G)-dependent binding of the initiator tRNA to chloroplast ribosomal 30s subunits in which the central section is evolutionary related to the sequence of bacterial IF-3 .
Translation initiation factor 3, N-terminal (Translation_initiation_fac_3_N)
Type: Domain

Initiation factor 3 (IF-3) (gene infC) is one of the three factors required for the initiation of protein biosynthesis in bacteria. IF-3 is thought to function as a fidelity factor during the assembly of the ternary initiation complex which consist of the 30S ribosomal subunit, the initiator tRNA and the messenger RNA. IF-3 is a basic protein that binds to the 30S ribosomal subunit . The chloroplast initiation factor IF-3(chl) is a protein that enhances the poly(A,U,G)-dependent binding of the initiator tRNA to chloroplast ribosomal 30s subunits in which the central section is evolutionary related to the sequence of bacterial IF-3 .
Translation initiation factor 3, C-terminal (Translation_initiation_fac_3_C)
Type: Domain

Initiation factor 3 (IF-3) (gene infC) is one of the three factors required for the initiation of protein biosynthesis in bacteria. IF-3 is thought to function as a fidelity factor during the assembly of the ternary initiation complex which consist of the 30S ribosomal subunit, the initiator tRNA and the messenger RNA. IF-3 is a basic protein that binds to the 30S ribosomal subunit . The chloroplast initiation factor IF-3(chl) is a protein that enhances the poly(A,U,G)-dependent binding of the initiator tRNA to chloroplast ribosomal 30s subunits in which the central section is evolutionary related to the sequence of bacterial IF-3 .