SII-SWORD/CoKE huggingface dataset:
Glycerol-3-phosphate dehydrogenase, GlpB subunit (G3P_DH_GlpB_su)
Type: Family

This entry represents the GlpB subunit. An archaeal homologue has also recently been characterised , which appears to be used under aerobic conditions in halophilic archaea.

In bacteria, glycerol uptake is mediated by the glycerol diffusion facilitator, an integral membrane protein catalysing the rapid equilibration of concentration gradients of glycerol across the cytoplasmic membrane. Intracellular glycerol is converted to glycerol-3-phosphate that is further metabolised to dihydroxyacetone phosphate (DHAP) by either of two membrane-bound enzymes, depending on the growth conditions.

Under aerobic growth conditions, in the presence of glycerol, a glycerol-3-phopshate dehydrogenase (encoded by the glpD gene) is induced, which passes the reducing equivalents to an electron transport chain terminating with oxygen as the electron acceptor. Under anaerobic growth conditions, in the presence of glycerol and fumarate, a different dehydrogenase is induced . Electrons derived from this reaction are ultimately passed to fumarate as the terminal electron acceptor. The enzyme is composed of three subunits, encoded by the glpABC operon, which are all essential for anaerobic growth on glycerol-3-phosphate . GlpA and B form the soluble subunit which carries the catalytic site of glycerol-3-phosphate oxidation; while GlpC forms a membrane-bound iron-sulphur subunit, which may act as an anchor for the soluble subunit, and is thought to function in electron transfer from GlpAB to the terminal electron acceptor.
Dihydrofolate reductase, type II (Dhfr_type_II)
Type: Family

Dihydrofolate reductase (DHFR) (

) catalyses the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate, an essential step in
de novo
synthesis both of glycine and of purines and deoxythymidine phosphate (the precursors of DNA synthesis) , and important also in the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate. Although DHFR is found ubiquitously in prokaryotes and eukaryotes, and is found in all dividing cells, maintaining levels of fully reduced folate coenzymes, the catabolic steps are still not well understood .

Bacterial species possesses distinct DHFR enzymes (based on their pattern of binding diaminoheterocyclic molecules), but mammalian DHFRs are highly similar . The active site is situated in the N-terminal half of the sequence, which includes a conserved Pro-Trp dipeptide; the tryptophan has been shown to be involved in the binding of substrate by the enzyme. Its central role in DNA precursor synthesis, coupled with its inhibition by antagonists such as trimethoprim and methotrexate, which are used as anti-bacterial or anti-cancer agents, has made DHFR a target of anticancer chemotherapy. However, resistance has developed against some drugs, as a result of changes in DHFR itself .

This entry represents a plasmid-encoded DHFR which shows a high level of resistance to the antibiotic trimethoprim. It is a homotetramer with an unusual pore, which contains the active site, passing through the middle of the molecule . Its structure is unrelated to that of chromosomal DHFRs.
Acyl-CoA desaturase, haem/steroid binding domain-containing (Acyl-CoA_deSatase_haem/ster-bd)
Type: Family

This entry represents acyl-CoA desaturases 1 (also known as stearoyl-CoA desaturase 1 or Ole1) (

) that contain a C-terminal haem/steroid binding domain (cytochrome b
5
b) in addition to the N-terminal catalytic domain.
ATP-dependent 6-phosphofructokinase, eukaryotic-type (6-Pfructokinase_euk)
Type: Family

Phosphofructokinase (PFK) catalyses the phosphorylation of fructose-6-phosphate to fructose-1,6-biphosphate, which then enters the Embden-Meyerhof pathway. PFK is a key regulatory enzyme in glycolysis.

This entry represent eukaryotic type of ATP-dependent PFKs. They belong to the PFK domain superfamily of proteins, which also includes pyrophosphate (PPi)-dependent PFKs (

) and bacterial ATP-dependent PFKs (

). Unlike the bacterial PFKs, eukaryotic PFKs have a large N-terminal extension bearing an additional PFK domain . Proteins in this entry largely resemble group E PFKs .

Classification of PFK proteins revealed that major functional specialization can occur by mutation in one single amino acid residue. Based on the energy phosphoryl donors, the PFKs can be divided into two groups: ATP dependent PFKs (ATP-PFK) and inorganic pyrophosphate dependent PFKs (PPi-PFK). The eukaryotic ATP-PFKs are twice the size of the prokaryotic ATP-PFKs and have arisen through gene duplication and fusion of the ancestral bacterial gene. Not surprisingly, eukaryotic ATP-PFK homodimers are essentially equivalent to prokaryotic homotetramers. The PPi-PFKs, unlike the majority of ATP-PFKs, are not monophyletic in origin. The ability to use ATP or PPi is suggested to be dependent on the presence of one invariant glycine residue; therefore it is not surprising that the ability to utilise PPi has arisen more than once, and some recent changes in the phosphoryl donor (ATP to PPi) can be seen in several bacterial PFKs from

. It has been hypothesized that PPi-PFK may provide organisms niche-specific advantages, because the PPi phosphoryl donor allows both conservation of ATP and reaction reversibility; thus, it can function in both glycolysis and gluconeogenesis. It is likely that these enzymes evolved from the irreversible glycolysis form (ATP-dependent) towards the reversible reaction form (PPi-dependent). If a single point mutation can induce a change of the phosphoryl donor, it could be argued that the opposite mutation could also take place, thereby converting a PPi-PFK into an ATP-PFK. An example of such opposite mutation can be found in

.
RNA polymerase, 30kDa subunit, chordopox-type (RNA_pol_30_chordopoxvir-type)
Type: Family

All three classes of poxvirus genes -early, intermediate and late -are transcribed by the viral RNA polymerase compex . This complex is composed of nine distinct subunits which total more than 500kDa in mass. The two largest subunits (147 and 136kDa) are homologous to the largest subunits of eukaryotic and prokaryotic RNA polymerases and, like them, are thought to form a claw-shaped structure whose cleft is the site of template interaction and phosphodiester bond formation. While the smaller subunits of poxvirus RNA polymerase show much less similarity, if any, to the smaller subunits of the eukaryotic and prokaryotic enzymes, it is thought that they may play a similar role in interacting with transcription factors.

This entry represents the 30kDa subunit of RNA polymerase from the chordopox branch of poxviruses . This subunit may have a role in RNA chain elongation.
Ap4A phosphorylase 1/2 (Ap4A_phos1/2)
Type: Family

This entry represents a group of ATP adenylyltransferases found in bacteria and lower eukaryotes which catalyse the interconversion of Ap4A to ATP and ADP . While these enzymes are thought to act primarily to break down Ap4A, there is evidence to suggest that in some circumstances they may also act in a biosynthetic role. Some variability in substrate range is apparent (e.g., the cyanobacterial enzyme can also utilise Ap3A as a substrate, while the Saccharomyces enzymes apparently cannot).

Proteins in this entry include Apa1 and Apa2 from budding yeasts. Apa1 is a bifunctional Diadenosine 5',5'''-P1,P4-tetraphosphate phosphorylase and ADP sulfurylase involved in catabolism of bis(5'-nucleosidyl) tetraphosphates . Apa2 is a Diadenosine 5',5'''-P1,P4-tetraphosphate phosphorylase II .
Fructose-1,6-bisphosphatase class 3 (FBPtase_class3)
Type: Family

Fructose 1,6-bisphosphatase catalyses the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate . This is an essential reaction in the process of gluconeogenesis, the process by which non-carbohydrate precursors are converted to glucose, and hence this enzyme is found almost universally. Enzyme activity can be regulated by a number of different mechanisms including AMP inhibition, cylic AMP-dependent phosphorylation and light-dependent-activation.

This entry represents the class 3 fructose 1,6-bisphosphatases . The Bacillus subtilis enzyme is inhibited by AMP, though this can be overcome by phosphoenolpyruvate, and is dependent on Mn(2+) . Mutants lacking this enzyme are apparently still able to grow on gluconeogenic growth substrates such as malate and glycerol.
S-adenosylmethionine decarboxylase, bacterial (S-AdoMet_deCO2ase_bac)
Type: Family

Polyamines such as spermidine and spermine are essential for cellular growth under most conditions, being implicated in a large number of cellular processes including DNA, RNA and protein synthesis. S-adenosylmethionine decarboxylase (AdoMetDC) plays an essential regulatory role in the polyamine biosynthetic pathway by generating the n-propylamine residue required for the synthesis of spermidine and spermine from putrescein . Unlike many amino acid decarboxylases AdoMetDC uses a covalently bound pyruvate residue as a cofactor rather than the more common pyridoxal 5'-phosphate. These proteins can be divided into two main groups which show little sequence similarity either to each other, or to other pyruvoyl-dependent amino acid decarboxylases: class I enzymes found in bacteria and archaea, and class II enzymes found in eukaryotes. In both groups the active enzyme is generated by the post-translational autocatalytic cleavage of a precursor protein. This cleavage generates the pyruvate precursor from an internal serine residue and results in the formation of two non-identical subunits termed alpha and beta which form the active enzyme.

This entry represents a set of known and predicted AdoMetDC enzymes from proteobacteria. The Escherichia coli enzyme is a heterooctamer composed of four alpha and four beta chains, and is dependent on mgnesium for activity .
Annexin A13 (ANX13)
Type: Family

The annexins (or lipocortins) are a family of proteins that bind to phospholipids in a calcium-dependent manner . The 12 annexins common to vertebrates are classified in the annexin A family and named as annexins A1-A13 (or ANXA1-ANXA13), leaving A12 unassigned in the official nomenclature. Annexins outside vertebrates are classified into families B (in invertebrates), C (in fungi and some groups of unicellular eukaryotes), D (in plants), and E (in protists) . Annexins are absent from yeasts and prokaryotes .

Most eukaryotic species have 1-20 annexin (ANX) genes. All annexins share a core domain made up of four similar repeats, each approximately 70 amino acids long . Each individual annexin repeat (sometimes referred to as endonexin folds) is folded into five α-helices, and in turn are wound into a right-handed super-helix; they usually contain a characteristic 'type 2' motif for binding calcium ions with the sequence 'GxGT-[38 residues]-D/E'. Animal and fungal annexins also have variable amino-terminal domains. The core domains of most vertebrate annexins have been analysed by X-ray crystallography, revealing conservation of their secondary and tertiary structures despite only 45-55% amino-acid identity among individual members. The four repeats pack into a structure that resembles a flattened disc, with a slightly convex surface on which the Ca2+ -binding loops are located and a concave surface at which the amino and carboxyl termini come into close apposition.

Annexins are traditionally thought of as calcium-dependent phospholipid-binding proteins, but recent work suggests a more complex set of functions. The family has been linked with inhibition of phospholipase activity, exocytosis and endocytosis, signal transduction, organisation of the extracellular matrix, resistance to reactive oxygen species and DNA replication .

This entry represents Type XIII annexin. Screening of a cDNA library with intestine-specific sequences revealed a cDNA deriving from apparently gut-specific mRNA. Subsequent analysis revealed that this encoded a 316-residue protein belonging to the annexin/ lipocortin family (specifically, annexin XIII). Type XIII annexin is also referred to as intestine-specific annexin (ISA) .
Erythropoietin receptor (Erythropoietin_rcpt)
Type: Family

A number of receptors for lymphokines, hematopoietic growth factors and growth hormone-related molecules have been found to share a common binding domain. These receptors are designated as hematopoietin receptors and the corresponding ligands as hematopoietins. Further, hematopoietins have been subdivided into two major structural groups: Large/long and small/short hematopoietins.

Several receptor chains for large hematopoietins are structurally related such that their extracellular parts strictly contain the 200 amino-acids hematopoietin domain, duplicated in the thrombopoietin receptor and in avian prolactin receptors. This subgroup of receptor chains contains: Growth hormone receptor (GHR), Prolactin receptor (PRLR), Erythropoietin receptor (EPOR), Thrombopoietin receptor (TPOR).

A schematic representation of the structure of these receptors is shown below:

+----------------------------------------xxxxxxx-------------------------+
| C C C C Extracellular XXXXXXX Cytoplasmic |
+-|-|-------|--|-------------------------xxxxxxx-------------------------+
| | | | Transmembrane
+-+ +--+

These receptor chains are single components of receptors that homodimerise upon binding of the cognate cytokine, following the structural model described for the growth hormone-receptor complex .

This entry describes receptors for erythropoietin (EPO), a plasma glycoprotein, which is the primary physiological mediator of erythrocite production . They are expressed in relatively mature erythroid progenitor cells and in EPO-responsive erythroleukemia cells, and their physiological role is to mediate erythropoietin-induced erythroblast proliferation and differentiation. The receptors dimerise upon stimulation, triggering the JAK2/STAT5 signalling cascade .
Calreticulin (Calreticulin)
Type: Family

Calreticulin is a ubiquitous protein found in a wide range of species and in all nucleated cell types. It is an ancient and highly conserved protein with an exceptionally wide scope and variety of functions. Initially known as the high-affinity calcium-binding endoplasmic reticulum (ER) and sarcoplamic reticulum (SR) protein "calregulin", calreticulin is now known to associate with proteins in the cytoplasm, nucleus and extracellular compartment.

Calreticulin is a major Ca
2
-binding/storage chaperone residing in the ER lumen . Molecular chaperones residing in the ER facilitate the folding and prevent the aggregation of newly synthesized proteins. Interaction between the molecular chaperone and the misfolded protein leads to the retention, retranslocation and eventual degradation of the misfolded protein by the proteasome after ubiquitination . Calreticulin binds (buffers) Ca
2
with high capacity and participates in folding newly synthesized proteins and glycoproteins. It is an important component of the calreticulin/calnexin cycle and quality control pathways in the ER . Studies on calreticulin-deficient and calreticulin-transgenic mice revealed that calreticulin is a new cardiac embryonic gene and is essential during cardiac development . Calreticulin has also been characterised as an extracellular lectin, an intracellular mediator of integrin-mediated cell adhesion, an inhibitor of steroid hormone-regulated gene expression and a C1q-binding protein .

A proposed model of calreticulin domains includes a globular N-domain, a central proline-rich P-domain and an acidic C-domain. A detailed structure of the central P-domain was revealed by NMR studies, while a model of the globular N-domain of calreticulin is based on crystallographic data reported for the highly similar calnexin .

Calreticulin is also known as calregulin, Erp60, CRP55, CAB-63 and CaBP3 .
PR domain zinc finger protein 2 (PRDM2)
Type: Family

PRDM2 (also known as RIZ) is a transcriptional regulator and tumour suppressor that catalyzes methylation of lysine 9 of histone H3. Its PR domain is responsible for its catalytic activity . PRDM2 belongs to the PRDM family, whose members are characterised by the presence of an N-terminal PR (PRDI-BF1 and RIZ1 homology) domain followed by multiple zinc fingers which confer DNA binding activity. PR domains are only distantly related to the classical SET methyltransferase domains . PRDM2 interacts with another tumour suppressor, the retinoblastoma protein (Rb). A short motif, IRCDE, in the acidic region (AR) of RIZ is important for this interaction .
Orthopoxvirus C13 (Orthopox_C13)
Type: Family

This group represents an uncharacterised conserved protein belonging to the poxvirus C13 family . Members of this protein family are also known as Protein OPG209.
Chemokine-binding protein, viral (Chemkine-bd_vir)
Type: Family

This entry includes a group of chemokine binding proteins, including C23L from Vaccinia virus. C23L inhibits host immune defense by binding to host chemokines. It binds host CC chemokines (beta chemokines) such as RANTES with high affinity, but not CXC or C chemokines (alpha and gamma chemokines). This entry also includes the truncated/inactive chemokine-binding proteins, which is presumably inactive, because the lack of signal peptide prevents the protein of being secreted .
Orthopoxvirus, Protein K7 (Orthopox_K7)
Type: Family

This family represents Protein K7 from Orthopoxvirus. K7 is Bcl-2-like protein which, through its interaction with the DEAD box RNA helicase DDX3X/DDX3, prevents TBK1/IKKepsilon-mediated IRF3 activation . It contributes to virulence by binding to the host TRAF6 and IRAK2 and preventing host NF-kappa-B activation and affects the acute immune response to infection . In vaccinia virus, this protein has been related to the increase in cellular histone methylation during infection .
Poxvirus I2 (Poxvirus_I2)
Type: Family

This entry represents Protein I2 from Vaccinia virus, also known as Protein OPG078, and similar sequences from poxvirus. I2 is a late protein which probably plays a role in virus entry into the host cell .
Vaccinia virus, B7/C8 (Vaccinia_virus_B7/C8)
Type: Family

This entry is represented by the Vaccinia virus, B7 and C8 proteins; they are families of uncharacterised viral proteins. B7, also known as Protein OPG192, resides in the host endoplasmic reticulum .
Orthopoxvirus C5 (Orthopox_C5)
Type: Family

This group represents uncharacterised conserved proteins belonging to the poxviruses C5 family. C5 is also known as Protein OPG030.
Protein E3 (E3L)
Type: Family

RNA-binding protein E3 from Vaccinia virus (E3L, also known as RNA-binding protein OPG065) is a dsRNA-binding protein capable of inhibiting protein kinase R and is an effective IRF3 and -7 phosphorylation inhibitor . It inhibits NF-kappa-B activation and the ubiquitin-like protein ISG15, which is an early antiviral protein . The C terminus of E3 binds to double-stranded RNA (dsRNA), while the N-terminal Z-nucleic acid binding domain of E3 is required for the additional regulation of eIF2alpha phosphorylation and the recognition and binding of Z-RNA structures. RNA-binding activity is required to escape host ZBP1-dependent necroptosis .

Protein E3 from Variola virus is also included in this family. It plays a role in the inhibition of multiple cellular antiviral responses activated by dsRNA, such as inhibition of PKR activation, apoptosis, and IFN-mediated antiviral activities .
Methanogenesis marker 8 protein (Methan_mark_8)
Type: Family

The exact function of this protein is unknown, but likely is linked to methanogenesis or a process closely connected to it .
Uncharacterised conserved protein UCP004962 (UCP004962)
Type: Family

There are currently no experimental data for members of this group of archaeal proteins, nor do they exhibit features indicative of any function.
Predicted nucleotidyltransferase (Nucleotidl_trans)
Type: Family

Detailed sequence analysis suggests that members of this family represent the minimal domain of the PolB nucleotidyltransferase superfamily . The conservation of the nucleotidyltransferase core and particularly the negatively charged metal-chelating residues lead to the prediction that members of this family possess nucleotidyltransferase activity. Their small size, however, leaves very little beyond the core catalytic domain to help in specific substrate recognition as seen in other, larger members of the PolB superfamily . The conserved region of the MNTs ("minimal" nucleotidyltransferases) includes approximately 90 amino acid residues that correspond to the core domain of kanamycin nucleotidyltransferase . A structural model of the MNT domain has been proposed .
Predicted nickel metalloenzyme maturation factor, AIR synthase-related (Ni_metllenz_mat)
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 .

One such group of accessory proteins is represented by

, whose members are from archaea and are required for hydrogenase maturation (though their exact function is still unknown). Proteins from this family have similar sequences to

members. Thus, members of this family are predicted to play a role in maturation of some nickel metalloenzyme(s). However, other functions can not be ruled out. Both this family and

are related to proteins that use both purine derivatives and ATP as substrates. They belong to a superfamily of AIR synthase-related proteins that also includes PurM phosphoribosylaminoimidazole synthetase (AIR synthase), thiamine monophosphate kinase (

), phosphoribosylformylglycinamidine synthase (FGAM synthase,

), and selenophosphate synthase (selenide, water dikinase). They all contain two conserved domains and seem to dimerize. The N-terminal domain forms the dimer interface and is a putative ATP binding domain .
Non-homologous end joining protein Ku, prokaryotic type (Prok_Ku)
Type: Family

This superfamily consists of prokaryotic Ku domain containing proteins. In the eukaryotes it has been shown that the Ku protein is involved in repairing DNA double-strand breaks by non-homologous end-joining . The Ku protein is a heterodimer of approximately 70kDa and 80kDa subunits . Both these subunits have strong sequence similarity and it has been suggested that they may have evolved by gene duplication from a homodimeric ancestor in eukaryotes . The prokaryotic Ku members are homodimers and they have been predicted to be involved in the DNA repair system, which is mechanistically similar to eukaryotic non-homologous end joining . Recent findings have implicated yeast Ku in telomeric structure maintenance in addition to on-homologous end-joining. Some of the phenotypes of the Ku-knockout mice may indicate a similar role for Ku at mammalian telomeres .

Ιt is difficult to determine the correct evolutionary trajectory of the Ku domain. It is possible that the core Ku domain was present in bacteria and archaea even before the presence of the eukaryotes. Eukaryotes might have vertically inherited the Ku-core protein, from a common ancestor shared with a certain archaeal lineage or through horizontal transfer from bacteria. Alternatively, the core Ku domain could have evolved in the eukaryotic lineage and then horizontally transferred to the prokaryotes. Sequencing of additional archaeal genomes and those of early-branching eukaryotes may help resolving the evolutionary history of the Ku domain.

The eukaryotic Ku heterodimer comprises an α/β N-terminal, a central β-barrel domain and a helical C-terminal arm . Structural analysis of the Ku70/80 heterodimer bound to DNA indicate that subunit contacts lead to the formation of a highly charged channel through which the DNA passes without making any contacts with the DNA bases .

For additional information please see .