SII-SWORD/CoKE huggingface dataset:
Formate-tetrahydrofolate ligase, FTHFS, conserved site (Formate_THF_ligase_CS)
Type: Conserved_site

Formate--tetrahydrofolate ligase (

) (formyltetrahydrofolate synthetase) (FTHFS) is one of the enzymes participating in the transfer of one-carbon units, an essential element of various biosynthetic pathways. FTHFS catalyzes the ATP-dependent activation of formate ion via its addition to the N10 position of tetrahydrofolate. FTHFS is a highly expressed key enzyme in both the Wood-Ljungdahl pathway of autotrophic CO
2
fixation (acetogenesis) and the glycine synthase/reductase pathways of purinolysis. The key physiological role of this enzyme in acetogens is to catalyze the formylation of tetrahydrofolate, an initial step in the reduction of carbon dioxide and other one-carbon precursors to acetate. In purinolytic organisms, the enzymatic reaction is reversed, liberating formate from 10-formyltetrahydrofolate with concurrent production of ATP . In many of these processes the transfers of one-carbon units are mediated by the coenzyme tetrahydrofolate (THF). In eukaryotes the FTHFS activity is expressed by a multifunctional enzyme, C-1-tetrahydrofolate synthase (C1-THF synthase), which also catalyses the dehydrogenase and cyclohydrolase activities. Two forms of C1-THF synthases are known , one is located in the mitochondrial matrix, while the second one is cytoplasmic. In both forms the FTHFS domain consists of about 600 amino acid residues and is located in the C-terminal section of C1-THF synthase. In prokaryotes FTHFS activity is expressed by a monofunctional homotetrameric enzyme of about 560 amino acid residues .

The crystal structure of N(10)-formyltetrahydrofolate synthetase from Moorella thermoacetica shows that the subunit is composed of three domains organised around three mixed β-sheets. There are two cavities between adjacent domains. One of them was identified as the nucleotide binding site by homology modelling. The large domain contains a seven-stranded β-sheet surrounded by helices on both sides. The second domain contains a five-stranded β-sheet with two α-helices packed on one side while the other two are a wall of the active site cavity. The third domain contains a four-stranded β-sheet forming a half-barrel. The concave side is covered by two helices while the convex side is another wall of the large cavity. Arg 97 is likely involved in formyl phosphate binding. The tetrameric molecule is relatively flat with the shape of the letter X, and the active sites are located at the end of the subunits far from the subunit interface .

These signature patterns cover two regions that are almost perfectly conserved. The first one is a glycine-rich segment located in the N-terminal part of FTHFS and which could be part of an ATP-binding domain . The second pattern is located in the central section of FTHFS.
Formamidopyrimidine-DNA glycosylase (FPG_Glyclase)
Type: Family

This entry represents formamidopyrimidine-DNA glycosylase proteins mostly found in bacteria.

Formamidopyrimidine-DNA glycosylases (Fpg, MutM) are trifunctional DNA base excision repair enzymes that remove a wide range of oxidation-damaged bases (N-glycosylase activity;

) and cleave both the 3'- and 5'-phosphodiester bonds of the resulting apurinic/apyrimidinic site (AP lyase activity;

). Fpg has a preference for oxidised purines, excising oxidised purine bases such as 7,8-dihydro-8-oxoguanine (8-oxoG). Its AP (apurinic/apyrimidinic) lyase activity introduces nicks in the DNA strand, cleaving the DNA backbone by beta-delta elimination to generate a single-strand break at the site of the removed base with both 3'- and 5'-phosphates. Fpg is a monomer composed of 2 domains connected by a flexible hinge . The two DNA-binding motifs (a zinc finger and the helix-two-turns-helix motifs) suggest that the oxidised base is flipped out from double-stranded DNA in the binding mode and excised by a catalytic mechanism similar to that of bifunctional base excision repair enzymes . Fpg binds one ion of zinc at the C-terminal, which contains four conserved and essential cysteines .
Tetrahydrofolate dehydrogenase/cyclohydrolase, catalytic domain (THF_DH/CycHdrlase_cat_dom)
Type: Domain

This entry represents the N-terminal catalytic domain of enzymes that belong to the tetrahydrofolate dehydrogenase/cyclohydrolase family, which are mainly found in bacteria but also in archaeal and eukaryotic organisms.

Enzymes that participate in the transfer of one-carbon units require the coenzyme tetrahydrofolate (THF). Various reactions generate one-carbon derivatives of THF, which can be interconverted between different oxidation states by methylene-THF dehydrogenase (

), methenyl-THF cyclohydrolase (

) and formyl-THF synthetase (

) . The dehydrogenase and cyclohydrolase activities are expressed by a variety of multifunctional enzymes, including the tri-functional eukaryotic C1-tetrahydrofolate synthase ; a bifunctional eukaryotic mitochondrial protein; and the bifunctional Escherichia coli folD protein . Methylene-tetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclo-hydrolase share an overlapping active site , and as such are usually located together in proteins, acting in tandem on the carbon-nitrogen bonds of substrates other than peptide bonds.
Tetrahydrofolate dehydrogenase/cyclohydrolase, NAD(P)-binding domain (THF_DH/CycHdrlase_NAD-bd_dom)
Type: Domain

This entry represents the NAD(P)-binding domain found in enzymes that belong to the tetrahydrofolate dehydrogenase/cyclohydrolase family, which are mainly found in bacteria but also in archaeal and eukaryotic organisms.

Enzymes that participate in the transfer of one-carbon units require the coenzyme tetrahydrofolate (THF). Various reactions generate one-carbon derivatives of THF, which can be interconverted between different oxidation states by methylene-THF dehydrogenase (

), methenyl-THF cyclohydrolase (

) and formyl-THF synthetase (

) . The dehydrogenase and cyclohydrolase activities are expressed by a variety of multifunctional enzymes, including the tri-functional eukaryotic C1-tetrahydrofolate synthase ; a bifunctional eukaryotic mitochondrial protein; and the bifunctional Escherichia coli folD protein . Methylene-tetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclo-hydrolase share an overlapping active site , and as such are usually located together in proteins, acting in tandem on the carbon-nitrogen bonds of substrates other than peptide bonds.
Thymidine kinase, conserved site (Thymidine_kinase_CS)
Type: Conserved_site

Thymidine kinase (TK) (

) is an ubiquitous enzyme that catalyzes the ATP-dependent phosphorylation of thymidine.

This entry represents a conserved site of thymidine kinase.
Tyrosine-protein kinase, catalytic domain (Tyr_kinase_cat_dom)
Type: Domain

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 .

Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups :

Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis . RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction .

Cytoplasmic/non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases .
Tryptophan-tRNA ligase, archaea (Tryptophan-tRNA-ligase_arc)
Type: Family

Tryptophan-tRNA ligases (also known as Tryptophanyl-tRNA synthetases) are widely distributed, being found in archaea, bacteria and eukaryotes. This entry represents an archaeal subgroup of the enzymes.

The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction . These proteins differ widely in size and oligomeric state, and have limited sequence homology . The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric . Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices , and are mostly dimeric or multimeric, containing at least three conserved regions . However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c .

The class Ia aminoacyl-tRNA synthetases consist of the isoleucyl, methionyl, valyl, leucyl, cysteinyl, and arginyl-tRNA synthetases; the class Ib include the glutamyl and glutaminyl-tRNA synthetases, and the class Ic are the tyrosyl and tryptophanyl-tRNA synthetases .
DNA mismatch repair protein, MutL (DNA_mismatch_repair_MutL)
Type: Family

Mismatch repair is one of five major DNA repair pathways, the others being homologous recombination repair, non-homologous end joining, nucleotide excision repair, and base excision repair. The mismatch repair system recognises and repairs mispaired or unpaired nucleotides that result from errors in DNA replication. Many proteins involved in the different repair processes also play a role in apoptosis when DNA damage is excessive, thereby helping to prevent carcinogenesis . The mismatch repair protein, Mlh1 (mutL homologue 1), has a dual role in DNA repair and apoptosis. Mlh1 acts as a heterodimer in conjunction with Pms2, Pms1 (post-meiotic segregation 1 and 2) or Mlh3 (MutL homologue 3), which function as adaptor proteins that link Msh (MutS homologue) heterodimers to the DNA repair machinery, resulting in excision and repair of the mispaired base .

This entry represents the mismatch repair protein MutL.
Ribose-5-phosphate isomerase, type A, subgroup (Ribose5P_isomerase_typA_subgr)
Type: Family

Ribose 5-phosphate isomerase, also known as phosphoriboisomerase, catalyses the reversible conversion of D-ribose 5-phosphate to D-ribulose 5-phosphate, the first step in the non-oxidative branch of the pentose phosphate pathway . This reaction enables ribose to be synthesized from sugars, as well as the recycling of sugars during the degradation of nucleotides. There are two unrelated types of ribose 5-phosphate isomerases: type A (RpiA) is the most common and is found in most organisms, while type B (RpiB) is restricted to specific eukaryotic and prokaryotic species. Escherichia coli produces both RpiA and RpiB (also known as AlsB), although RpiA accounts for 99% of total RPI enzymes .

This entry represents a subgroup of type A ribose-5-phosphate isomerase that is found in bacteria, archaea and eukaryotes (plants and Metazoa), but excluding those found in fungi.
Death-associated protein kinase 1, catalytic domain (DAPK1_cat)
Type: Domain

This entry represents the catalytic domain of Death-associated protein kinases 1 (DAPK1), which act as a positive regulator of apoptosis .

Loss of DAPK1 expression, usually because of DNA methylation, is implicated in many tumour types .
DAPK1 is highly abundant in the brain and has also been associated with neurodegeneration .

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 .
Domain of unknown function DUF3447 (DUF3447)
Type: Domain

This presumed domain is functionally uncharacterised. This domain is found in eukaryotes. This domain is about 80 amino acids in length. This domain is found associated with [

]. This domain has a conserved SHN sequence motif. It seems likely that this region represents divergent Ankyrin repeats.
Rho-associated protein kinase 1/2 (ROCK1/ROCK2)
Type: Family

Eukaryotic protein kinases are enzymes that belong to a very extensive family of proteins which share a conserved catalytic core common with both serine/threonine and tyrosine protein kinases.

Rho kinases are serine/threonine kinases that are important in cell migration, cell proliferation and cell survival. Disorders of the central nervous system including stroke, inflammatory and demyelinating diseases, Alzheimer's disease and neuropathic pain may be linked to abnormal activation of Rho kinases .

This entry represents a set of Rho-associated, coiled-coil-containing, protein kinases. They phosphorylate a large number of important signalling proteins and help regulate the assembly of the actin cytoskeleton. Proteins in this entry have been shown to play a role in smooth muscle formation, and promote the formation of stress fibres and of focal adhesion complexes .
Tyrosine-protein kinase, non-receptor Jak2 (Tyr_kinase_non-rcpt_Jak2)
Type: Family

Janus kinases (JAKs) are tyrosine kinases that function in membrane-proximal signalling events initiated by a variety of extracellular factors binding to cell surface receptors . Many type I and II cytokine receptors lack a protein tyrosine kinase domain and rely on JAKs to initiate the cytoplasmic signal transduction cascade. Ligand binding induces oligomerisation of the receptors, which then activates the cytoplasmic receptor-associated JAKs. These subsequently phosphorylate tyrosine residues along the receptor chains with which they are associated. The phosphotyrosine residues are a target for a variety of SH2 domain-containing transducer proteins. Amongst these are the signal transducers and activators of transcription (STAT) proteins, which, after binding to the receptor chains, are phosphorylated by the JAK proteins. Phosphorylation enables the STAT proteins to dimerise and translocate into the nucleus, where they alter the expression of cytokine-regulated genes. This system is known as the JAK-STAT pathway.

Four mammalian JAK family members have been identified: JAK1, JAK2, JAK3, and TYK2. They are relatively large kinases of approximately 1150 amino acids, with molecular weights of ~120-130kDa. Their amino acid sequences are characterised by the presence of 7 highly conserved domains, termed JAK homology (JH) domains. The C-terminal domain (JH1) is responsible for the tyrosine kinase function. The next domain in the sequence (JH2) is known as the tyrosine kinase-like domain, as its sequence shows high similarity to functional kinases but does not possess any catalytic activity. Although the function of this domain is not well established, there is some evidence for a regulatory role on the JH1 domain, thus modulating catalytic activity. The N-terminal portion of the JAKs (spanning JH7 to JH3) is important for receptor association and non-catalytic activity, and consists of JH3-JH4, which is homologous to the SH2 domain, and lastly JH5-JH7, which is a FERM domain.

This entry represents the non-receptor tyrosine kinase JAK2 . JAK2 was initially cloned using a PCR-based strategy utilising primers corresponding to conserved motifs within the catalytic domain of protein-tyrosine kinases . In common with JAK1 and TYK2, and by contrast with JAK3, JAK2 appears to be ubiquitously expressed.
DNA-directed RNA polymerase, 14-18kDa subunit, conserved site (DNA-dir_RNA_polK_14-18kDa_CS)
Type: Conserved_site

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.

A component of 14 to 18kDa shared by all three forms of eukaryotic RNA polymerases and which has been sequenced in budding yeast (gene RPB6 or RPO26), in fission yeast (gene rpb6 or rpo15), in human and in African swine fever virus (ASFV) is evolutionary related to archaeal subunit K (gene rpoK). The archaeal protein is colinear with the C-terminal part of the eukaryotic subunit.
Apoptosis regulator, Bcl-2, BH1 motif, conserved site (Bcl2_BH1_motif_CS)
Type: Conserved_site

Active cell suicide (apoptosis) is induced by events such as growth factor withdrawal and toxins. It is controlled by regulators, which have either an inhibitory effect on programmed cell death (anti-apoptotic) or block the protective effect of inhibitors (pro-apoptotic) . Many viruses have found a way of countering defensive apoptosis by encoding their own anti-apoptosis genes preventing their target-cells from dying too soon.

All proteins belonging to the Bcl-2 family contain either a BH1, BH2, BH3, or BH4 motif. All anti-apoptotic proteins contain BH1 and BH2 motifs; some of them contain an additional N-terminal BH4 motif (Bcl-2, Bcl-x(L), Bcl-w), which is never seen in pro-apoptotic proteins, except for Bcl-x(S). On the other hand, all pro-apoptotic proteins contain a BH3 motif (except for Bad) necessary for dimerisation with other proteins of Bcl-2 family and crucial for their killing activity; some of them also contain BH1 and BH2 motifs (Bax, Bak). The BH3 motif is also present in some anti-apoptotic protein, such as Bcl-2 or Bcl-x(L).
RNA 3'-terminal phosphate cyclase-like, conserved site (RNA3'_term_phos_cycl-like_CS)
Type: Conserved_site

RNA cyclases are a family of RNA-modifying enzymes that are conserved in eukaryotes, bacteria and archaea. Type 1 RNA 3'-terminal phosphate cyclases (

) catalyse the conversion of 3'-phosphate to a 2',3'-cyclic phosphodiester at the end of RNA:

ATP + RNA 3'-terminal-phosphate = AMP + diphosphate + RNA terminal-2',3'-cyclic-phosphate

The physiological function of the cyclase is not known, but the enzyme could be involved in the maintenance of cyclic ends in tRNA splicing intermediates or in the cyclisation of the 3' end of U6 snRNA .

A second subfamily of RNA 3'-terminal phosphate cyclases (type 2) that do not have cyclase activity have been identified in eukaryotes. They are localised to the nucleolus and are involved in ribosomal modification .

RNA 3'-terminal phosphate cyclases contain a conserved glycine-rich stretch of residues located in the central part of the sequence, which is reminiscent of various ATP, GTP or AMP glycine-rich loops, and may be involved in AMP binding. This entry represents the conserved site.