SII-SWORD/CoKE huggingface dataset:
Molybdenum cofactor biosynthesis, conserved site (MoCF_biosynth_CS)
Type: Conserved_site

Eukaryotic and prokaryotic molybdoenzymes require a molybdopterin cofactor (MoCF) for their activity. The biosynthesis of this cofactor involves a complex multistep enzymatic pathway. One of the eukaryotic proteins involved in this pathway is the Drosophila protein cinnamon which is highly similar to gephyrin, a rat microtubule-associated protein which was thought to anchor the glycine receptor to subsynaptic microtubules.

Cinnamon and gephyrin are evolutionary related, in their N-terminal half, to the Escherichia coli MoCF biosynthesis proteins mog/chlG and moaB/chlA2.
Orn/Lys/Arg decarboxylase, C-terminal (Prn/Lys/Arg_de-COase_C)
Type: Domain

Pyridoxal-dependent decarboxylases are bacterial proteins acting on ornithine, lysine, arginine and related substrates . One of the regions of sequence similarity contains a conserved lysine residue, which is the site of attachment of the pyridoxal-phosphate group. Ornithine decarboxylase is a dodecamer composed of six homodimers and catalyzes the decarboxylation of tryptophan. Arginine decarboxylase catalyzes the decarboxylation of arginine and lysine decarboxylase catalyzes the decarboxylation of lysine. Members of this family are widely found in all three forms of life .
Poly [ADP-ribose] polymerase (PARP)
Type: Family

Poly(ADP-ribose) synthase and poly(ADP-ribose) polymerase (PARP, also known as ADPRT) catalyse the DNA-dependent covalent attachment of ADP-ribose to various nuclear proteins . They are used by the eukaryotic cell to cope with numerous environmental and endogenous genotoxic agents that cause DNA strand breaks. PARP plays a role in many cellular processes, including DNA repair, recombination, cell proliferation and death, as well as genomic stability . The DNA-binding region of the protein contains a pair of zinc finger domains, which have been shown to bind DNA in a zinc-dependent manner . PARP also contains a BRCT domain involved in cell cycle checkpoint functions responsive to DNA damage , a catalyic domain and a regulatory domain.
Pentafunctional AroM protein (Pentafunct_AroM)
Type: Family

Each member of this group contains five functional domains catalysing five sequential steps of the shikimate pathway. Each domain corresponds to a monofunctional prokaryotic enzyme of the same pathway: 3-dehydroquinate synthase, 3-dehydroquinate dehydratase, shikimate 5-dehydrogenase, shikimate kinase, and 3-phosphoshikimate 1-carboxyvinyltransferase. The multifunctional gene is regulated in response to amino acid limitation by coordinate regulation, which provides an economical means of simultaneously synthesizing five shikimate pathway enzymes .
Phosphatidylinositol 3-kinase, Vps34 type (PI3K_Vps34)
Type: Family

Members of this family are Class III phosphatidylinositol 3-kinases (PI3Ks) (catalytic subunits). PI3K is a lipid kinase and a key signaling enzyme involved in cell survival and proliferation, cell motility and adhesion, cytoskeletal rearrangement and vesicle trafficking . The different PI3K isoforms have cell-specific functions. In yeast, VPS34 is a key enzyme required for cell division, vacuolar protein sorting, and vacuole segregation . The major components of the yeast VPS intracellular trafficking complex are conserved in humans .

There are three major classes of PI3Ks, I and III (Class I is also subdivided into Ia and Ib), and a more distantly related Class IV which contains Ser/Thr kinases. The different classes of PI3K catalyse phosphorylation of the 3'-OH position of phosphatidyl myo-inositol (PtdIns) lipids, generating different 3'-phosphorylated lipid products that act as secondary messengers. The classification of PI3Ks is based upon sequence analysis and domain architecture of the catalytic subunits, but the divisions also reflect the biochemical properties and the differential association with a variety of regulatory adaptor subunits. This division is mirrored not only in their specialised functions but also in the different modes of regulation of the different enzymes in the family . Furthermore, each of the PI3K classes differ in their preferred lipid substrate. Class III PI3Ks use only phosphatidylinositol as substrate, whereas Class Ia and Ib PI3K activity is focused upon phosphatidylinositol (4,5)-bisphosphate as substrate in vivo . These substrate-related differences are presumed to result from subtle variations in the structures of the active sites of the different PI3Ks.

Class III PI3Ks contain only the core catalytic subunit, which consists of the N-terminal C2 domain, the helical domain and the double-lobed catalytic domain. Class I and II contain an additional Ras-binding domain. The N-terminal C2 domain interacts mainly with the scaffolding helical domain of the enzyme . The function of the central helical domain is not clear, it has been suggested to be involved in substrate presentation . The C-terminal catalytic domain is shared by the PI3- and PI4-kinases. This domain is distantly related to the catalytic domain of protein kinases, with a global similarity of the core topological features but significant differences in the substrate-binding sites .

For additional information please see .
Glucoamylase, starch-binding (Glucoamylase_SBD)
Type: Family

Glucoamylase (GA), also known as glucan 1,4-alpha-glucosidase, which belongs to family 15 (

) in the classification of glycosyl hydrolases.

GA catalyses the release of D-glucose from the non-reducing ends of starch and other oligo- or poly-saccharides. Studies of fungal GA have indicated 3 closely-clustered acidic residues that play a role in the catalytic mechanism . This region is also conserved in a recently sequenced bacterial GA .

This entry represents a glucoamylase subfamily that contains a starch binding domain in their C-terminal section.
Haptoglobin (Haptoglobin)
Type: Family

Haptoglobin is a plasma protein that binds haemoglobin. The resulting complex is too large to be excreted by the kidney, thereby preventing loss of iron and damage to the kidney. The haptoglobin-haemoglobin complex is degraded in the liver, which is also the site of haptoglobin synthesis. The mature haptoglobin molecule is a tetramer, consisting of two alpha and two beta chains. Alpha and beta chains arise from proteolytic processing of the same precursor. Each beta chain can bind an α-β heterodimer of haemoglobin so that each haptoglobin tetramer binds one haemoglobin tetramer. In Pan troglodytes (Chimpanzee), haptoglobin genes form a small multigene family of three genes: HP, HPR (haptoglobin-related protein, which may be non-functional), and HPP (haptoglobin-primate) . In contrast, most humans have a two-gene cluster due to an unequal homologous crossover event between HPR and HPP in the human lineage . Such events may be common among these closely related genes as Macaca mulatta (Rhesus macaque) was found to have haplotypes of one- or two-gene clusters that appear to have formed from unequal crossover among an ancestral three-gene cluster . The haptoglobin precursor contains a signal sequence, a sushi domain (in mature alpha chain), and a trypsin domain (in mature beta chain) which belongs to the MEROPS peptidase family S1 (clan PA(S)). Haptoglobins have no enzymatic activity as the active site residues typical of trypsin-related proteases are not conserved, they are therefore classed as non-peptidase homologues. A common allelic variant in humans contains two sushi domains.

Uncleaved haptoglobin is also known as zonulin, and plays a role in intestinal permeability .
Meprin alpha/beta subunit (Meprin)
Type: Family

Meprins are metazoan zinc metallopeptidases belonging to MEROPS peptidase family M12 (clan MA(M)), subfamily M12A (astacin family). They are complex and structurally unique homo- or heterotetrameric glycoproteins composed of evolutionarily related alpha and/or beta subunits that contain disulphide-bridged dimers. The two subunits are differentially expressed and processed to yield latent and active proteases as well as membrane-associated and secreted forms. They are excellent models of homo- and hetero-oligomeric enzymes that are regulated at the transcriptional and post translational levels . Each chain contains an astacin domain, MAM, MATH, and AM (after MATH) domains , and an EGF-like domain.

The astacin domain is a Zn-metalloprotease domain characterised by a unique 18-amino acid signature sequence, HEXXHXXGFXHEXXRXDR , which begins with the zinc binding motif HEXXH. The MAM domain is necessary for correct folding and transport through the secretory pathway. The MATH domain is required for folding of an activatable zymogen, and the AM domain is important for activity against proteins and efficient secretion of the protein.
Tissue factor pathway inhibitor-like (TFPI-like)
Type: Family

Tissue factor pathway inhibitor (TFPI or TFPI1), also called lipoprotein-associated coagulation inhibitor (LACI) or extrinsic pathway inhibitor, is an anti-coagulation plasma protein that acts as a Kunitz-type serine protease inhibitor. Though TFPI lacks a membrane attachment signal, it remains associated with the endothelial surface through its association with a GPI-anchored co-receptor, which acts as a molecular chaperone to move TFPI to the cell surface . TFPI is a dual inhibitor, binding directly to factor Xa (FXa), and to tissue factor/factor VIIa (TF/FVIIa) in a FXa-dependent way, presumably by forming a quaternary FXa/TFPI/FVIIa/TF complex, thereby blocking the continuation of the coagulation pathway. TFPI is thought to be important in modulating tissue factor-induced thrombogenesis .

The homologous tissue factor pathway inhibitor 2 (TFPI-2) has a similar structure and is thought to play a role in the regulation of extracellular matrix digestion and remodelling . This entry also includes SmCI from Sabellastarte magnifica. SmCI is a bifunctional inhibitor of metallo carboxypeptidase and serine proteinase .
Notch (Notch)
Type: Family

Notch cell surface receptors are large, single-pass type-1 transmembrane proteins found in a diverse range of metazoan species, from human to Caenorhabditis species. The fruit fly, Drosophila melanogaster, possesses only one Notch protein, whereas in C.elegans, two receptors have been found; by contrast, four Notch paralogues (designated N1-4) have been identified in mammals, playing both unique and redundant roles.

The hetero-oligomer Notch comprises a large extracellular domain (ECD), containing 10-36 tandem Epidermal Growth Factor (EFG)-like repeats, which are involved in ligand interactions; a negative regulatory region, including three cysteine-rich Lin12-Notch Repeats (LNR); a single trans-membrane domain (TM); a small intracellular domain (ICD), which includes a RAM (RBPjk-association module) domain; six ankyrin repeats (ANK), which are involved in protein-protein interactions; and a PEST domain. Drosophila Notch also contains an OPA domain .

Notch signalling is an evolutionarily conserved pathway involved in a wide variety of developmental processes, including adult homeostasis and stem cell maintenance, cell proliferation and apoptosis . Notch is activated by a range of ligands -the so-called DSL ligands (Delta/Seratte/LAG-2). Activation is also mediated by a sequence of proteolytic events: ligand binding leads to cleavage of Notch by ADAM proteases at site 2 (S2) and presenilin-1/g-secretase at sites 3 (S3)and 4 (S4) .The last cleavage releases the Notch intracellular part of the protein (NICD) from the membrane and, upon release, the NICD translocates to the nucleus where it associates with a CBF1/RBJk/Su(H)/Lag1 (CSL) family of DNA-binding proteins. The subsequent recruitment of a co-activator mastermind like (MAML1) protein promotes transcriptional activation of Notch target genes: well established Notch targets are the Hes and Hey gene families.
Prephenate dehydrogenase/arogenate dehydrogenase (Prep_DH/arog_DH)
Type: Family

Members of this group catalyse a step in tyrosine biosynthesis in the shikimate pathway, which is present only in bacteria, fungi, and plants. They contain both a prephenate dehydrogenase domain (PDH) and a regulatory domain.
Phosphate propanoyltransferase (PTAC)
Type: Family

This family includes phosphotransacylases (PTACs) required for the degradation of 1,2-propanediol (1,2-PD) .
Peptidoglycan beta-N-acetylmuramidase NamZ (NamZ)
Type: Family

NamZ is an exo-beta-N-acetylmuramidase which catalyses an exo-lytic cleavage of beta-1,4-acetylmuramic acid from from the non-reducing ends of peptidoglycan chains and it is a founding member of a new family of glycosidases (

). NamZ consists of a N-terminal catalytic domain with a Rossmann-like fold (

) and a C-terminal auxiliary α/β domain (

) . It is predominantly found in bacteroidetes but also in firmicutes, proteobacteria and actinobacteria.
Methanogenesis marker protein 14 (Methan_mark_14)
Type: Family

Members of this protein family, to date, are found in a completed prokaryotic genome if and only if the species is one of the archaeal methanogens. The exact function is unknown, but likely is linked to methanogenesis or a process closely connected to it .
Uncharacterised conserved protein UCP017998 (UCP017998)
Type: Family

This family consists of several hypothetical archaeal and bacterial proteins of unknown function, including

from Aquifex aeolicus. The structure of this protein has been solved but its function remains unknown. Members of this family seem to have an acyl-CoA N-acyltransferase topology.
Uncharacterised conserved protein UCP018008 (UCP018008)
Type: Family

There are currently no experimental data for members of this group or their homologues, nor do they exhibit features indicative of any function.
Uncharacterised conserved protein UCP018957 (UCP018957)
Type: Family

There are currently no experimental data for members of this group or their homologues, nor do they exhibit features indicative of any function.
YpbB protein (YpbB-like)
Type: Family

This entry represents the YpbB proteins from Bacillus subtilis and related proteins found mainly in Bacillales. YpbB assemble with RecS into a single complex able to interact with a protein of the replisome, the Single-Stranded DNA Binding protein (SSB), resulting in its targeting to active chromosome replication forks .
Probable chaperone-like protein YdbL (YdbL)
Type: Family

This entry represents YdbL (previously uncharacterised) and related bacterial proteins. This protein contains a small β-sheet connected to small α-helices.

YdbL probably acts as a chaperone-like protein that contributes to, but is not essential for, the formation of the YdbH-YnbE intermembrane bridge. It affects both the function and structure of the YdbH-YnbE complex, suggesting a regulatory or stabilising role. Notably, overexpression of YdbL has a negative effect on YdbH-YnbE function, indicating that its levels must be tightly controlled to maintain proper complex activity .
UPF0735 ACT domain-containing protein (UPF0735_ACT_dom-cont)
Type: Family

Members of this family contain a regulatory ACT domain with an additional N-terminal extension of ~70 aa, and therefore may be a stand-alone regulatory protein.
Uncharacterised conserved protein UCP028101 (UCP028101)
Type: Family

There are currently no experimental data for members of this group or their homologues, nor do they exhibit features indicative of any function.
Type VI secretion system sheath protein TssB1 (T6SS_TssB1)
Type: Family

This entry includes TssB1, which is a sheath protein of the bacterial type VI secretion system (T6SS) .

The type VI secretion system (T6SS), also known as CIS contractile injection system , is a supra-molecular bacterial complex that resembles phage tails. It is a toxin delivery systems which fires toxins into target cells upon contraction of its TssBC sheath . Thirteen essential core proteins are conserved in all T6SSs: the membrane associated complex TssJ-TssL-TssM, the baseplate proteins TssE, TssF, TssG, and TssK, the bacteriophage-related puncturing complex composed of the tube (Hcp), the tip/puncturing device VgrG, and the contractile sheath structure (TssB and TssC). Finally, the starfish-shaped dodecameric protein, TssA, limits contractile sheath polymerization at its distal part when TagA captures TssA .
Metal-independent alpha-mannosidase (GH125)
Type: Family

This family includes proteins from bacteria and fungi. It was originally identified as a protein of unknown function from Schizosaccharomyces pombe, which was isolated from a screen to identify novel genes required for meiosis . Members of this family have since been characterised from Streptococcus pneumoniae (

) and Clostridium perfringens (

), and represent a new glycoside hydrolase family, also known as GH125. This family is the first characterised metal-independent alpha-mannosidase family . Proteins in this family have been reported to be strict exo-alpha-1,6-mannosidases that operate via a metal-independent inverting catalytic mechanism .
N(4)-acetylcytidine amidohydrolase (AC4CH)
Type: Family

N(4)-acetylcytidine amidohydrolase catalyses the hydrolysis of N4-acetylcytidine (ac4C). It contains the human activating signal cointegrator homology (ASCH) domain with unknown function, although this domain has been suggested to be responsible for RNA binding during transcription activation, RNA processing and regulation of translation . This entry includes Escherichia coli protein YqfB, which is an amidohydrolase responsible for the catabolism of N4-acetylcytidine (ac4C) as well as other structurally different N4-acylated cytosines/cytidines. YqfB contains a unique Thr-Lys-Glu catalytic triad, and Arg acting as an oxyanion hole .
Uncharacterised conserved protein UCP029876 (UCP029876)
Type: Family

There are currently no experimental data for members of this group or their homologues, nor do they exhibit features indicative of any function.
Uncharacterised conserved protein UCP030561 (UCP030561)
Type: Family

There are currently no experimental data for members of this group or their homologues, nor do they exhibit features indicative of any function. Though the N-terminal half of these proteins is related to the N-terminal half of steroid delta-isomerase, the C-terminal half is predicted to be structurally unrelated. Both halves of the latter protein contain key active site residues (Tyr14, Asp99) that are missing from the proteins in this group.
Uncharacterised conserved protein UCP030820 (UCP030820)
Type: Family

There are currently no experimental data for members of this group or their homologues, nor do they exhibit features indicative of any function.
GyrI-like cyclopropanoid cyclopropyl hydrolase Lin2189-like (GyrI-like_CCH_Lin2189-like)
Type: Family

This family of prokaryotic GyrI-like proteins include Lin2189 protein from Listeria innocua (

), a cyclopropanoid cyclopropyl hydrolase (CCHs) that can catalyse the hydrolysis of the potent DNA-alkylating agents yatakemycin (YTM) and CC-1065, protecting the cells. This protein shows three α-helices and six β-strands and contains a GyrI-like small molecule binding domain (

) .
Uncharacterised conserved protein UCP032025 (UCP032025)
Type: Family

This family consists of several hypothetical bacterial proteins of around 150 residues in length. Members of this family seem to be founds exclusively in the Class Alphaproteobacteria. The function of this family is unknown.
Uncharacterised conserved protein UCP032146 (UCP032146)
Type: Family

This protein family is functionally uncharacterised.
Uncharacterised protein family UPF0261 (UPF0261)
Type: Family

The proteins in this entry are functionally uncharacterised.
Uncharacterised conserved protein UCP033563 (UCP033563)
Type: Family

There are currently no experimental data for members of this group or their homologues, nor do they exhibit features indicative of any function.
EipA-like (EipA-like)
Type: Family

The member of this family for Brucella abortus, named EipA, has been characterised as a molecular determinant of virulence that functions to maintain cell envelope integrity .
Pyruvate dehydrogenase inhibitor-like (PdhI-like)
Type: Family

This entry represents Pyruvate dehydrogenase inhibitor from Bacillus subtilis (PdhI) and similar sequences from firmicutes. PdhI functions as an inhibitor of the pyruvate dehydrogenase .
Peptidase M17, peptidase B (Pept_M17_PepB)
Type: Family

This family represents the peptidase B group of leucyl aminopeptidases, which are restricted to the gammaproteobacteria. They contain a C-terminal aminopeptidase catalytic domain and an N-terminal domain of unknown function. They are zinc-dependent exopeptidases (

) and belong to MEROPS peptidase family M17 (leucyl aminopeptidase family, clan MF).

They selectively release N-terminal amino acid residues from polypeptides and proteins and are involved in the processing, catabolism and degradation of intracellular proteins . Leucyl aminopeptidase forms a homohexamer containing two trimers stacked on top of one another . Each monomer binds two zinc ions. The zinc-binding and catalytic sites are located within the C-terminal catalytic domain .

The same catalytic aminopeptidase domain is found in the other M17 peptidases

. These two groups of aminopeptidases differ by their N-terminal domains. The N-terminal domain in members of

has been implicated in DNA binding and it is not associated with members of this family which have a different N-terminal domain and therefore are not expected to bind DNA or be involved in transcriptional regulation. In addition, there are related proteins with the same catalytic domain and unique N-terminal sequences unrelated to any of the two N-terminal domains discussed above.

For additional information please see .

Over 70 metallopeptidase families have been identified to date. In these enzymes a divalent cation, which is usually zinc but may be cobalt, manganese or copper, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. In some families of co-catalytic metallopeptidases, two metal ions are observed in crystal structures ligated by five amino acids, with one amino acid ligating both metal ions. The known metal ligands are His, Glu, Asp or Lys. At least one other residue is required for catalysis, which may play an electrophilic role.

Many metalloproteases contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site . The HEXXH motif is relatively common but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin, 'b' is an uncharged residue, and 'c' a hydrophobic residue. Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases .
Ferritin/DPS domain (Ferritin_DPS_dom)
Type: Domain

This entry represents the main structural domain of ferritin. The domain is also found in other ferritin-like proteins such as members of the DNA protection during starvation (DPS) family and bacterioferritins .

Ferritin is one of the major non-haem iron storage proteins in animals, plants, and microorganisms . It consists of a mineral core of hydrated ferric oxide, and a multi-subunit protein shell that encloses the former and assures its solubility in an aqueous environment.

In animals, the protein is mainly cytoplasmic and there are generally two or more genes that encode closely related subunits - in mammals there are two subunits which are known as H(eavy) and L(ight). In plants ferritin is found in the chloroplast .