SII-SWORD/CoKE huggingface dataset:
Deferrochelatase (EfeB/EfeN)
Type: Family

This entry represents a small family of proteins with a typical Tat (twin-arginine translocation) signal sequence, suggesting that the family is exported in a folded state, perhaps with a bound redox cofactor. Proteins in this family include deferrochelatase/peroxidase EfeB, which is involved in the recovery of exogenous heme iron. It extracts iron from heme while preserving the tetrapyrrole ring intact . Crystal structure of EfeB revealed that it has ferredoxin-like fold domains (N-and C-terminal) consisting of an α+β fold that contains an antiparallel β-sheet composed of four β-strands. A large heme binding pocket is located in the C-terminal domain . This entry also includes deferrochelatase/peroxidase EfeN from Bacillus subtilis, which shows two domains with a ferredoxin-fold and best activity in the acidic range of pH .
Dyp-type peroxidase (Dyp_peroxidase)
Type: Family

Heme peroxidases were originally divided into two superfamilies, namely, the animal peroxidases and the plant peroxidases (class I, II and III), which include fungal (class II) and bacterial peroxidases. The DyP (for dye decolorizing peroxidase) family constitutes a novel class of heme peroxidase. Because these enzymes were derived from fungal sources, the DyP family was thought to be structurally related to the class II secretory fungal peroxidases. However, the DyP family exhibits only low sequence similarity to classical fungal peroxidases, such as LiP and MnP, and does not contain the conserved proximal and distal histidines and an essential arginine found in other plant peroxidase superfamily members.

DyP proteins have several characteristics that distinguish them from all other peroxidases, including a particularly wide substrate specificity, a lack of homology to most other peroxidases, and the ability to function well under much lower pH conditions compared with the other plant peroxidases . In terms of substrate specificity, DyP degrades the typical peroxidase substrates, but also degrades hydroxyl-free anthraquinone (many dyes are derived from anthraquinone compounds).

Crystal structures of DyP family members reveal two domains, each one adopting a ferredoxin-like fold . The proteins consist of an N-terminal domain and a C-terminal domain likely to be related by a duplication of an ancestral gene, as inferred from the conserved topology of the domains. The heme iron is penta-coordinated, with the protein contributing a conserved histidine ligand to the iron centre. A conserved Asp most likely acts as a proton donor/acceptor and takes the place of the catalytic histidine used by plant peroxidases. This Asp substitution helps explain why the DyP family is active at low pH .
Outer membrane autotransporter barrel domain (OM_autotransptr_brl_dom)
Type: Domain

The secretion of protein products occurs by a number of different pathways in bacteria and several secretion mechanisms have been described for Gram-negative bacteria , an increasing number employ a highly efficient but simple mechanism first described for the immunoglobulin A1 (IgA1) proteases .
Tryptophan synthase, beta chain-like (Trp_synth_b-like)
Type: Family

These sequences represent a family of pyridoxal-phosphate dependent enzymes that are closely related to the beta subunit of tryptophan synthase.
Ubiquinol-cytochrome c reductase, iron-sulphur subunit (Ubiquinol_cyt_c_Rdtase_Fe-S-su)
Type: Domain

These sequences represent the Proteobacterial and mitochondrial type of the Rieske [2Fe-2S] iron-sulphur subunit as found in ubiquinol-cytochrome c reductase. Not included in this group are the Rieske iron-sulphur protein as found in the cytochrome b6-f complex of the Cyanobacteria and chloroplasts. Most members of this family have a recognizable twin-arginine translocation (tat) signal sequence (DeltaPh-dependent translocation in chloroplast) for transport across the membrane with the 2Fe-2S group already bound. These signal sequences include a motif resembling RRxFLK before the transmembrane helix.
Phosphotransferase system, enzyme I-like (PTS_EI-like)
Type: Domain

Most proteins with this domain are known or deduced to function as the phosphoenolpyruvate-protein phosphotransferases (or enzyme I) of PTS sugar transport systems. Enzyme I transfers the phosphoryl group from phosphoenolpyruvate (PEP) to the phosphoryl carrier protein (HPr). This domain is also found in enzyme I-Ntr, which transfers the phosphoryl group from PEP to the phosphoryl carrier protein NPr, and is involved in regulating nitrogen metabolism , indicating that not all phosphotransferase system components are associated directly with sugar transport. In Xanthomonas campestris, FruB is a multiphosphoryl transfer protein involved in fructose transport that consists of three domains: a fructose-specific enzyme-IIA-like N-terminal domain, followed by an HPr-like domain and an enzyme-I-like C-terminal domain, represented by this entry .
Phosphoenolpyruvate synthase (PEP_synth)
Type: Family

Phosphoenolpyruvate synthase converts pyruvate into phosphoenolpyruvate
(PEP). This is an essential step in gluconeogenesis when pyruvate or lactate are used as a carbon source . PEP can also be utilised as an energy source for the phosphotransferase system of sugar uptake .
Phosphotransferase system, IIA-like nitrogen-regulatory protein PtsN (PTS_Nitro_regul)
Type: Family

The phosphoenolpyruvate-dependent sugar phosphotransferase system (PTS) is a major carbohydrate transport system in bacteria. The PTS catalyses the phosphorylation of incoming sugar substrates and coupled with translocation across the cell membrane, makes the PTS a link between the uptake and metabolism of sugars.

The general mechanism of the PTS is the following: a phosphoryl group from phosphoenolpyruvate (PEP) is transferred via a signal transduction pathway, to enzyme I (EI) which in turn transfers it to a phosphoryl carrier, the histidine protein (HPr). Phospho-HPr then transfers the phosphoryl group to a sugar-specific permease, a membrane-bound complex known as enzyme 2 (EII), which transports the sugar to the cell. EII consists of at least three structurally distinct domains IIA, IIB and IIC . These can either be fused together in a single polypeptide chain or exist as two or three interactive chains, formerly called enzymes II (EII) and III (EIII).

These sequences, which are about 160 residues in length, are closely related to the fructose-specific phosphotransferase (PTS) system IIA component. It is a regulatory protein found only in species with a phosphoenolpyruvate-protein phosphotransferase (enzyme I of PTS systems) and an HPr-like phosphocarrier protein, but not all species have a IIC-like permease. Members of this family are found in Proteobacteria, Chlamydia, and the spirochete Treponema pallidum .
Pilus retraction protein PilT/PilU (PilT/PilU)
Type: Family

Bacterial type IV pili are critical surface appendages involved in diverse biological processes including horizontal gene transfer, surface and host cell adhesion, biofilm formation, colonization, twitching and virulence. These pili extend and retract from the cell surface, requiring the action of an extension ATPase, often called PilB, and a retraction ATPase PilT, respectively . PilT depolymerizes the pilus fibre and recycles pilin subunits into the inner membrane. Many type IVa pilus systems also have a homologue of the retraction ATPase PilT, called PilU, which promotes type IV pilus retraction in a PilT-dependent manner through its ATPase activity. PilT and PilU are required for twitching motility and form independent homo-hexamers, which directly interact. PilU is important for generating maximal retraction forces . Members of this family may be found in some species that do not have type IV pili but have related structures for DNA uptake and natural transformation.
Glutathione reductase, eukaryote/bacterial (Glutathione_Rdtase_euk/bac)
Type: Family

This entry represents glutathione reductase (GSHR or GRase) from bacteria, animals and fungi. This protein family is one of two closely related subfamilies of GRase, which are also closely related to trypanothione reductase. GRase regenerates glutathione disulphide and NADPH from oxidized glutathione and NADP. In mice, this dimeric enzyme is responsible for an effective innate immune response against bacteria . In humans, it may be a target for improving the treatment of glioblastoma multiforme as it has been related to drug resistance in glioblastoma cells .
Phosphonoacetaldehyde hydrolase (Phosphonoacetald_hydro)
Type: Family

Phosphonoacetaldehyde hydrolase or phosphonatase catalyses the cleavage of the carbon-phosphorous bond of a phosphonate.

This enzyme is a member of the Haloacid Dehalogenase (HAD) superfamily of aspartate-nucleophile hydrolases, and contains a modified version of the conserved catalytic motifs of that superfamily . The first motif is usually DxDx(T/V); here it is DxAxT. In the third motif the normally conserved lysine is instead an arginine. Additionally, the enzyme from Bacillus cereus contains a unique conserved catalytic lysine which is involved in the binding and activation of the substrate through the formation of a Schiff base .

The substrate of this enzyme is the product of 2-aminoethylphosphonate (AEP) transaminase, phosphonoacetaldehyde. This degradation pathway for AEP may be related to its toxic properties which are utilised by microorganisms as a chemical warfare agent.
Glutathione reductase (GSHR)
Type: Family

This entry represents glutathione reductase (GSHR or GRase) from proteobacteria, cyanobacteria and plants. This protein family is one of two closely related subfamilies of GRase, both also closely related to trypanothione reductase. GRase regenerates glutathione disulphide and NADPH from oxidized glutathione and NADP. This enzyme is responsible for maintaining the cellular thiol/disulphide status and for protecting against reactive oxygen species (ROS) such as hydrogen peroxide . In plants, this enzyme play important roles in the sulphur assimilation pathway and for an efficient photosynthesis . In Sinorhizobium meliloti, this enzyme is required for redox homeostasis and oxidative stress protection and contributes to nitrogen fixation symbiosis .
Signal recognition particle, SRP54 subunit, eukaryotic (SRP54_euk)
Type: Family

The signal recognition particle (SRP) is a multimeric protein, which along with its conjugate receptor (SR), is involved in targeting secretory proteins to the rough endoplasmic reticulum (RER) membrane in eukaryotes, or to the plasma membrane in prokaryotes . SRP recognises the signal sequence of the nascent polypeptide on the ribosome. In eukaryotes this retards its elongation until SRP docks the ribosome-polypeptide complex to the RER membrane via the SR receptor . Eukaryotic SRP consists of six polypeptides (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) and a single 300 nucleotide 7S RNA molecule. The RNA component catalyses the interaction of SRP with its SR receptor . In higher eukaryotes, the SRP complex consists of the Alu domain and the S domain linked by the SRP RNA. The Alu domain consists of a heterodimer of SRP9 and SRP14 bound to the 5' and 3' terminal sequences of SRP RNA. This domain is necessary for retarding the elongation of the nascent polypeptide chain, which gives SRP time to dock the ribosome-polypeptide complex to the RER membrane. In archaea, the SRP complex contains 7S RNA like its eukaryotic counterpart, yet only includes two of the six protein subunits found in the eukaryotic complex: SRP19 and SRP54 .

This entry represents the 54kDa SRP54 component, a GTP-binding protein that interacts with the signal sequence when it emerges from the ribosome. SRP54 of the signal recognition particle has a three-domain structure: an N-terminal helical bundle domain, a GTPase domain, and the M-domain that binds the 7s RNA and also binds the signal sequence. The extreme C-terminal region is glycine-rich and lower in complexity and poorly conserved between species. In human, mutations of SRP54 cause Shwachman-Diamond syndrome (SDS), an inherited bone marrow failure syndrome characterised by neutropenia and exocrine pancreatic insufficiency, as it plays a role in proliferation and differentiation of granulocytic cells, neutrophils migration capacity and exocrine pancreas development .
UDP-glycosyltransferase, MGT-like (UDPGT_MGT-like)
Type: Family

This entry includes sequences that belong to the UDP-glucuronosyltransferase family such as Macrolide glycosyltransferase from Streptomyces lividans (MGT), a glucosyl transferase for macrolide antibiotic inactivation, and Demethyllactenocin mycarosyltransferase from Streptomyces fradiae, a transferase of glucose-related sugars for macrolide antibiotic production . This entry also includes NDP-glycosyltransferase YjiC from Bacillus subtilis, a gycosyltransferase that can glycosylate a wide range of substrates, including various flavonoids, phenyl ketones, curcuminoid, lignins, zingerone, triterpenes, stilbene, anthraquinone and simple aromatics . Other members are Oleandomycin glycosyltransferase involved in 2'-O-glycosylation of oleandomycin and some uncharacterised UDP-glucosyltransferases .
Phosphotransferase system, fructose IIC component (PTS_IIC_fruc)
Type: Domain

This entry represents the IIC component, or IIC region of a IIABC or IIBC polypeptide of a phosphotransferase system for carbohydrate transport. Members of this family belong to the fructose-specific subfamily of the broader family of PTS EIIC proteins. Members should be found as part of the same chain or in the same operon as fructose family IIA (

) and IIB (

) protein regions. A number of bacterial species have members in two different branches of this subfamily, suggesting some diversity in substrate specificity of its members.

PTS systems commonly occur in bacteria. An archaeal version has also been discovered . This entry identifies both the bacterial family members and archaeal homologues.
L-2-Haloacid dehalogenase (2-HAD)
Type: Family

These proteins catalyse the hydrolytic dehalogenation of small L-2-haloalkanoic acids to yield the corresponding D-2-hydroxyalkanoic acids . They belong to the Haloacid Dehalogenase (HAD) superfamily of aspartate-nucleophile hydrolases, class (subfamily) I. Note that the Type I HAD enzymes have not yet been fully characterised, but clearly utilise a substantially different catalytic mechanism and are thus unlikely to be related.
AMP deaminase (AMPD)
Type: Family

AMP-deaminase (AMPD) (

) is a large, well-conserved eukaryotic protein that catalyses the hydrolytic deamination of adenosine monophosphate (AMP) to inosine monophosphate (IMP), and so plays an important role in purine and energy metabolism . This entry also includes inactive deaminases from yeast, which lack the conserved His residues essential for binding the catalytic zinc ion and the conserved residues important for substrate binding and catalysis.
Adenosine/adenine deaminase (Ado/ade_deaminase)
Type: Family

Adenosine deaminases (

) are monomeric zinc dependent enzymes involved in purine metabolism. They are required for the breakdown of adenosine from food and for the turnover of nucleic acids in tissues. Adenosine deaminases convert adenosine to the related nucleoside inosine by the substitution of the amino group for a hydroxyl group. These enzymes are distantly related to AMP deaminases as they share three regions of sequence similarities; these regions are centred on residues which are proposed to play an important role in the catalytic mechanism of these two enzymes.

This entry also includes a group of adenine deaminases more related to the bacterial and eukaryotic adenosine deaminases than to Bacillus subtilis adenine deaminase and its bacterial homologues . Adenine deaminase catalyses the hydrolytic deamination of adenine to hypoxanthine.
Adenosine deaminase-related growth factor (ADGF)
Type: Family

Members of this family have been described as secreted proteins with growth factor activity and regions of adenosine deaminase homology in insects, molluscs, and vertebrates .

Adenosine deaminase-related growth factors (ADGF) are also known as CECR1 in vertebrates. They are a novel family of growth factors with sequence similarity to classical cellular adenosine deaminase. In Xenopus, it is essential for growth factor activity and is expressed in the somites, pronephros, eyes, cement gland, neural tube, and neural floor plate of the embryos . It is also essential for insect development . The mollusc derived growth factor (MDGF) is a member of the adenosine deaminase-related growth factor (ADGF) subfamily.
Quinol oxidase subunit II (QoxA)
Type: Family

Members of this family catalyze the oxidation of quinol with the concomitant reduction of molecular oxygen to water. This acts as the terminal electron acceptor in the respiratory chain. This subunit contains two transmembrane helices and a large external domain responsible for the binding and oxidation of quinol. QuoX is (presently) only found in Gram-positive bacteria of the Bacillus/Staphylococcus group . Like CyoA, the ubiquinol oxidase found in proteobacteria, the residues responsible for the ligation of Cu(a) and cytochrome c (found in the related cyt. c oxidases) are absent. Unlike CyoA, QoxA is in complex with a subunit I which contains cytochromes similar to the cytochrome c oxidases (as opposed to cytochromes b).
Cytochrome o ubiquinol oxidase subunit II (Cyt_o_ubiquinol_oxidase_su2)
Type: Family

This enzyme catalyses the oxidation of ubiquinol with the concomitant reduction of molecular oxygen to water. This acts as the terminal electron acceptor in the respiratory chain. Subunit II is responsible for binding and oxidation of the ubiquinone substrate. This sequence is closely related to QoxA, which oxidizes quinol in Gram-positive bacteria but which is in complex with subunits which utilise cytochrome a in the reduction of molecular oxygen. Slightly more distantly related is subunit II of cytochrome c oxidase which uses cytochrome c as the oxidant .
Glutamate--cysteine ligase, monofunctional (Glut_cys_ligase)
Type: Family

These sequences represent glutamate--cysteine ligase, also known as gamma-glutamylcysteine synthetase, an enzyme in the biosynthesis of glutathione (GSH). GSH is one of several low molecular weight cysteine derivatives that can serve to protect against oxidative damage and participate in biosynthetic or detoxification reactions.
Glutathione biosynthesis bifunctional protein GshAB (Glut_biosynth)
Type: Family

This entry represents a family with an N-terminal region similar to proteobacterial glutamate-cysteine ligase (gamma-glutamylcysteine synthetase). The C-terminal region is homologous to cyanophycin synthetase of cyanobacteria, and to D-alanine-D-alanine ligases . Cyanophycin is a storage molecule composed of arginine, aspartic acid, and some glutamic acid. Members of this family are found in Listeria and Enterococcus, Gram-positive lineages in which glutathione is produced , and in proteobacterium Pasteurella multocida.
Glutamate--cysteine ligase, GCS2 (GCS2)
Type: Family

Also known as gamma-glutamylcysteine synthetase and gamma-ECS (

). This enzyme catalyses the first and rate limiting step in de novo glutathione biosynthesis. Members of this family are found in archaea, bacteria and plants. May and Leaver discuss the possible evolutionary origins of glutamate-cysteine ligase enzymes in different organisms and suggest that it evolved independently in different eukaryotes, from an ancestral bacterial enzyme. They also state that Arabidopsis thaliana (Mouse-ear cress) gamma-glutamylcysteine synthetase is structurally unrelated to mammalian, yeast and Escherichia coli homologues. In plants, there are separate cytosolic and chloroplast forms of the enzyme.
D-glucosaminate-6-phosphate ammonia lyase DgaE-like (DgaE-like)
Type: Family

DgaE catalyses the conversion of D-glucosaminate 6-phosphate to yield keto-3-deoxygluconate 6-phosphate (KDGP) .
Thioredoxin/glutathione reductase selenoprotein (Thioredoxin/glutathione_Rdtase)
Type: Family

This entry represents thioredoxin reductase family, including thioredoxin reductase 1 and 2 from animals. This homodimeric, FAD-containing member of the pyridine nucleotide disulphide oxidoreductase family contains a C-terminal motif Cys-SeCys-Gly, where SeCys is selenocysteine encoded by TGA (in some sequence reports interpreted as a stop codon). In some members of this subfamily, Cys-SeCys-Gly is replaced by Cys-Cys-Gly. The reach of the selenium atom at the C-terminal arm of the protein is proposed to allow broad substrate specificity .
Protein of unknown function DUF436 (DUF436)
Type: Family

Members of this family are uncharacterised proteins predominantly found in Firmicutes in no more than one copy per genome.
Acid-soluble spore protein, gamma-type (Spore_gamma)
Type: Family

This is a family of small, glutamine and asparagine-rich peptides that store amino acids in the spores of Bacillus subtilis and related bacteria. Most members of the family have two copies of the spore protease (GPR) cleavage motif, typically EFASE in this family, separating three low-complexity repeats.
Methyltransferase FkbM (FkbM_mtfrase)
Type: Domain

This domain is characterised by two well-conserved short regions separated by a variable region in both sequence and length. The first of the two regions is found in a large number of proteins outside this group, a number of which have been characterised as methyltransferases. One member of this group, FkbM, was shown to be required for a specific methylation in the biosynthesis of the immunosuppressant FK506 in Streptomyces strain MA6548 .

This domain is also found in other methyltransferases such as SdnD from the fungus Sordaria araneosa, involved in the biosynthesis of glycoside antibiotics with tetracyclic diterpene aglycone structure and in AMB antimetabolite synthase AmbE from Pseudomonas aeruginosa, which participates in the biosynthesis of the antimetabolite L-2-amino-4-methoxy-trans-3-butenoic acid (AMB), a non-proteinogenic amino acid which is toxic for prokaryotes and eukaryotes .
DnaB/C, C-terminal domain (DnaB/C_C)
Type: Domain

This entry describes the C-terminal domain in DnaB, DnaD and related bacterial proteins. This domain is α-helical.

DnaB is a key component of the bacterial DNA replication machinery, involved in both initiation and replication restart. It functions in coordination with DnaI to assist in loading the replicative helicase DnaC onto single-stranded DNA. During initiation at the chromosomal origin of replication, oriC, DnaB acts downstream of DnaA and requires the prior action of DnaD. Beyond its role at oriC, DnaB is also a component of the replication restart primosome, enabling helicase reloading at alternative chromosomal sites, possibly through a PriA-independent pathway. DnaB and DnaD work cooperatively to enable DnaB access to single-stranded DNA, and they are essential for helicase loading at the oriN of the repN plasmid. DnaB is believed to mediate replication initiation at the inner face of the cell membrane and is critical for anchoring the origin region of both chromosomal DNA and plasmids to the membrane. It binds weakly to single-stranded DNA, shows a preference for double-stranded DNA and replication fork-like substrates, and remodels DNA by laterally compacting supercoiled and linear plasmid DNA, forming bead-like structures along double-stranded DNA. Together with DnaD, DnaB forms bipolar complexes on plasmid DNA, highlighting its central role in DNA replication and structural organisation .

The DnaD protein is a component of the PriA primosome. The PriA primosome functions to recruit the replication fork helicase onto the DNA . Members, both chromosomal or phage-associated, are found in the Bacillus/Clostridium group of Gram-positive bacteria . DnaD consists of two domains with distinct activities: an N-terminal domain with oligomerisation activity and a C-terminal domain with DNA-binding activity and a second DNA-induced oligomerisation activity .