SII-SWORD/CoKE huggingface dataset:
Restriction endonuclease, type II, BamHI/BglIII/BstY (BamHI/BglII/BstY)
Type: Homologous_superfamily

Restriction endonucleases BamHI, BglII, BstYI and OkrAI share a strong structural consensus mapping to the α/β core domain, represented by this superfamily. BamHI recognises the DNA sequence GGATCC and cleaves after G-1 , BglII recognises AGATCT and cleaves after A-1 , BstYI recognises RGATCY and cleaves after the purine R and OkrAI recognises the double-stranded sequence 5'-GGATCC-3' and cleaves after G-1 .
Cysteine desulfurase-related (Cys_dSase-rel)
Type: Family

This entry describes probable pyridoxal phosphate-dependent enzymes in the aminotransferase class V family. The most closely related characterised proteins are active as cysteine desulfurases, selenocysteine lyases, or both; some are involved in FeS cofactor biosynthesis and are designated NifS. An active site Cys residue present in those sequences, in motifs resembling GHHC or GSAC, is not found in this family. The function of
members of this family is unknown.
Shikimate dehydrogenase (Shikimate_DH)
Type: Family

The shikimate pathway links the metabolism of carbohydrates to the biosynthesis of aromatic compounds and is essential for the biosynthesis of aromatic amino acids and other aromatic compounds in bacteria, eukaryotic microorganisms and plants . It is a seven-step pathway which converts phosphoenolpyruvate and erythrose 4-phosphate to chorismate, the common precursor for the synthesis of folic acid, ubiquinone, vitamins E and K, and aromatic amino acids. Since this pathway is absent in metazoans, which must therefore obtain the essential amino acids phenylalanine and tryptophan from their diet, the enzymes in this pathway are important targets for the development of novel herbicides and antimicrobial compounds.

This entry represents shikimate 5-dehydrogenases from prokaryotes and functionally equivalent C-terminal domains from larger, multifunctional proteins, the majority of which have an N-terminal quinate dehydrogenase domain. These multifunctional proteins occur in plants, chlamydiae, planctomycetes and a limited number of marine proteobacteria. Shikimate 5-dehydrogenase catalyses the fourth step of the shikimate pathway, which is the NADP-dependent reduction of 3-dehydroshikimate to shikimate .

Structural studies suggests that some shikimate dehydrogenases are monmers while others form homodimers . Each shikimate dehydrogenase monomer forms a compact two-domain α/β sandwich with a deep interdomain cleft. The N-terminal substrate-binding domain forms a three layer α-β-α sandwich, while the C-terminal NADP-binding domain forms a nearly typical Rossman fold. The active site is thought to be located within the interdomain cleft, with substrate binding causing a conformational change which closes the active site cleft, forming a productive active site.
Deoxyribose-phosphate aldolase (DeoC)
Type: Family

Aldolases play important roles in essential metabolic pathways, such as gluconeogenesis and glycolysis. They are classified with respect to their catalytic mechanism into two classes: class I adolases are are characterised by formation of covalent Schiff base intermediates, while class II aldolases are metallodependent enzymes and use a divalent transition metal ion to polarize the substrate ketose .

Deoxyribose-phosphate aldolase (DERA) belongs to the class I aldolases. It is a widely distributed enzyme, which catalyses the following reversible reaction:

2-deoxy-D-ribose 5-phosphate = D-glyceraldehyde 3-phosphate + acetaldehyde

While the physiological role of this enzyme remains unknown in eukaryotes, in prokaryotes it is thought to function in the catabolism of deoxyribonucleotides .

In all studied structures, the deoxyribose-phosphate aldolase subunits adopt the classical eight-bladed TIM barrel fold . The oligomerization state of the enzyme appears to depend on the living temperature of the organism - the Escherichia coli enzyme (

) is a homodimer, while the enzymes from the thermophilic microorganisms Thermus thermophilus and Aeropyrum pernix (

) are homotetramers. The degree of oligomerization does not, however, appear to affect catalysis.

Deoxyribose-phosphate aldolase is unique in catalysing the aldol reaction between two aldehydes, and its broad substrate specificity confers considerable utility as a biocatalyst, offering an environmentally benign alternative to chiral transition metal catalysis of the asymmetric aldol reaction .

This entry also includes divergent deoxyribose-phosphate aldolase-like protein (DPA) from Toxoplasma gondii which is involved in regulation of actin dynamics. This protein has likely diverged to the point of losing deoxyribose-phosphate aldolase enzymatic activity , given the fact that the residues implicated in substrate binding and the key catalytic residue are not conserved compared to catalytically active deoxyribose-phosphate aldolases .
Single-stranded DNA-binding protein (ssDNA-bd)
Type: Family

Single-stranded DNA-binding protein (SSB) plays an important role in DNA replication, recombination and repair. It binds to ssDNA and to an array of partner proteins to recruit them to their sites of action during DNA metabolism .
High-molecular-weight cytochrome c (Cyt_cc3)
Type: Family

Cytochromes c (cytC) can be defined as electron-transfer proteins having one or several haem c groups, bound to the protein by one or, more generally, two thioether bonds involving sulphydryl groups of cysteine residues. The fifth haem iron ligand is always provided by a histidine residue. CytC possess a wide range of properties and function in a large number of different redox processes.

This family, found in sulphate-reducers, represents a cytochrome containing sixteen haem groups which forms part of a transmembrane protein complex that allows electron flow from the periplasmic hydrogenase to the cytoplasmic enzymes that catalyse reduction of sulphates . HmcA (

) from Desulfovibrio vulgaris strain Hildenborough is composed of three distinct regions; an N-terminal three-haem domain homologous to cytochrome c7, a four-haem cyctochrome c3-like domain, and a C-terminal nine-haem cytochrome Hcc-like domain . This last domain is composed of two cytochrome c3-like domains with an isolated haem group inserted between them. HcmA interacts specifically with cytochrome c3 , where the last haem group of HcmA and haem four of cytochrome c3 interact to provide the likely site of electron transfer between molecules .
17beta-dehydrogenase (17beta_DH)
Type: Family

This entry represents 17beta-hydroxysteroid dehydrogenases (17B-HSDs), a group of enzymes which catalyse the last step in the biosynthesis of all androgens and estrogens -the reversible NAD(P)-linked transfer of a hydride to and from the 17-position of steroid molecules . A total of six isozymes have been identified which vary in substrate specificity, tissue specificity and preferred direction of the reaction.

The most intensively studied enzyme in this entry is human estrogenic 17beta-hydroxysteroid dehydrogenase (

) which is responsible for the last step in the synthesis of all estrogens. As active estrogens stimulate the proliferation of breast cancer cells, this enzyme is a potential target for drugs to treat breast cancer . It is a membrane-associated homodimer which posseses the Tyr-X-X-X-Lys motif typical of short-chain dehydrogenases and forms a typical Rossman fold .

This family also includes Retinol dehydrogenase 8 which is closely related to 17-beta-hydroxysteroid dehydrogenase 1 .
Peptidase M17, leucine aminopeptidase/peptidase B (Leucine_aapep/pepB)
Type: Family

The majority of members of this family are zinc-dependent exopeptidases belonging to MEROPS peptidase family M17 (leucyl aminopeptidase, clan MF).

Leucyl aminopeptidase (LAP;

) selectively release N-terminal amino acid residues from polypeptides and proteins; in general they 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 . Leucine aminopeptidase has been shown to be identical with prolyl aminopeptidase (

) in mammals .
Complement B/C2 (Compl_C2_B)
Type: Family

These proteins belong to MEROPS peptidase family S1 (chymotrypsin family, clan PA(S)), subfamily S1A.

This family contains two mammalian proteins, complement C2 and complement factor B, which, respectively, have analogous roles in the classical and alternative pathways of complement activation. These proteins are composed of three regions, an N-terminal three-module complement control protein domain, a von Willebrand factor A domain, and a C-terminal serine protease domain. Briefly, they are activated by cleavage and function as the serine protease components of the C3/C5 convertases, which play similar roles in these pathways although composed of different proteins. Homologs in non-mammalian species are often more or less equally related to mammalian C2 and B and may be designated as complement B/C2. Strongylocentrotus purpuratus (Purple sea urchin) has an atypical factor B with a five-module complement control protein domain.

The structures of the von Willebrand factor A and serine protease domains from human complement factor B (

) have been analysed . The A domain forms the classical vWF A domain fold, which consists of a central β-sheet flanked on both sides by amphipathic α helices. It contains an integrin-like MIDAS (metal ion-dependent adhesion site) motif that adopts the open conformation typical of integrin-ligand complexes, with an acidic residue from another A domain (provided by a fortuitous crystal contact) completing the coordination of the metal ion. Although a closed conformation was not observed, modelling studies suggest that the A domain could adopt this conformation, implying that as with integrins, ligand-binding may induce conformational changes which transduce a signal to other domains in the protein . The serine protease domain forms a chymotrypsin fold with several novel features . Like other serine proteases it forms two β-sheets, composed of six β-strands each, surrounded by surface helices and loops. However, several novel deletions and insertions occur within these surface helices and loops, and differences in active site conformation also exist.
Dorsal-related immunity factor Dif (Dif)
Type: Family

The Dorsal morphogen directs formation of the Drosophila dorsoventral axis by both activating and repressing transcription. It contains an N-terminal Rel homology domain (RHD), which is responsible for DNA binding and regulated nuclear import, and a C-terminal domain (CTD) that contains activation and repression motifs . In wild-type embryos, the dorsal protein is found in the cytoplasm during cleavage. After the nuclei migrate to the periphery of the embryo, a ventral-to-dorsal gradient of nuclear dorsal protein is established .

Dorsal-related immunity factor Dif does not appear to participate in dorsoventral patterning, but instead mediates an immune response in Drosophila larvae. Dif is normally localised in the cytoplasm of the larval fat body, but quickly accumulates in the nucleus upon bacterial infection or injury. Once in the nucleus, Dif binds to kappa B-like sequence motifs present in promoter regions of immunity genes .
Breast cancer type 1 susceptibility protein (BRCA1) (BRCA1)
Type: Family

Breast cancer is a common malignancy, affecting 1 in 8 women. A major contributary factor in disease development lies in a positive family history, a correlation that is striking for early-onset breast cancer. Mutations in the DNA-damage repair protein BRCA1 are believed to be responsible for 45% of inherited breast cancer and more than 80% of inherited breast and ovarian cancer.

The BRCA1 protein is a E3 ubiquitin-protein ligase that specifically mediates the formation of 'Lys-6'-linked polyubiquitin chains and plays a central role in DNA repair by facilitating cellular responses to DNA damage . It contains an N-terminal zinc-finger domain. It also contains a BRCT C-terminal domain, an approximately 100 amino acid tandem repeat, which appears to act as a phospho-protein binding domain .
Cytokine IL-3/IL-5/GM-CSF receptor common beta chain (IL3_rcpt_beta)
Type: Family

This group represents a cytokine IL-3/IL-5/GM-CSF receptor common beta chain. Please see the following relevant reference: .
MfnE family (MfnE)
Type: Family

This family includes the MJ0458 protein from Methanocaldococcus jannaschii (Methanococcus jannaschii), which was predicted to be related to aspartokinase and uridylate kinase . MJ0458 has been characterised and renamed as MfnE. It functions as a 5-(aminomethyl)-3-furanmethanol phosphate kinase in the methanofuran biosynthetic pathway .
NTP Pyrophosphohydrolase MazG-related, GP37 (MazG-related_GP37)
Type: Family

Members of this group are distantly related to MazG-type NTP pyrophosphohydrolase. Conserved residues of the MazG domain (at least three of the Glu residues, Asp, Lys and Arg), which include those shown to be functionally important , are also conserved here. MazG protein of Thermotoga maritima has been shown to have both nucleoside triphosphate pyrophosphohydrolase and pyrophosphatase activities, while Escherichia coli MazG has only NTP pyrophosphohydrolase activity . Therefore, members of this group are predicted to be pyrophosphohydrolases.
Histone-lysine N-methyltransferase SUV39H1/2-like (H3-K9_MeTrfase_SUV39H1/2-like)
Type: Family

Members of this family trimethylate 'Lys-9' of histone H3 using monomethylated H3 'Lys-9' as substrate, including histone-lysine N-methyltransferase Su(var)3-9 from Drosophila melanogaster and its orthologue from human, SUV39H1. SUV39H1 also weakly methylates histone H1 (in vitro). H3 'Lys-9' trimethylation represents a specific tag for epigenetic transcriptional repression by recruiting HP1 (CBX1, CBX3 and/or CBX5) proteins to methylated histones. This enzyme mainly functions in heterochromatin regions, thereby playing a central role in the establishment of constitutive heterochromatin at pericentric and telomere regions. H3 'Lys-9' trimethylation is also required to direct DNA methylation at pericentric repeats .

SUV39H1 is targeted to histone H3 via its interaction with RB1 and is involved in many processes, such as repression of MYOD1-stimulated differentiation, regulation of the control switch for exiting the cell cycle and entering differentiation, repression by the PML-RARA fusion protein , BMP-induced repression, repression of switch recombination to IgA and regulation of telomere length . SUV39H1 is a component of the eNoSC (energy-dependent nucleolar silencing) complex, a complex that mediates silencing of rDNA in response to intracellular energy status and acts by recruiting histone-modifying enzymes. The eNoSC complex is able to sense the energy status of cell: upon glucose starvation, elevation of NAD+/NADP+ ratio activates SIRT1, leading to histone H3 deacetylation followed by dimethylation of H3 at 'Lys-9' (H3K9me2) by SUV39H1 and the formation of silent chromatin in the rDNA locus .

Methyltransferases (EC [ec:2.1.1.-]) constitute an important class of enzymes present in every life form. They transfer a methyl group most frequently from S-adenosyl L-methionine (SAM or AdoMet) to a nucleophilic acceptor such as oxygen leading to S-adenosyl-L-homocysteine (AdoHcy) and a methylated molecule . All these enzymes have in common a conserved region of about 130 amino acid residues that allow them to bind SAM . The substrates that are methylated by these enzymes cover virtually every kind of biomolecules ranging from small molecules, to lipids, proteins and nucleic acids . Methyltransferase are therefore involved in many essential cellular processes including biosynthesis, signal transduction, protein repair, chromatin regulation and gene silencing . More than 230 families of methyltransferases have been described so far, of which more than 220 use SAM as the methyl donor.
N-lysine methyltransferase SETD6 (N-lys_methylase_SETD6)
Type: Family

SET domain methyltransferases can be involved both in translational and transcriptional roles. N-lysine methyltransferase SETD6 is a SET domain protein that specifically monomethylates 'Lys-310' of the RELA subunit of NF-kappa-B complex, leading to down-regulation of NF-kappa-B transcription factor activity . Homologues in yeast monomethylate 60S ribosomal protein L42 (RPL42A and RPL42B) at 'Lys-55' .
Putative site-specific recombinase Gcr (Site-sp_rcmbase)
Type: Family

This group represents a putative site-specific recombinase Gcr .
Putative ATP-NAD kinase (Put_ATP-NAD_kin)
Type: Family

Members of this group are predicted to be kinases (possibly ATP-NAD kinases,

) on the basis of distant sequence similarity.
Translation initiation factor 2A (TIF2A)
Type: Family

Eukaryotic initiation factor 2A (eIF2A) directly binds the initiator methionyl-tRNA (Met-tRNA(i)) to 40 S ribosomal subunits in a codon-dependent manner . It may act by impiging the expression of specific proteins .
Sphingolipid delta4-desaturase (DES1/DES2)
Type: Family

This group represents sphingolipid delta-4 desaturase (DEGS), an integral membrane protein required for sphingosine biosynthesis. It converts D-erythro-sphinganine to D-erythro-sphingosine (E-sphing-4-enine) . Delta4-desaturated sphingolipids provide an early signal that triggers the entry into both meiotic and spermatid differentiation pathways during Drosophila spermatogenesis .
Acetoin catabolism kinase AcoX (AcoX_kinase)
Type: Family

Members of this group are involved in acetoin catabolism and are encoded in the
aco
operon. They are predicted to be kinases (possibly ATP-NAD kinases,

) on the basis of distant sequence similarity.
Tellurite resistance, TerY (Tellurite-R_TerY)
Type: Family

This group represents a phage/colicin/tellurite resistance cluster protein, TerY type.
Alpha glucuronidase (Glyco_hydro_67_aGlcAse)
Type: Family

Alpha-glucuronidases belong to an ensemble of enzymes, which are central to the recycling of photosynthetic biomass. To date, all of the alpha-glucuronidases are classified as family 67 glycosidases, which catalyze the hydrolysis via the investing mechanism . They hydrolyze the alpha1,2-glycosidic bond between 4-O-methyl-d-glucuronic acid (4-O-MeGlcA) and the xylan or xylooligosaccharide backbone . They have three domains, the central of which is a (β/α)(8) barrel, which houses the catalytic apparatus . The carboxylate and methyl groups of aldobiouronic acid can act as substrate recognition determinants .
Phosphorothioated DNA-binding restriction endonuclease (PT_DNA_restrict)
Type: Family

This entry represents a group of proteins from bacteria that are distantly related to the C-terminal half of the type IV restriction endonuclease McrA from Streptomyces coelicolor (

), which can act on phosphorothioated DNA (PT-DNA), as do members of this family. This family was previously known as UCP030850.
Intramembrane metalloprotease YhfC (YhfC)
Type: Family

This family includes proteins that are mainly from Firmicutes and Proteobacteria. Family members bear the consensus signature of -EExxR- the second motif -HxxxE- and the third motif -H/Qxxxs-. The fourth motif, -HxxxB-, is shared by the PrsW proteases (

) and the CPBP (

), and APH-1 families. There are currently no experimental functional data for members of this group, however, they are predicted to be integral membrane proteins with several transmembrane segments and hypothesized metalloprotease function. YhfC intramembrane metalloprotease, CPBP family (type II CAAX Proteases and Bacteriocin Processing enzymes), PrsW proteases and APH-1 are distantly related. They share four predicted core transmembrane segments and possess similar, yet distinct sets of sequence motifs .
Nitrous oxide reductase expression regulator NosR (NosR)
Type: Family

The bacterial protein NosR is involved in N
2
O respiration. It is a membrane bound iron-sulphur flavoprotein that is required for the transcription of nosZ genes and also for cellular activity of its homologue, NosZ .
Eukaryotic translation initiation factor 3 subunit B (EIF3B)
Type: Family

Eukaryotic translation initiation factor 3 subunit B (EIF3B) is a component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is required for several steps in the initiation of protein synthesis. EIF3B is considered to be the major scaffolding subunit and interacts with subunits A, G, I, and J . It contains an RNA recognition motif (RRM) in its N-terminal region .
Phosphoesterase, YvnB (Pesterase_YvnB)
Type: Family

This is a small family of large proteins (~1300-1500 residues) containing one copy of the metallophosphoesterase domain. With the exception of glutamine replacing one metal-binding histidine, they possess the motifs characteristic of a variety of enzymatically active phosphoesterases , including acid and alkaline phosphatases, phosphoprotein phosphatases, 5'-nucleotidase, bis(5'-nucleosyl)-tetraphosphatase (symmetrical), sphingomyelin phosphodiesterase, 2',3'-cylic-nucleotide 2'-phosphodiesterase, and the 3',5'-nucleotide phosphodiesterase CpdA.

Although the sequences within this family are well-conserved throughout most of their lengths, with the exception of the portion of the protein containing the metallophosphoesterase domain (about one-sixth of the whole), they have little similarity to any other type of characterised protein.
Phospholipase D, plant (PLipase_D_pln)
Type: Family

This entry represents the plant phospholipase D (PLD), a calcium-dependent enzyme that hydrolyses glycerol-phospholipids at the terminal phosphodiesteric bond. Arabidopsis PLD has been implicated in plant response to macronutrient availability . PLD alpha 1 from Setaria italica (foxtail millet) has been linked to drought tolerance .
Pyrophosphate-dependent phosphofructokinase TM0289 type (PPi-PFK_TM0289)
Type: Family

This entry represents the pyrophosphate-dependent phosphofructokinase, TM0289 type. It catalyses the phosphorylation of D-fructose 6-phosphate, the first committing step of glycolysis. It uses inorganic phosphate (PPi) as phosphoryl donor instead of ATP like common ATP-dependent phosphofructokinases (ATP-PFKs), which renders the reaction reversible, and can thus function both in glycolysis and gluconeogenesis .
Pyrophosphate--fructose 6-phosphate 1-phosphotransferase (PPi-PFK)
Type: Family

This entry represents pyrophosphate--fructose 6-phosphate 1-phosphotransferase, initially described as XF0274 type . It catalyses the phosphorylation of D-fructose 6-phosphate, the first committing step of glycolysis .
Pyrophosphate-dependent phosphofructokinase SMc01852 type (PPi-PFK_SMc01852)
Type: Family

This entry represents a family of pyrophosphate-dependent phosphofructokinases. It catalyses the phosphorylation of D-fructose 6-phosphate, the first committing step of glycolysis .
10-formyltetrahydrofolate dehydrogenase (10_FTHF_DH)
Type: Family

This group represents a 10-formyltetrahydrofolate dehydrogenase (FDH). This enzyme catalyses the reaction:
10-formyltetrahydrofolate + H2O + NADP+ = tetrahydrofolate + CO2 + NADPH + H+

As such it acts as an NADP-dependent aldehyde dehydrogenase . It is composed of two catalytic domains (the N- and C-terminal domains), which are connected by a 100-amino acid residue linker (intermediate domain). The intermediate domain functions similarly to an acyl carrier protein by binding to 4'-phosphopantetheine . FDH differs from other members of the aldehyde dehydrogenase family in that it binds the 2'-phosphate group of NADP via a water-mediated contact with Gln600, which may contribute to the specificity of the enzyme for NADP over NAD .
Aldehyde dehydrogenase (Aldehyde_DH)
Type: Family

This group represents a predicted aldehyde dehydrogenase with a duplicated domain. Even though the proteins in this entry belong to the aldehyde dehydrogenase family, the active site cysteine and glutamate residues are not conserved. Their activity is, therefore, not clear.