SII-SWORD/CoKE huggingface dataset:
Polyribonucleotide nucleotidyltransferase (PNPase)
Type: Family

The eukaryotic exosome and the prokaryotic degradosome are important protein complexes involved in RNA processing and maintaining appropriate RNA levels within the cell . Both of these complexes contain exoribonucleases (exoRNases) which degrade RNA from the 3' end. The hydrolytic exoRNases produce nucleoside monophosphates, while the phosphorolytic exoRNases add orthophosphate at the cleaved bond to produce nucleoside monophosphates.

This entry represents polyribonucleotide nucleotidyltransferase (

), also known as polynucleotide phosphorylase (PNPase), found in bacterial and eukaryotic organelle degradosomes. This enzyme can process single-stranded RNA, but is stalled by double-stranded structures such as stem-loops. Structural studies show that PNPase is a trimeric multidomain protein with a central channel . Each subunit contains duplicated RNase PH-like domains which, though structurally homologous, are thought to be functionally distinct. The first domain is more divergent in sequence than than the second domain and is thought to be involved in the flexible binding of RNA substrate and the formation of the trimer channel structure. The second domain is thought to contain the catalytic site and show exoRNase activity. The catalytic mechanism of the enzyme is not yet known but it seems likely that single-stranded RNA would be threaded through the channel to be processed by the three active sites within the trimer, which would thus be restricted to a single substrate molecule per trimer. PNPase activity would thus be tightly regulated by secondary structural elements within the RNA .
Sialyltransferase (Sialyl_trans)
Type: Family

The sialyltransferase family represents a group of enzymes that transfers sialic acid from its common nucleotide sugar donor, CMP-beta-N-acetylneuraminate, to the terminal carbohydrates group of various glycoproteins and glycolipids. Animal sialyltransferases have type II transmembrane topology, and are thought to localise to the Golgi body. Gene homologues of animal sialyltransferases have been detected in plants .

This entry includes a subset of sialyltransferases that belong to the glycosyltransferase family 29 . Beta-galactoside alpha-2,6-sialyltransferase 2 is not included in this entry.
DNA-directed RNA polymerase subunit/transcription factor S (Rpa12/Rpb9/Rpc10/TFS)
Type: Family

DNA-directed RNA polymerases

(also known as DNA-dependent RNA polymerases) are responsible for the polymerisation of ribonucleotides into a sequence complementary to the template DNA. In eukaryotes, there are three different forms of DNA-directed RNA polymerases transcribing different sets of genes. Most RNA polymerases are multimeric enzymes and are composed of a variable number of subunits. The core RNA polymerase complex consists of five subunits (two alpha, one beta, one beta-prime and one omega) and is sufficient for transcription elongation and termination but is unable to initiate transcription. Transcription initiation from promoter elements requires a sixth, dissociable subunit called a sigma factor, which reversibly associates with the core RNA polymerase complex to form a holoenzyme . The core RNA polymerase complex forms a "crab claw"-like structure with an internal channel running along the full length . The key functional sites of the enzyme, as defined by mutational and cross-linking analysis, are located on the inner wall of this channel.

RNA synthesis follows after the attachment of RNA polymerase to a specific site, the promoter, on the template DNA strand. The RNA synthesis process continues until a termination sequence is reached. The RNA product, which is synthesised in the 5' to 3' direction, is known as the primary transcript.

Eukaryotic nuclei contain three distinct types of RNA polymerases that differ in the RNA they synthesise:

RNA polymerase I: located in the nucleoli, synthesises precursors of most ribosomal RNAs.

RNA polymerase II: occurs in the nucleoplasm, synthesises mRNA precursors.

RNA polymerase III: also occurs in the nucleoplasm, synthesises the precursors of 5S ribosomal RNA, the tRNAs, and a variety of other small nuclear and cytosolic RNAs.

Eukaryotic cells are also known to contain separate mitochondrial and chloroplast RNA polymerases. Eukaryotic RNA polymerases, whose molecular masses vary in size from 500 to 700kDa, contain two non-identical large (>100kDa) subunits and an array of up to 12 different small (less than 50kDa) subunits.

In archaebacteria, there is generally a single form of RNA polymerase which also consist of an oligomeric assemblage of 10 to 13 polypeptides.

This entry represents the conserved small (~15kDa), zinc ribbon-containing, subunit which is found in archaeal and eukaryotic polymerases and forms part of the catalytic core of the enzyme . This entry also includes transcription factor S (TFS), a protein related in size and sequence to DNA-directed RNA polymerase subunit M, and in sequence and function to the much larger eukaryotic transcription factor IIS (TFIIS). Although originally suggested to be a subunit of the archaeal RNA polymerase (known as archaeal DNA-directed RNA polymerase subunit M), it elutes separately from active polymerase in gel filtration experiments and acts, like TFIIs, as an induction factor for RNA cleavage by RNA polymerase .

This entry also includes uncharacterised sequences from virus.
Cytochrome-c3 hydrogenase, gamma subunit (Cyt_c3_hydrogenase_gsu)
Type: Family

This entry consists of electron transfer proteins found as components of oxidoreductase enzymes in bacteria and archaea. So far, these proteins have been shown to be components of sulphite reductase, which catalyses the production of hydrogen sulphide from sulphite, dihydroorotate dehydrogenase involved in pyrimidine biosynthesis, and hydrogenase . Structural studies of the PyrK component of dihydroorotate dehydrogenase show that it contains a 2Fe-2S cluster, an FAD cofactor and an NAD(+) binding region, with a similar overall fold to other members of the NADPH-ferrodoxin superfamily . Its role is to transfer electrons derived from oxidation of the physiological substrate, via the iron-sulphur cluster, to the FAD cofactor where the ultimate electron acceptor is reduced.
Uncharacterised protein family RocB (Uncharacterised_RocB)
Type: Family

This group contains RocB of Bacillus subtilis and related proteins. RocB is one of the three genes found in the rocABC operon in B. subtilis, which is sigma L dependent and induced by arginine, suggesting it is involved in the arginine degradation pathway. The function of members of this family is unknown, though they are related to metallopeptidases belonging to MEROPS peptidase family M20, subfamily M20A (clan MH).
Cyclin, epsilonretrovirus (Cyclin_epsilonretrovir)
Type: Family

Cyclins are eukaryotic proteins that play an active role in controlling nuclear cell division cycles , and regulate cyclin dependent kinases (CDKs). Cyclins, together with the p34 (cdc2) or cdk2 kinases, form the Maturation Promoting Factor (MPF). There are two main groups of cyclins, G1/S cyclins, which are essential for the control of the cell cycle at the G1/S (start) transition, and G2/M cyclins, which are essential for the control of the cell cycle at the G2/M (mitosis) transition. G2/M cyclins accumulate steadily during G2 and are abruptly destroyed as cells exit from mitosis (at the end of the M-phase). In most species, there are multiple forms of G1 and G2 cyclins. For example, in vertebrates, there are two G2 cyclins, A and B, and at least three G1 cyclins, C, D, and E.

Cyclin homologues have been found in various viruses, including Saimiriine herpesvirus 2 (Herpesvirus saimiri) and Human herpesvirus 8 (HHV-8) (Kaposi's sarcoma-associated herpesvirus). These viral homologues differ from their cellular counterparts in that the viral proteins have gained new functions and eliminated others to harness the cell and benefit the virus .

This group represents a predicted cyclin found in epsilon-retroviruses, including walleye epidermal hyperplasia virus and walleye dermal sarcoma virus (WDSV).
TFIIH subunit Ssl1/p44 (TFIIH_SSL1/p44)
Type: Family

This entry represents Ssl1/p44m (also known as GTF2H2), which is a component of the transcription factor TFIIH core (includes XPB, p62, p52, p44, p34) . TFIIH complex is involved in nucleotide excision repair (NER) of damaged DNA and in RNA transcription by RNA polymerase II .
Fatty acid desaturase (Fatty_acid_desaturase)
Type: Family

This entry includes fatty acid desaturase family members from bacteria, fungi, plants and animals. Proteins in this family contain the fatty acid desaturase domain (

). The eukaryotic members, including human FADS1 and FADS2, are fusion proteins containing an N-terminal cytochrome b5-like domain and a C-terminal multiple membrane-spanning desaturase portion .

Three human fatty acid desaturase genes have been identified, fatty acid desaturase 1-3 (FADS1-3) . FADS1 and FADS2 encode delta-5 desaturase (D5D) and delta-6 desaturase (D6D) respectively. They are membrane-bound enzymes that catalyse the rate-limiting formation of endogenous long-chain polyunsaturated fatty acid (PUFA). FADS3 is a ceramide desaturase that produces sphinga-4,14-dienine-containing ceramides (SPD ceramides). FADS3 also acts as a methyl-end fatty acyl coenzyme A (CoA) desaturase that introduces a cis double bond between the preexisting double bond and the terminal methyl group of the fatty acyl chain. .
U3 small nucleolar ribonucleoprotein complex, subunit Mpp10 (Mpp10)
Type: Family

Mpp10 (M phase phosphoprotein 10) is a component of the 60-80S U3 small nucleolar ribonucleoprotein (U3 snoRNP) required for three cleavage events that generate the mature 18S rRNA from the pre-rRNA .
Xanthine dehydrogenase, small subunit, bacteria (Xanth_DH_ssu_bac)
Type: Family

Xanthine dehydrogenase is a complex metallo-flavoprotein catalysing the oxidation of hypoxanthine to xanthine followed by oxidation of xanthine to uric acid, linked to the reduction of NAD(+). Additionally, this enzyme can catalyse the oxidative hydroxylation of purines, pyrimidines, pterins, and aldehyde substrates. The mammalian form of this enzyme is a homodimer in which each monomer acts as an independent catalytic unit, while the bacterial form is a cytoplasmic heterotetramer composed of two small (alpha) and two large (beta) subunits .

In the bacterial enzyme, each heterotetramer is composed of two functionally independent large-small heterodimers . The small subunit binds two iron-sulphur clusters and FAD, while the large subunit binds molybdenum cofactor (MoCF). The small unit is composed of an N-terminal iron-sulphur binding domain with a ferredoxin-like fold, and a C-terminal FAD-binding domain similar in structure to other flavoproteins. The large subunit contains the Moco cofactor, located near the subunit interface, the substrate-binding site, and the site of dimerisation between heterodimers. The overall fold of the protein is similar to that of the mammalian enzyme, despite the difference in subunit composition. During catalysis, the electrons derived from substrate oxidation are transferred to molybdenum, then passed via the iron-sulphur clusters to the FAD cofactor, which is the site of NAD(+) reduction.

This entry represents the small subunit of the bacterial enzyme.
Bifunctional nitroreductase/nicotinate-nucleotide-dimethylbenzimidazole, phosphoribosyltransferase (NRdtase/NN_dMeBzImd_PRibTrfase)
Type: Family

Nicotinate mononucleotide (NaMN):5,6-dimethylbenzimidazole (DMB) phosphoribosyltransferase (CobT) plays a central role in the synthesis of alpha-ribazole-5'-phosphate, an intermediate for the lower ligand of cobalamin . It is one of the enzymes of the anaerobic pathway of cobalamin biosynthesis, and one of the four proteins (CobU, CobT, CobC, and CobS) involved in the synthesis of the lower ligand and the assembly of the nucleotide loop .

Vitamin B
12
(cobalamin) is used as a cofactor in a number of enzyme-catalysed reactions in bacteria, archaea and eukaryotes . The biosynthetic pathway to adenosylcobalamin from its five-carbon precursor, 5-aminolaevulinic acid, can be divided into three sections: (1) the biosynthesis of uroporphyrinogen III from 5-aminolaevulinic acid; (2) the conversion of uroporphyrinogen III into the ring-contracted, deacylated intermediate precorrin 6 or cobalt-precorrin 6; and (3) the transformation of this intermediate to form adenosylcobalamin . Cobalamin is synthesised by bacteria and archaea via two alternative routes that differ primarily in the steps of section 2 that lead to the contraction of the macrocycle and excision of the extruded carbon molecule (and its attached methyl group) . One pathway (exemplified by Pseudomonas denitrificans) incorporates molecular oxygen into the macrocycle as a prerequisite to ring contraction, and has consequently been termed the aerobic pathway. The alternative, anaerobic, route (exemplified by Salmonella typhimurium) takes advantage of a chelated cobalt ion, in the absence of oxygen, to set the stage for ring contraction .

This entry represents predicted bifunctional nitroreductase/nicotinate-nucleotide-dimethylbenzimidazole phosphoribosyltransferases.
Thiamine triphosphatase, eukaryotes (ThTPase_euk)
Type: Family

Thiamine triphosphate (ThTP), the triphosphorylated form of vitamin B1, is found in most organisms including bacteria, fungi, plants and animals. In mammals, cytosolic ThTP concentration is kept low by a highly specific soluble phosphohydrolase, the 25kDa thiamine triphosphatase (ThTPase) .

This entry includes the 25kDa thiamine triphosphatase (ThTPase) and its homologues mostly from mammals.
Replication factor C subunit 1 (RFC1)
Type: Family

This entry represents replication factor C subunit 1 (RFC1), which is the large subunit of replication factor C (RF-C), a five subunit DNA polymerase accessory protein. RF-C is a DNA binding protein complex and ATPase that acts as a clamp loader of the proliferating cell nuclear antigen (PCNA) processivity factor for DNA polymerases delta and epsilon . It also may have a role in telomere stability .
[NiFe]-hydrogenase-3-type complex Ech, subunit EchD (NiFe-hyd_3_EchD)
Type: Family

[NiFe] hydrogenases function in H2 metabolism in a variety of microorganisms, enabling them to use H2 as a source of reducing equivalent under aerobic and anaerobic conditions [NiFe] hydrogenases consist of two subunits, hydrogenase large and hydrogenase small. The large subunit contains the binuclear [NiFe] active site, while the small subunit binds at least one [4Fe-4S] cluster .

Energy-converting [NiFe] hydrogenases (or [NiFe]-hydrogenase-3-type) form a distinct group within the [NiFe] hydrogenase family . Members of this subgroup include:

Hydrogenase 3 and 4 (Hyc and Hyf) from Escherichia coli

CO-induced hydrogenase (Coo) from Rhodospirillum rubrum

Mbh hydrogenase from Pyrococcus furiosus

Eha and Ehb hydrogenases from Methanothermobacter species

Ech hydrogenase from Methanosarcina barkeri

Energy-converting [NiFe] hydrogenases are membrane-bound enzymes with a six-subunit core: the large and small hydrogenase subunits, plus two hydrophilic proteins and two integral membrane proteins. Their large and small subunits show little sequence similarity to other [NiFe] hydrogenases, except for key conserved residues coordinating the active site and [FeS] cluster. However, they show considerable sequence similarity to the six-subunit, energy-conserving NADH:quinone oxidoreductases (complex I), which are present in cytoplasmic membranes of many bacteria and in inner mitochondrial membranes. However, the reactions they catalyse differ significantly from complex I. Energy-converting [NiFe] hydrogenases function as ion pumps.

This entry represents subunit EchD from the [NiFe]-hydrogenase-3-type complex Ech.
Predicted bifunctional ATPase/phosphotransferase (Bifunc_ATPase/PTrfase)
Type: Family

This entry represents a predicted bifunctional ATPase/phosphotransferase involved in cell wall biosynthesis.
Bifunctional molybdenum cofactor biosynthesis MobB/MoeA (MobB_MoeA)
Type: Family

The majority of molybdenum-containing enzymes utilise a molybdenum cofactor (MoCF or Moco) consisting of a Mo atom coordinated via a cis-dithiolene moiety to molybdopterin (MPT). MoCF is ubiquitous in nature, and the pathway for MoCF biosynthesis is conserved in all three domains of life. MoCF-containing enzymes function as oxidoreductases in carbon, nitrogen, and sulphur metabolism .

This group represents a predicted bifunctional molybdenum cofactor biosynthesis protein MobB/MoeA.
FAD synthetase with the MoaB/Mog domain (FAD_synth_MoaB/Mog-bd)
Type: Family

This group represents a predicted FAD synthetase with the MoaB/Mog domain. It requires magnesium as a cofactor and is highly specific for ATP as a phosphate donor . The cofactors FMN and FAD participate in numerous processes in all organisms, including mitochondrial electron transport, photosynthesis, fatty-acid oxidation, and metabolism of vitamin B6, vitamin B12 and folates . This entry includes the eukaryotic enzymes.

Riboflavin is converted into catalytically active cofactors (FAD and FMN) by the actions of riboflavin kinase (

), which converts it into FMN, and FAD synthetase (

), which adenylates FMN to FAD. Eukaryotes usually have two separate enzymes, while most prokaryotes have a single bifunctional protein that can carry out both catalyses, although exceptions occur in both cases. While eukaryotic monofunctional riboflavin kinase is orthologous to the bifunctional prokaryotic enzyme , the monofunctional FAD synthetase differs from its prokaryotic counterpart, and is instead related to the PAPS-reductase family . The bacterial FAD synthetase that is part of the bifunctional enzyme has remote similarity to nucleotidyl transferases and, hence, it may be involved in the adenylylation reaction of FAD synthetases .
Bifunctional molybdopterin binding protein /nucleotidyl transferase, putative (Bifunc_Mopterin-bd)
Type: Family

This group represents a predicted bifunctional molybdopterin binding protein /nucleotidyl transferase.
Adenine modification methylase, M.StsI-type (Ade-mod_methylase_MStsI)
Type: Family

In prokaryotes, the major role of DNA methylation is to protect host DNA against degradation by restriction enzymes. Adenine modification methylases are a large group of enzymes, most of which form so-called 'restriction-modification systems'. Methylation of specific adenine residues is required for both restriction and modification activities. This methylase catalyses the reaction:
S-adenosyl-L-methionine + DNA adenine = S-adenosyl-L-homocysteine + DNA 6-methylaminopurine

It recognises the double-stranded sequence 5'-GGATG-3' in one strand and 3'-CATCC-5' in the other, causing specific methylation on the A of both strands. This protects the DNA from cleavage by the FokI endonuclease. The 2 domains of the protein participate in the modification of the two strands.

This group represents a modification methylase (adenine-specific), M.StsI type.
Disulphide bond formation protein BdbC (Disulphide_bond_form_BdbC)
Type: Family

Disulphide bonds contribute to folding, maturation, stability, and regulation of proteins, in particular those localized out of the cytosol. Oxidation of selected pairs of cysteines to disulphide in vivo requires cellular factors present in the bacterial periplasmic space or in the endoplasmic reticulum of eukaryotic cells .

This family represents disulphide bond formation protein C (BdbC) from Bacillus subtilis which functionally corresponds to the well-characterised E. coli DsbB .
NAD(P)-dependent malic enzyme (ME_PTA)
Type: Family

Malic enzymes, or malate oxidoreductases, catalyze the oxidative decarboxylation of malate into pyruvate important for a wide range of metabolic pathways .
Peptidase M28E, aminopeptidase AP1 (Pept_M28E_Ap1)
Type: Family

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 .

This family are metallopeptidases belonging to MEROPS peptidase family M28, subfamily M28E (aminopeptidase Ap1, clan MH). Representative members are aminopeptidase Ap1 from Vibrio proteolyticus (Vibrio proteolyticus (Aeromonas proteolytica)) and aminopeptidase apAC from Aeromonas punctata (Aeromona caviae) .
Uncharacterised conserved protein UCP036698, YpmA (UCP036698)
Type: Family

This group represents an uncharacterised conserved protein, Bacillus YpmA type.
cAMP-dependent protein kinase regulatory subunit (cAMP_dep_PK_reg_su)
Type: Family

Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity :

Serine/threonine-protein kinases

Tyrosine-protein kinases

Dual specificity protein kinases (e.g. MEK -phosphorylates both Thr and Tyr on target proteins)

Protein kinase function is evolutionarily conserved from Escherichia coli to human . Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved , leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases .

In the absence of cAMP, protein kinase A (PKA) exists as an equimolar tetramer of regulatory (R) and catalytic (C) subunits. In addition to its role as an inhibitor of the C subunit, the R subunit anchors the holoenzyme to specific intracellular locations and prevents the C subunit from entering the nucleus. Typical R subunits have a conserved domain structure, consisting of the N-terminal dimerisation domain, inhibitory region, cAMP-binding domain A and cAMP-binding domain B. R subunits interact with C subunits primarily through the inhibitory site. The cAMP-binding domains show extensive sequence similarity and bind cAMP cooperatively.

On the basis of phylogenetic trees generated from multiple sequence alignment of complete sequences, this family was divided into four sub-families, types I to IV . Types I and II, found in animals, differ in molecular weight, sequence, autophosphorylation capability, cellular location and tissue distribution. Types I and II are further sub-divided into alpha and beta subtypes, based mainly on sequence similarity. Type III are from fungi and type IV are from alveolates.