SII-SWORD/CoKE huggingface dataset:
3-isopropylmalate dehydratase, large subunit (3-IsopropMal_deHydase_lsu)
Type: Family

3-isopropylmalate dehydratase (or isopropylmalate isomerase;

) catalyses the stereo-specific isomerisation of 2-isopropylmalate and 3-isopropylmalate, via the formation of 2-isopropylmaleate. This enzyme performs the second step in the biosynthesis of leucine, and is present in most prokaryotes and many fungal species. The prokaryotic enzyme is a heterodimer composed of a large (LeuC) and small (LeuD) subunit, while the fungal form is a monomeric enzyme. Both forms of isopropylmalate are related and are part of the larger aconitase family . Aconitases are mostly monomeric proteins which share four domains in common and contain a single, labile [4Fe-4S] cluster. Three structural domains (1, 2 and 3) are tightly packed around the iron-sulphur cluster, while a fourth domain (4) forms a deep active-site cleft. The prokaryotic enzyme is encoded by two adjacent genes, leuC and leuD, corresponding to aconitase domains 1-3 and 4 respectively . LeuC does not bind an iron-sulphur cluster. It is thought that some prokaryotic isopropylamalate dehydrogenases can also function as homoaconitase

, converting cis-homoaconitate to homoisocitric acid in lysine biosynthesis . Homoaconitase has been identified in higher fungi (mitochondria) and several archaea and one thermophilic species of bacteria, Thermus thermophilus . It is also found in the higher plant Arabidopsis thaliana, where it is targeted to the chloroplast .

This entry represents the large subunit of 3-isopropylmalate dehydratase, or the large subunit domain of single-chain forms of this enzyme. Homoaconitase, aconitase, and 3-isopropylmalate dehydratase have similar overall structures. All are dehydratases (

) and bind a [4Fe-4S]-cluster. 3-isopropylmalate dehydratase is split into large (leuC) and small (leuD) chains in eubacteria. Several pairs of archaeal proteins resemble the leuC and leuD pair in length and sequence but even more closely resemble the respective domains of homoaconitase, and their identity is uncertain. The archaeal leuC-like proteins are not included in group.
3-isopropylmalate dehydratase, small subunit (3-IsopropMal_deHydase_ssu)
Type: Family

3-isopropylmalate dehydratase (or isopropylmalate isomerase;

) catalyses the stereo-specific isomerisation of 2-isopropylmalate and 3-isopropylmalate, via the formation of 2-isopropylmaleate. This enzyme performs the second step in the biosynthesis of leucine, and is present in most prokaryotes and many fungal species. The prokaryotic enzyme is a heterodimer composed of a large (LeuC) and small (LeuD) subunit, while the fungal form is a monomeric enzyme. Both forms of isopropylmalate are related and are part of the larger aconitase family . Aconitases are mostly monomeric proteins which share four domains in common and contain a single, labile [4Fe-4S] cluster. Three structural domains (1, 2 and 3) are tightly packed around the iron-sulphur cluster, while a fourth domain (4) forms a deep active-site cleft. The prokaryotic enzyme is encoded by two adjacent genes, leuC and leuD, corresponding to aconitase domains 1-3 and 4 respectively . LeuC does not bind an iron-sulphur cluster. It is thought that some prokaryotic isopropylamalate dehydrogenases can also function as homoaconitase

, converting cis-homoaconitate to homoisocitric acid in lysine biosynthesis . Homoaconitase has been identified in higher fungi (mitochondria) and several archaea and one thermophilic species of bacteria, Thermus thermophilus . It is also found in the higher plant Arabidopsis thaliana, where it is targeted to the chloroplast .

This entry represents a region of the small subunit. The structure of the Pyrococcus horikoshii small subunit (

) has recently been determined . As expected the structure of this polypeptide is similar to that of aconitase domain 4, though one α helix is replaced by a short loop with relatively high temperature factor values. This loop region is thought to be important for substrate recognition. Unlike other aconitase family proteins, this subunit formed a tetramer through disulphide linkages, though it is not expected to interfere with its interaction with the large subunit. These disulphide linkages would be expected to confer thermostability on the enzyme, reflecting the thermophilic lifestyle of the organism.

Homoaconitase, aconitase, and 3-isopropylmalate dehydratase have similar overall structures. All are dehydratases (

) and bind a [4Fe-4S]-cluster. 3-isopropylmalate dehydratase is split into large (leuC) and small (leuD) chains in eubacteria. Several pairs of archaeal proteins resemble the leuC and leuD pair in length and sequence but even more closely resemble the respective domains of homoaconitase, and their identity is uncertain. The archaeal leuD-like proteins are not included in group.
Polyketide-type polyunsaturated fatty acid synthase, PfaA (Omega_3_polyunsat_FA_synth)
Type: Family

Members of this entry represent PfaA, which is involved in omega-3 polyunsaturated fatty acid biosynthesis, for example PfaA from the eicosapentaenoic acid biosynthesis operon in Photobacterium profundum SS9. PfaA is found together with PfaB, PfaC, and PfaD, and the functions of the individual polypeptides have not yet been described. More distant homologues of PfaA, also included in this entry, appear to be involved in polyketide-like biosynthetic mechanisms of polyunsaturated fatty acid biosynthesis; an alternative to the more familiar iterated mechanism of chain extension and desaturation, and like PfaA the more distant homologues are likewise found near genes for homologues of PfaB, PfaC, and/or PfaD.
2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexene-1-carboxylic-acid synthase (MenaQ_synth_MenD)
Type: Family

MenD was thought to act as SHCHC synthase, but has recently been shown to act instead as SEPHCHC synthase. Conversion of SEPHCHC into SHCHC and pyruvate may occur spontaneously but is catalyzed efficiently, at least in some organisms, by MenH. 2-oxoglutarate decarboxylase/SHCHC synthase (menD) is a thiamine pyrophosphate enzyme involved in menaquinone biosynthesis .
Isocitrate dehydrogenase NAD-dependent (Isocitrate_DH_NAD)
Type: Family

Several NAD- or NADP-dependent dehydrogenases, including 3-isopropylmalate dehydrogenase, tartrate dehydrogenase, and the multimeric 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.

Mitochondrial NAD-dependent isocitrate dehydrogenases (IDH) resemble prokaryotic NADP-dependent IDH and 3-isopropylmalate dehydrogenase (an NAD-dependent enzyme) more closely than they resemble eukaryotic NADP-dependent IDH. The mitochondrial NAD-dependent isocitrate dehydrogenase is believed to be an α(2)-β-γ heterotetramer. All subunits are homologous and belog to this group.

The NADP-dependent IDH of Thermus thermophilus strain HB8 resembles these NAD-dependent IDH, except for the residues involved in cofactor specificity, much more closely than it resembles other prokaryotic NADP-dependent IDH, including that of Thermus aquaticus.
Molybdopterin-guanine dinucleotide biosynthesis protein B (MobB) domain (MobB_dom)
Type: Domain

The MobB domain is similar to that of the urease accessory protein UreG and the hydrogenase accessory protein HypB, both GTP hydrolases involved in loading nickel into the metallocentres of their respective target enzymes. It is involved in the final step of molybdenum-cofactor biosynthesis. While its precise function has not been identified it is thought to be involved in the transfer of a guanine dinucleotide moiety to molybdopterin, as it shows GTP-binding and weak GTPase activity . The MobB protein (

) from Escherichia coli, which is comprised of this domain, is a homodimer . Each molecule is composed of two distinct regions - an outer region comprised of 6 β-strands and three α helices, and an inner region comprised of a two-strand β hairpin followed by an α helix. These regions require interaction with the second monomer to allow proper folding to occur. The two monomers are intertwined and form an extensive 16-stranded β-sheet. While the active site could not be positively identified, the presence of highly conserved residues suggests the substrate binding site occurs in the central solvent channel.

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 .
Isocitrate dehydrogenase NADP-dependent, monomeric (Isocitrate_DH_NADP_mono)
Type: Family

This family of enzymes catalyses the NADP(+)-dependent oxidative decarboxylation of isocitrate to form 2-oxoglutarate, CO2, and NADPH within the Krebs cycle (

). Thus this enzyme supplies the cell with a key intermediate in energy metabolism, and precursors for biosynthetic pathways. The activity of this enzyme, which is controlled by phosphorylation, helps regulate carbon flux between the Krebs cycle and the glyoxylate bypass, which is an alternate route that accumulates carbon for biosynthesis when acetate is the sole carbon source for growth . The phosphorylation state of this enzyme is controlled by isocitrate dehydrogenase kinase/phosphatase. This family has been found in a number of bacterial species including Azotobacter vinelandii, Corynebacterium glutamicum, Rhodomicrobium vannielii, and Neisseria meningitidis.

The structure of isocitrate dehydrogenase from Azotobacter vinelandii (

) has been determined . This molecule consists of two distinct domains, a small domain and a large domain, with a folding topology similar to that of dimeric isocitrate dehydrogenase from Escherichia coli (

). The structure of the large domain repeats a motif observed in the dimeric enzyme. Such a fusional structure by domain duplication enables a single polypeptide chain to form a structure at the catalytic site that is homologous to the dimeric enzyme, the catalytic site of which is located at the interface of two identical subunits.
ParB/RepB/Spo0J partition protein (ParB/RepB/Spo0J)
Type: Domain

This domain is found in chromosomal and plasmid partition proteins related to ParB, including Spo0J, RepB, and SopB.
Peptidase M3B, oligoendopeptidase F (Peptidase_M3B)
Type: Family

This group of metallopeptidases belong to MEROPS peptidase family M3 (clan MA(E)), the type example being oligoendopeptidase F from Lactococcus lactis. The enzyme hydrolyses peptides of 7 and 17 amino acids with fairly broad specificity. Differences in substrate specificity should be expected in other species. The gene is duplicated in L. lactis on the plasmid that bears it. A shortened second copy is found in Bacillus subtilis.

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 .
Isocitrate dehydrogenase NADP-dependent, dimeric, prokaryotic (Isocitrate_DH_NADP_dimer_prok)
Type: Family

Bacterial isocitrate dehydrogenases (IDHs) (

) can be classified into two types on the basis of their subunit structure. One is a homodimer, consisting of subunits of about 40-45kDa, which exists in many bacterial species, including Escherichia coli. The other is a monomer with a molecular mass of 80-100kDa, which has been reported in several bacteria, including Azotobacter vinelandii, Vibrio parahaemolyticus and Corynebacterium glutamicum. Although bacterial monomeric and dimeric IDHs catalyse the same reaction, homology of amino acid sequence is hardly found between both types of IDHs .
RNA methyltransferase TrmH (rRNA_MeTrfase_TrmH)
Type: Family

The TrmH family of RNA methyltransferases are involved in rRNA base modification .
YjeF N-terminal domain (YjeF_N_dom)
Type: Domain

In bacteria or archaea, YjeF N-terminal domains occur either as single domain proteins or fused with other domains and are commonly associated with enzymes. YjeF N-terminal domains (also known as NAD(P)H-hydrate epimerase) are often fused to a YjeF C-terminal domain. It is a bifunctional enzyme that catalyses the epimerisation of the S- and R-forms of NAD(P)HX and the dehydration of the S-form of NAD(P)HX at the expense of ADP, which is converted to AMP .
Sodium/glutamate symport carrier protein GltS (GltS)
Type: Family

This entry represents a membrane protein, GltS, which is a glutamate carrier of an Na+-dependent, binding protein-independent, and glutamate-specific transport system .
D,D-heptose 1,7-bisphosphate phosphatase (Heptose_bisP_phosphatase)
Type: Family

In a number of species, including Escherichia coli, the histidine biosynthetic enzymes imidazole glycerol phosphate dehydratase and histidinol phosphatase are found together in the bifunctional protein HisB. This family represents a protein closely related to the histidinol phosphatase domain of HisB. The protein is found both in Helicobacter pylori, for which the histidine biosynthetic pathway appears to be absent, and in species that also have a bifunctional HisB protein.

Members of this family have been characterised as D,D-heptose 1,7-bisphosphate phosphatase, which converts the D-glycero-beta-D-manno-heptose 1,7-bisphosphate intermediate into D-glycero-beta-D-manno-heptose 1-phosphate by removing the phosphate group at the C-7 position.
C-terminal-processing peptidase S41A (Peptidase_S41A)
Type: Family

This group of serine peptidases belong to MEROPS peptidase family S41 (clan SM), subfamily S41A (C-terminal processing peptidase).
It is a family of C-terminal peptidases with different substrates in different species, including processing of D1 protein of the photosystem II reaction centre in higher plants , and cleavage of a peptide of 11 residues from the precursor form of penicillin-binding protein in Escherichia coli .
Nitrate reductas, NapE, periplasmic (Nitrate_reductase_NapE)
Type: Family

NapE, homologous to TorE (

), is a membrane protein of unknown function that is part of the periplasmic nitrate reductase system; it may be part of the enzyme complex. The periplasmic nitrate reductase allows f or nitrate respiration in anaerobic conditions.
Phosphohistidine phosphatase SixA (SixA)
Type: Family

Phosphohistidine phosphatase SixA (

) from Escherichia coli exhibits phosphatase activity towards the HPT domain of the ArcB sensor involved in the multistep His-Asp phosphorelay .
Threonine synthase-like (Thr_synthase-like)
Type: Family

Threonine synthase (

) is involved in threonine biosynthesis. It catalyses the conversion of O-phospho-L-homoserine and water into L-threonine and orthophosphate, using pyridoxal phosphate as a cofactor. The pyridoxal-phosphate binding site is a Lys (K) residue. The enzyme is distantly related to the serine/threonine dehydratases which are also pyridoxal-phosphate dependent enzymes .

This entry includes threonine synthases and its homologues (threonine synthases like proteins) from archaea, bacteria, fungi, plants and metazoans. The function of the threonine synthase-like proteins from metazoan is still not clear .
Multi-protein bridging factor 1 -like, archaea (aMBF1-like)
Type: Family

This family represents a group of proteins from archaea, including Multiprotein Bridging Factor (aMBF1) from Saccharolobus solfataricus (

), the archaeal homologue of MFB1 from Saccharomyces cerevisiae. MFB1 is a transcriptional coactivator that prevent stalled ribosomes from frameshifting. Members of this group contain an helix-turn-helix domain (

), which is directly involved in the association of aMBF1 with ribosomes .
L-lactate oxidation iron-sulfur protein LutB/LldF (LutB/LldF)
Type: Family

Members of this family, including LutB from Bacillus subtilis and LldF from Shewanella oneidensis, have a perfect 4Fe-4S binding motif C-x(2)-C-x(2)-C-x(3)-CP followed by either a perfect or imperfect (the first Cys replaced by Ser) second copy. Members probably bind two 4fe-4S iron-sulfur clusters, and are involved in lactate utilization .
Epoxyqueuosine reductase QueG (QueG)
Type: Family

Proteins in this family are epoxyqueuosine reductases that catalyse the conversion of epoxyqueuosine (oQ) to queuosine (Q), which is a hypermodified base found in the wobble positions of tRNA(Asp), tRNA(Asn), tRNA(His) and tRNA(Tyr) .
These proteins contain the 4Fe-4S ferredoxins iron-sulphur binding domain.
HD-related protein (HD-related)
Type: Family

The archaeal proteins containing this domain are as yet uncharacterised and of unknown function.
2,3-bisphosphoglycerate-independent phosphoglycerate mutase (Pglycerate_mutase_ApgM)
Type: Family

This family represents 2,3-bisphosphoglycerate-independent phosphoglycerate mutase (iPGAM), it is a metalloenzyme found particularly in archaea and some eubacteria. It is responsible for the interconversion of 2-phosphoglycerate and 3-phosphoglycerate . It is distantly related to the iPGAM (

) characteristic of plants and many eubacteria. The common active site and metal-binding residues of the phosphatase domain are easily identified, but the putative phosphotransferase domain is highly diverged. These proteins are unrelated to the cofactor-dependent PGAM. Activity has been demonstrated for proteins from Methanocaldococcus jannaschii (Methanococcus jannaschii) , Pyrococcus furiosus , and Sulfolobus solfataricus . These proteins were initially misidentified as phosphonopyruvate decarboxylase.
Zinc finger, ZPR1-type (Znf_ZPR1)
Type: Domain

This entry represents ZPR1-type zinc finger domains. ZPR1 is an experimentally proven zinc-binding protein that binds the tyrosine kinase domain of the epidermal growth factor receptor (EGFR); binding is inhibited by EGF stimulation and tyrosine phosphorylation, and activation by EGF is followed by some redistribution of ZPR1 to the nucleus.

The function of ZPR1 from archaea and eukaryotes is not yet clear. However, Zpr1 from yeast acts as a protein folding chaperone for elongation factor 1-alpha . ZPR1 is present in both the cytoplasm and nucleoplasm and its subcellular distribution changes during proliferation . ZPR1 binds to the cytoplasmic tyrosine kinase domain of the epidermal growth factor receptor (EGFR) and is a component of downstream signaling of both EGFR and FGFR signaling . It has been associated with susceptibility to type 2 diabetes and is downregulated in patients with spinal muscular atrophy , a disease characterised by degeneration of the alpha-motor neurons in the spinal cord that can arise from mutations affecting the expression of Survival Motor Neurons (SMN) . ZPR1 interacts with complexes formed by SMN , and may act as a modifier that affects the severity of SMA.

Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates . Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few . Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target.
Translation initiation factor 2, beta subunit (TIF2_bsu_arc)
Type: Family

Archaeal transcription initiation factor 2 is, like its eukaryotic homologue, a heterotrimeric protein with alpha, beta and gamma subunits . It is thought play an essential role in the recognition of the correct codon for the start of translation, similar to the role of eukaryotic transcription initiation factor. The eukaryotic factor forms a ternary complex with the methionine initiator tRNA and GTP, which binds to the 40S ribosomal subunit as part of the 43S preinitiation complex . The beta and gamma subunits are responsible for recruiting the initiator tRNA and GTP, while the alpha subunit is involved in the regulation of the translation initiation process. The beta subunit has also been shown to interact with other transcription factors. All three subunits of the archaeal and eukaryotic factors are well conserved among the diverse species of eukaryotes and archaea, but do not occur in prokaryotes.

The archaeal beta subunit has an unfolded N-terminal domain, a mixed α/β core domain and a C-terminal zinc finger . The N-terminal region is thought to interact with the gamma subunit, while the central and C-terminal domains are thought to provide RNA-binding sites.
Cobyric acid synthase CobQ (CobQ_synth)
Type: Family

Cobyric acid synthase (CobQ) plays a role in the cobalamin (vitamin B12) biosynthesis pathway. This enzyme catalyses amidations at positions B, D, E, and G on adenosylcobyrinic A,C-diamide in the biosynthesis of cobalamin. NH(2) groups are provided by glutamine, and one molecule of ATP is hydrogenolysed for each amidation .
Acetyl-CoA decarbonylase/synthase complex subunit alpha (CdhA)
Type: Family

Acetyl-CoA decarbonylase/synthase (ACDS) is a 5-subunit-containing multienzyme complex found exclusively in methanogens and certain other Archaea . ACDS catalyses the central reaction of acetyl C-C bond cleavage in methanogens growing on acetate and is also responsible for synthesis of acetyl units during growth on C-1 substrates .

The ACDS complex contains five subunits, among which beta possesses an Ni-Fe-S active-site metal cluster, the A-cluster, at which reaction with acetyl-CoA takes place, generating an acetyl-enzyme species poised for C-C bond cleavage . The ACDS complex is made up of alpha, epsilon, beta, gamma and delta chains with a probable stoichiometry of (alpha(2)epsilon(2))(4)-beta(8)-(gamma(1)delta(1))(8).

This entry represents the alpha subunit.