SII-SWORD/CoKE huggingface dataset:
RNA methyltransferase, RsmD (RNA_MeTrfase_RsmD)
Type: Family

This entry contains ribosomal RNA small subunit methyltransferase D as well as the putative rRNA methyltransferase YlbH. They methylate the guanosine in position 966 of 16S rRNA in the assembled 30S particle . RsmD-like protein Rv2966 from Mycobacterium tuberculosis, also can methylate and modulate host cellular DNA within an infected mammalian cell, altering the host epigenetic machinery . It binds to specific host DNA sequences and methylates cytosines predominantly in a non-CpG context .
Hydroxymethylpyrimidine kinase/phosphomethylpyrimidine kinase domain (HMP/HMP-P_kinase_dom)
Type: Domain

This entry represents a bifunctional enzyme, phosphomethylpyrimidine (HMP-P) kinase (

)/Hydroxymethylpyrimidine (HMP) kinase (

), the ThiD/J protein of thiamine biosynthesis. It catalyses two consecutive phosphorylation reactions in the thiamine phosphate biosynthesis pathway, first phosphorylating HMP to HMP-P, and then HMP-P to HMP-PP . The protein is commonly observed within operons containing other thiamine biosynthesis genes. Numerous examples are fusion proteins with other thiamine-biosynthetic domains.
Urease accessory protein UreG (UreG)
Type: Family

Urease is a nickel-binding enzyme that catalyses the hydrolysis of urea to form ammonia and carbamate. The activation of urease requires GTP hydrolysis and the formation of a preactivation complex consisting of apo-urease and urease accessory proteins UreF, UreH, and UreG. UreG is a SIMIBI class GTPase that can be recruited by UreF-UreH complex .

Member of this family is also Ure7 from Cryptococcus neoformans which appears to combine the functions of bacterial UreE and UreG in activating the Ure1 apoenzyme and thus making this pathogen more similar to that seen in the plant system .
Nucleoid-associated protein YbaB/EbfC (YbaB/EbfC)
Type: Family

This is a family of DNA-binding proteins, mainly found in bacteria and plants. Members of this family form homodimers which bind DNA via a tweezer-like structure . The conformation of the DNA is changed when bound to these proteins . In bacteria, these proteins may play a role in DNA replication-recovery following DNA damage . The plant form contains an additional N-terminal region that may serve as a transit peptide and shows a close relationship to the cyanobacterial member, suggesting that it is a chloroplast protein.

The crystal structure YbaB from Haemophilus influenzae revealed a core structure consisting of two layers, α/β; YbaB forms a tight dimer with a 3-layer structure, β/α/β .
Purine nucleoside phosphorylase DeoD-type (DeoD-type)
Type: Family

Purine nucleoside phosphorylase

, also called inosine phosphorylase (pnp), catalyses the cleavage of the glycosidic bond of ribo- and deoxyribonucleosides in the presence of orthophospate . It is specific for guanosine, inosine and adenosine and cleavage results in formation of their respective bases and ribose phosphate molecules. Together with adenosine deanimase,

, purine nucleoside phophorylase is responsible for purine catabolism as part of the salvage pathway of nucleotides and nucleosides.
Peptide chain release factor eRF1/aRF1 (Peptide_chain-rel_eRF1/aRF1)
Type: Family

This entry represents the eRF1 and aRF1 proteins.

Terminating protein synthesis on the ribosome requires the presence of a class I polypeptide chain release factor (RF) to induce peptidyl-tRNA hydrolysis. Bacteria possess two class I RFs; RF1 which recognises UAG and UAA, and RF2 which recognises UGA and UAA. Mitochondrial RFs are related structurally and functionally to those of bacteria. Eukaryotes posses only a single class 1 factor, eRF1, which recognises all three termination codons. Similarly, in all archaeal species where the complete sequence of the genome is available, only a single class I factor, aRF1, has been identified so far. The aRF1 family is highly homologous to the eRF1 family, indicating a common origin and ancestor molecule. The bacterial and mitochondrial class I RFs show no significant sequence similarity with their eukaryotic and archaeal counterparts and are considered to form a separate family. For more information see .
Dihydroxy-acid dehydratase (DihydroxyA_deHydtase)
Type: Family

Two dehydratases, dihydroxy-acid dehydratase (gene ilvD or ILV3) and 6-phosphogluconate dehydratase (gene edd) have been shown to be evolutionary related . Dihydroxy-acid dehydratase catalyzes the fourth step in the biosynthesis of isoleucine and valine, the dehydratation of 2,3-dihydroxy-isovaleic acid into alpha-ketoisovaleric acid. 6-Phosphogluconate dehydratase catalyzes the first step in the Entner-Doudoroff pathway, the dehydratation of 6-phospho-D-gluconate into 6-phospho-2-dehydro-3-deoxy-D-gluconate. Another protein containing this signature is the Escherichia coli hypothetical protein yjhG. The N-terminal part of the proteins contains a cysteine that could be involved in the binding of a 2Fe-2S iron-sulphur cluster .

This family represents dihydroxy-acid dehydratase (DAD). It contains a catalytically essential [4Fe-4S] cluster and catalyses the fourth step in valine and isoleucine biosynthesis.
Translation release factor pelota (Transl-rel_pelota)
Type: Family

Pelota (known as DOM34 in yeast) binds Hbs1, which is EF1-alpha-related subfamily GTPase, and is considered to play a crucial role in mRNA surveillance for protein synthesis . It is involved in No-go decay (NGD) and non-stop decay (NSD) surveillance mechanisms that target mRNAs on which elongation complexes are stalled. Pelota/Hbs1 were shown to promote dissociation of stalled elongation complexes and release of intact peptidyl-tRNA in the presence of the ATP-binding cassette protein ABCE1 . Pelota is conserved in eukaryotes and archaea .
Biotin--acetyl-CoA-carboxylase ligase (Biotin_CoA_COase_ligase)
Type: Family

The biotin operon of Escherichia coli contains 5 structural genes involved in the synthesis of biotin. Transcription of the operon is regulated via one of these proteins, the biotin ligase BirA. BirA is an asymetric protein with 3 specific domains -an N-terminal DNA-binding domain, a central catalytic domain and a C-terminal of unknown function. The ligase reaction intermediate, biotinyl-5'-AMP, is the co-repressor that triggers DNA binding by BirA.
The α-helical N-terminal domain of the BirA protein has the helix-turn-helix structure of DNA-binding proteins with a central DNA recognition helix. BirA undergoes several conformational changes related to repressor function and the N-terminal DNA-binding function is connected to the rest of the molecule through a hinge which will allow relocation of the domains during the reaction . Biotin-binding causes a large structural change thought to facilitate ATP-binding.

Two repressor molecules form the operator-repressor complex, with dimer formation occuring simultaneously with DNA binding. DNA-binding may also cause a conformational change which allows this co-operative interaction. In the dimer structure, the β-sheets in the central domain of each monomer are arranged side-by-side to form a single, seamless β-sheet.
Biotin operon repressor, helix-turn-helix domain (Biotin_operon_repress_HTH)
Type: Domain

The biotin operon of Escherichia coli contains 5 structural genes involved in the synthesis of biotin. Transcription of the operon is regulated via one of these proteins, BirA. BirA is an asymetric protein with 3 specific domains. The ligase reaction intermediate, biotinyl-5'-AMP, is the co-repressor that triggers DNA binding by BirA.
The α-helical N-terminal domain of the BirA protein has the helix-turn-helix structure of DNA-binding proteins with a central DNA recognition helix. BirA undergoes several conformational changes related to repressor function and the N-terminal DNA-binding function is connected to the rest of the molecule through a hinge which will allow relocation of the domains during the reaction .
Malonyl CoA-acyl carrier protein transacylase, FabD-type (Malonyl_CoA-ACP_transAc_FabD)
Type: Family

Malonyl CoA-acyl carrier protein transacylases transfer the malonyl moiety from coenzyme A to acyl-carrier protein. This entry represents the FabD-type enzymes, which include the fatty acid biosynthesis protein FabD and the antibiotic biosynthesis proteins PksC, PksE, BaeE/C and ThaF .
Peptidase A31, coenzyme F420-reducing hydrogenase delta subunit (Pept_A31_F420-red_hyd_d)
Type: Family

This group of sequences are classed as unassigned endopeptidases belonging to the MEROPS peptidase family A31 (HybD endopeptidase family, clan AE). The sequences in this family represent the delta subunit, FrhD, of the nickel-containing 8-hydroxy-5-deazaflavin reducing hydrogenase, otherwise known as coenzyme F420-reducing hydrogenase. The delta subunit is not part of the active FRH heterotrimer, but is probably a protease required for maturation. The alpha subunit contains the metallo centre, which binds nickel. When nickel binds to the metallo centre the alpha subunit is processed to the active enzyme by cleavage at a conserved site near the C terminus. The delta subunit is thought to be responsible for these cleavages .
Glutamyl-tRNA(Gln) amidotransferase A subunit (GatA)
Type: Family

In many species, Gln-tRNA ligase is missing. tRNA(Gln) is misacylated with Glu after which a heterotrimeric amidotransferase converts Glu to Gln. This group represents the amidase chain of the heterotrimer, encoded by the gatA gene called glutamyl-tRNA(Gln) amidotransferase, A subunit

. This enzyme functions as an alternative to a direct Gln-tRNA synthetase (Gln-tRNA ligase) in mitochondria, chloroplasts, Gram-positive bacteria, cyanobacteria, and the Archaea.

The archaea have an Asp-tRNA(Asn) amidotransferase instead of an Asp-tRNA ligase. In the archaea, a paralog of gatB is found, here designated gatB_rel, that is a candidate B subunit of the Asp-tRNA(Asn) amidotransferase. The gatA-encoded subunit may be shared by gatB and gatB_rel.

Amidase signature (AS) enzymes are a large group of hydrolytic enzymes that contain a conserved stretch of approximately 130 amino acids known as the AS sequence. They are widespread, being found in both prokaryotes and eukaryotes. AS enzymes catalyse the hydrolysis of amide bonds (CO-NH2), although the family has diverged widely with regard to substrate specificity and function. Nonetheless, these enzymes maintain a core α/β/α structure, where the topologies of the N-and C-terminal halves are similar. AS enzymes characteristically have a highly conserved C-terminal region rich in serine and glycine residues, but devoid of aspartic acid and histidine residues, therefore they differ from classical serine hydrolases. These enzymes posses a unique, highly conserved Ser-Ser-Lys catalytic triad used for amide hydrolysis, although the catalytic mechanism for acyl-enzyme intermediate formation can differ between enzymes .

Examples of AS enzymes include:

Peptide amidase (Pam) , which catalyses the hydrolysis of the C-terminal amide bond of peptides.

Fatty acid amide hydrolases , which hydrolyse fatty acid amid substrates (e.g. cannabinoid anandamide and sleep-inducing oleamide), thereby controlling the level and duration of signalling induced by this diverse class of lipid transmitters.

Malonamidase E2 , which catalyses the hydrolysis of malonamate into malonate and ammonia, and which is involved in the transport of fixed nitrogen from bacteroids to plant cells in symbiotic nitrogen metabolism.

Subunit A of Glu-tRNA(Gln) amidotransferase ,a heterotrimeric enzyme that catalyses the formation of Gln-tRNA(Gln) by the transamidation of misacylated Glu-tRNA(Gln) via amidolysis of glutamine.
Aspartyl/glutamyl-tRNA(Asn/Gln) amidotransferase subunit B (GatB)
Type: Family

This entry represents the B subunit of aspartyl/glutamyl-tRNA(Asn/Gln) amidotransferase.

Aspartyl/glutamyl-tRNA(Asn/Gln) amidotransferase ([ec:6.3.5.-]) allows the formation of correctly charged Asn-tRNA(Asn) or Gln-tRNA(Gln) through the transamidation of misacylated Asp-tRNA(Asn) or Glu-tRNA(Gln) in organisms which lack either or both of asparaginyl-tRNA or glutaminyl-tRNA synthetases. The reaction takes place in the presence of glutamine and ATP through an activated phospho-Asp-tRNA(Asn) or phospho-Glu-tRNA(Gln) . The enzyme is composed of three subunits: A (an amidase), B and C. It also exists in eukaryotes as a protein targeted to the mitochondria.

The heterotrimer GatABC is involved in converting Glu to Gln and/or Asp to Asn, when the amino acid is attached to the appropriate tRNA. In Lactobacillus, GatABC is responsible for producing tRNA(Gln). In Archaea, GatABC is responsible for producing tRNA(Asn), while GatDE is responsible for producing tRNA(Gln). In lineages that include Thermus, Chlamydia, or Acidithiobacillus, the GatABC complex catalyses both tRNA(Gln) and tRNA(Asn).
Glutamyl-tRNA(Gln) amidotransferase subunit E (GatE)
Type: Family

Glutamyl-tRNA(Gln) amidotransferase, subunit E (GatE) is found only in the Archaea. It is part of a heterodimer, with GatD (

), that acts as an amidotransferase on misacylated Glu-tRNA(Gln) to produce Gln-tRNA(Gln) . The reaction takes place in the presence of glutamine and ATP through an activated gamma-phospho-Glu-tRNA(Gln). The GatDE system is specific for glutamate and does not act on aspartate. This function is carried out in bacteria by the GatABC system, which acts both on Asp-tRNA(Asn) and Glu-tRNA(Gln). GatABC orthologues also exist in some archaea, where it coexist with GatDE (GatE being paralogous to GatB); while other archaea only posses GatED and use an asparaginyl-tRNA synthetase to produce Asn-tRNA by direct acylation of the tRNA . The crystal structure of GatED showed tRNA(Gln) recognition by indirect readout based on shape complementarity .
tRNA uridine 5-carboxymethylaminomethyl modification enzyme MnmG (MnmG)
Type: Family

tRNA uridine 5-carboxymethylaminomethyl modification enzyme MnmG (also known as GidA) is a tRNA modification enzyme found in bacteria and mitochondria. MnmG forms a complex with MnmE which is involved in the formation of methyluridine derivatives at the wobble uridine base in some tRNAs . Sequence variations in the human mitochondrial protein may influence the severity of aminoglycoside-induced deafness .
Methylenetetrahydrofolate--tRNA-(uracil-5-)-methyltransferase TrmFO (TrmFO)
Type: Family

Proteins in this entry catalyse the folate-dependent formation of 5-methyl-uridine at position 54 (M-5-U54) in all tRNAs. They are closely related to GidA (glucose-inhibited division protein A, also known as MnmG), a protein involved in tRNA modification in bacteria and mitochondria.
Homoaconitase, mitochondrial (Homoaconitase_mito)
Type: Family

Homoaconitase (cis-homoaconitase;

) catalyses the dehydration of cis-homoaconitate to homoisocitric acid. It is an enzyme from the alpha-aminoadipate pathway of lysine biosynthesis, and has been identified in higher fungi and several archaea and one thermophilic species of bacteria, Thermus thermophilus . Like aconitase, this enzyme binds a [4Fe-4S]-cluster, and it has a similar domain architecture to aconitase and isopropylmalate isomerase family proteins, although it catalyses a different reaction . Homoaconitase is found in the mitochondria of certain fungi.
Peptidase A31, hydrogenase expression/formation protein (Pept_A31_hyd_express)
Type: Family

This family of peptidases consists of hydrogenase expression/formation proteins, such as HoxM from Cupriavidus necator (also known as Alcaligenes eutrophus) and HybD from E. coli. They belong to the MEROPS peptidase family A31.

Nickel/iron hydrogenases are synthesized as two subunits, with the larger subunit containing the metallo centre. Once nickel has bound, the large subunit is activated by processing at a conserved site near the C terminus . The HycI endopeptidase releases a 32-residue peptide by cleavage of an Arg+Met bond . A 15-residue peptide is released from hydrogenase 2 by cleavage of a His+Met bond by the HybD endopeptidase .

The tertiary structure of HybD has been solved, and shows a twisted β sheet with three α helices on one side and four on the other . The molecule binds a single cadmium ion, which led to the peptidase being incorrectly identified as a metallopeptidase. It is possible that the metal binding site interacts with the nickel in the hydrogenase substrate . The fold is similar to that of members of family A25, and both families A25 and A31 are included in the same clan, AE.
Peptidase A31, hydrogenase maturation protease HycI (Pept_A31_hyd_mat_HycI)
Type: Family

This group of metallopeptidases belong to the MEROPS peptidase family A31 (HybD endopeptidase family, clan AE). The family contains the HycI endopeptidases and their homologues. Hydrogenase 3 maturation protease (HycI) is a protease involved in the C-terminal processing of HycE, the large subunit of hydrogenase 3 .
Carbamoyltransferase, HypF-type (Carbamoyltransferase_HypF)
Type: Family

The large subunit of [NiFe]-hydrogenase, as well as other nickel metalloenzymes, is synthesized as a precursor devoid of the metalloenzyme active site. This precursor then undergoes a complex post-translational maturation process that requires a number of accessory proteins . Members of the HypF family are accessory proteins involved in hydrogenase maturation. They contain the following domains: acylphosphatase, zinc fingers (2 repeats), a YrdC-like domain, and a C-terminal domain with a putative O-carbamoyltransferase motif.

The presence of CO and CN- ligands of the active site iron atoms is essential for [NiFe]-hydrogenase enzyme activity . Both ligands have been suggested to originate from carbamoylphosphate , which is required for maturation of [NiFe]-hydrogenases . Escherichia coli HypF interacts with carbamoylphosphate as a substrate and releases inorganic phosphate . In addition, HypF also cleaves ATP into AMP and pyrophosphate in the presence of carbamoylphosphate. This, and the fact that HypF catalyzes a carbamoylphosphate-dependent pyrophosphate ATP exchange reaction, suggest that the protein catalyzes the activation of carbamoylphosphate .

The mechanism of action of HypF, as well as of its individual domains, is not yet clear. Mutations in any of the three major signature motifs, the acylphosphatase, the zinc fingers, and the O-carbamoyltransferase motif, can block carbamoylphosphate phosphatase activity. This indicates an integrated cooperativity between these domains in the cleavage reaction .

The N-terminal acylphosphatase (ACP) domain is thought to support the conversion of carbamoylphosphate into CO and CN- . Biochemical results demonstrating its ACP activity are not available . ACPs are small enzymes that specifically catalyze the hydrolysis of carboxyl-phosphate bonds in acylphosphates, including carbamoylphosphate . Zinc fingers have been implicated in bivalent cation binding or as part of a chaperone domain interacting with the large subunit precursor, but experimental studies on such a function are lacking thus far. The YrdC-like domain is present in protein families with regulatory functions and has been implicated in RNA binding . It is not clear what function it may have in members of the HypF family. A C-terminal domain is distantly related to peptidase M22, but contains a conserved O-carbamoyltransferase motif required for the carbamoylphosphate phosphatase activity . The function of this domain is not clear.

Nomenclature note: the following names are used as synonyms of HypF: HupY in Azotobacter chroococcum, HupN in Rhizobium leguminosarum, HydA in E. coli. In other organisms, these names are used to designate various "hydrogenase cluster" proteins unrelated to the members of this family.
Beta-ribofuranosylphenol 5'-phosphate synthase (RFAP_synthase)
Type: Family

This protein family includes Beta-ribofuranosylphenol 5'-phosphate synthase (also known as beta-ribofuranosylaminobenzene 5'-phosphate synthase, RFAP synthase) from Methanocaldococcus jannaschii and other archaeal species and similar proteins predominantly found in Proteobacteria and Planctomycetes. RFAP synthase is an enzyme involved in methanopterin biosynthesis . It catalyses the condensation of 4-hydroxybenzoate (HB) with 5-phospho-alpha-D-ribose 1-diphosphate (PRPP) to produce beta-ribofuranosylphenol 5'-phosphate (beta-RFH-P) .

In some species, two members of this family are found. It is unclear whether both act as beta-RFAP synthase. This family is related to the GHMP kinases (Galactokinase, Homoserine kinase, Mevalonate kinase, Phosphomevalonate kinase).
4-diphosphocytidyl-2C-methyl-D-erythritol kinase (IspE)
Type: Family

4-diphosphocytidyl-2C-methyl-D-erythritol kinase is a member of the family of GHMP kinases that were previously designated as conserved hypothetical protein YchB or as isopentenyl monophosphate kinase. In Solanum lycopersicum (Tomato) (Lycopersicon esculentum) and Escherichia coli the protein has been indentified as 4-diphosphocytidyl-2C-methyl-D-erythritol kinase, an enzyme of the deoxyxylulose phosphate pathway of terpenoid biosynthesis . This enzyme is involved in the non-mevalonate pathway for isoprenoid biosynthesis and in it is essential for for chloroplast development .
Proteasome assembly chaperone MJ0106-like (MJ0106-like)
Type: Family

This family represents one out of two closely related orthologous sets of proteins that, so far, are found only archaea. This orthologue set includes MJ0106 from Methanococcus jannaschii and AF1251 from Archaeoglobus fulgidus, but not MJ1210 or AF0525 (which are represented in

. Members of this entry belong to the proteasome assembly chaperone family of proteins, and their function is unknown.
Proteasome assembly chaperone MJ1210-like (MJ1210-like)
Type: Family

This family represents one out of two closely related orthologous sets of proteins that, so far, are found only in but, are universal among, the Archaea. This orthologue set includes MJ1210 from Methanocaldococcus jannaschii (Methanococcus jannaschii) and AF0525 from Archaeoglobus fulgidus, but not MJ0106 or AF1251 (which are represented in

. Members of this entry belong to the proteasome assembly chaperone family of proteins, and their function is unknown.
Isopropylmalate dehydrogenase (Isopropylmalate_DH)
Type: Family

Several NAD- or NADP-dependent dehydrogenases, including 3-isopropylmalate dehydrogenase, tartrate dehydrogenase, and the dimeric forms of isocitrate dehydrogenase, share a nucleotide binding domain unrelated to that of lactate dehydrogenase and its homologues. These enzymes dehydrogenate their substates at a H-C-OH site adjacent to a H-C-COOH site; the latter carbon, now adjacent to a carbonyl group, readily decarboxylates. Among these decarboxylating dehydrogenases of hydroxyacids, overall sequence homology indicates evolutionary history rather than actual substrate or cofactor specifity, which may be toggled experimentally by replacement of just a few amino acids. 3-isopropylmalate dehydrogenase is an NAD-dependent enzyme and should have a sequence resembling HGSAPDI around residue 340. The subtrate binding loop should include a sequence resembling E[KQR]X(0,1)LLXXR around residue 115.

3-isopropylmalate dehydrogenase (IPMDH or LeuB) is the third enzyme in leucine biosynthesis. It catalyzes the oxidation of 3-carboxy-2-hydroxy-4-methylpentanoate (3-isopropylmalate) to 3-carboxy-4-methyl-2-oxopentanoate . In the yeast
Glarea lozoyensis
, 3-isopropylmalate dehydrogenase gloI (EC 1.1.1.85) is required for the biosynthesis of the mycotoxin pneumocandin, a lipohexapeptide of the echinocandin family .