SII-SWORD/CoKE huggingface dataset:
ATP-dependent 6-phosphofructokinase, prokaryotic-type (ATP_PFK_prok-type)
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 .

The bacterial PFKs of this group are usually allosterically activated by ADP and inhibited by phosphoenolpyruvate . They belong to the PFK domain superfamily of proteins, which also includes pyrophosphate (PPi)-dependent PFKs (

) and eukaryotic ATP-dependent PFKs (

). The membership of this group largely resembles group B1 and III PFKs .

Classification of PFK proteins revealed that major functional specialisation 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. It has been hypothesised 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

.
Pyrophosphate-dependent phosphofructokinase TP0108-type (PyroP-dep_PFK_TP0108)
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 family consists of a group of plant and bacterial pyrophosphate-dependent phosphofructokinases related to TP0108 from Treponema . The bacterial versions are non-allosteric dimers, while the plant versions are allosteric heterotetramers . They belong to the PFK domain superfamily of proteins, which also includes prokaryotic (

) and eukaryotic ATP-dependent PFKs (

). The membership of this group largely resembles group B1 PFKs .
tRNA nucleotidyltransferase, proteobacteria (CCA_bact)
Type: Family

This family predominantly consists of bacterial versions of tRNA adenylyltransferases. tRNA nuceotidyltransferases are responsible for the synthesis or repair of the 3' terminal CCA sequence of tRNA molecules. They are encoded by essential genes in almost all organisms and add the three ribonucleotides C, C, and A to the 3' end of tRNAs in sequential order. Most members of this family contain an additional metal dependent phosphohydrolase domain (HD). Although the precise functional role of this domain is undetermined, the demonstration in Escherichia coli of 2',3'-cyclic phosphodiesterase, 2'-nucleotidase, and phosphatase activities has led to the suggestion that it is involved in the repair of the CCA terminus .

For additional information please see .
Serine/threonine-protein phosphatase with EF-hands (Ser/Thr-Pase_EF-hand_contain)
Type: Family

This well-conserved family of animal EF-hand-containing serine/threonine protein phosphatases functions in diverse sensory neurons. The protein comprises an IQ calmodulin-binding region, a metallo-phosphoesterase domain (

) of the serine/threonine-specific protein phosphatase and bis(5-nucleosyl)-tetraphosphatase type, and a C-terminal extension with three calcium-binding EF-hand motifs.

The prototype protein is the product of the fruit fly rdgC gene, which is required to prevent light-induced retinal degeneration . There are two homologous mammalian genes, PPEF1 and PPEF2. Although no essential role has been identified, PPEF2 is expressed in retinal rod photoreceptors, where it assumes several splice forms, and in the pineal gland. PPEF1 is expressed in photosensory neurons and inner ear cells in the developing mouse .
Urease, gamma subunit (Urease_gamma)
Type: Family

Urease (urea amidohydrolase,

) is a nickel-dependent metalloenzyme that catalyses the hydrolysis of urea to form ammonia and carbon dioxide. Nickel-dependent ureases are found in bacteria, archaea, fungi and plants. Their primary role is to allow the use of external and internally-generated urea as a nitrogen source. The enzyme consists of three subunits, alpha, beta and gamma, which can exist as separate proteins or can be fused on a single protein chain. The α-β-γ heterotrimer forms multimers, mainly trimers. The subunit composition of urease from different sources varies , but each holoenzyme consists of four domains : three structural domains and a nickel-binding catalytic domain common to amidohydrolases .

In Klebsiella aerogenes, urease exists as an alpha, beta and gamma subunit, with the alpha subunit possessing the catalytic domain. In Helicobacter pylori, the gamma and beta subunits are fused and called the alpha subunit, while the catalytic subunit is called the beta subunit. In Canavalia ensiformis, urease has a fused gamma-beta-alpha organisation.

This entry represents the urease gamma subunit.
Integrin beta-4 subunit (Integrin_bsu-4)
Type: Family

The beta 4 subunit differs from other beta subunits in three ways: 1) the cytoplasmic domain is larger; 2) it lacks some of the conserved cysteines in the extracellular domain; and 3) it has a unique domain organisation.

Integrin alpha-6/beta-4 is a receptor for laminin. It plays a critical structural role in the hemidesmosome of epithelial cells . Integrin beta-4 is required for the regulation of keratinocyte polarity and motility .

For additional information please see .

Integrins are the major metazoan receptors for cell adhesion to extracellular matrix proteins and, in vertebrates, also play important roles in certain cell-cell adhesions, make transmembrane connections to the cytoskeleton, and activate many intracellular signalling pathways . An integrin receptor is a heterodimer composed of alpha and beta subunits. Each subunit crosses the membrane once, with most of the polypeptide residing in the extracellular space, and has two short cytoplasmic domains. Some members of this family have EGF repeats at the C terminus and also have a VWA domain inserted within the integrin domain at the N-terminal.

Most integrins recognise relatively short peptide motifs and, in general, require an acidic amino acid to be present. Ligand specificity depends upon both the alpha and beta subunits . There are at least 18 types of alpha and 8 types of beta subunits recognised in humans . Each alpha subunit tends to associate only with one type of beta subunit, but there are exceptions to this rule . Each association of alpha and beta subunits has its binding specificity and signalling properties. Many integrins require activation on the cell surface before they can bind ligands. Integrins frequently intercommunicate, and binding at one integrin receptor activates or inhibits another.
Retroelement-encoded protein, env-related (Retroelement_env)
Type: Family

Members of this group are encoded by LTR-retrotransposons and have sequence similarity to env genes of retroviruses . ZAM and Idefix are two LTR-retrotransposons from Drosophila melanogaster and are similar in structure to vertebrate retroviruses. In most strains where the distribution has been studied, ZAM appears to be present exclusively in the intercalary heterochromatin, while Idefix copies are mainly found in the centromeric heterochromatin with very few copies in euchromatin . However, ZAM and Idefix have been noted to accumulate at a defined site in the D. melanogaster RevI strain . Like ZAM, Idefix displays the structural features of a vertebrate retrovirus. Its three open reading frames encode predicted products resembling the products of the gag, pol, and env genes of retroviruses .
Uncharacterised conserved protein HTH transcriptional regulator, archaea (UCP_HTH_arc)
Type: Family

This family consists of functionally uncharacterised proteins, which contain an N-terminal HTH (Winged helix-turn-helix) DNA-binding domain.
Phosphomevalonate dehydratase small subunit-like (PMDh-S-like)
Type: Family

This entry represents Phosphomevalonate dehydratase small subunit from Aeropyrum pernix (PMDh-S) and similar prokaryotic proteins. PMDh-S is a component of a hydro-lyase that catalyses the dehydration of mevalonate 5-phosphate (MVA5P) to form trans-anhydromevalonate 5-phosphate (tAHMP) . It is involved in the archaeal mevalonate (MVA) pathway, which provides fundamental precursors for isoprenoid biosynthesis, such as isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) . Members of this family were previously annotated as aconitase X subunit 2, the swiveling domain subunit .
Origin-associated protein OapB-like (OapB-like)
Type: Family

This entry includes archaeal proteins whose function is unclear. Some members of this entry have been described as OapB/Arvb, encoded by oapB gene which is part of the three-gene cluster oapABC (origin-associated proteins), involved in generation of extracellular vesicles (arv, archaeal vesiculating GTAse) . It has been suggested that OapB/ArvB could be a guanine nucleotide exchange factor (GEF), however, further experimental research is required to confirm this .
FeGP cofactor biosynthesis protein HcgB, guanylyltransferase (HcgB)
Type: Family

This entry represents the guanylyltransferase component of the Iron-guanylylpyridinol (FeGP) cofactor biosynthesis protein HcgB . HcgB transfers the guanosine monophosphate (GMP) moiety from guanosine triphosphate (GTP) to a pyridinol precursor .
AB hydrolase 4 family (ABHD4)
Type: Family

This entry represents a group of abhydrolase domain-containing proteins, including mammalian ABHD1/2/3/15 and budding yeast Eht1, Eeb1 and YMR210W.

Human ABHD3 is a phospholipase that may play a role in phospholipids remodeling. It may selectively cleave myristate (C14)-containing phosphatidylcholines through its predominant phospholipase 1 activity, cleaving preferentially acyl groups in sn1 position . Mouse ABHD2 may play a role in smooth muscle cells migration .

Yeast Eht1 and its paralogue, Eeb1, are Acyl-coenzymeA:ethanol O-acyltransferases involved in medium-chain fatty acid ethyl ester biosynthesis during fermentation . YMR210W does not seem to play an important role in medium-chain fatty acid ethyl ester formation .
Uncharacterised conserved protein UCP005278 (UCP005278)
Type: Family

There are currently no experimental data for members of this group or their homologues, nor do they exhibit features indicative of any function.
Protein of unknown function UCP005295 (UCP005295)
Type: Family

Members of this group are predicted to be metal-dependent hydrolases based on sequence analysis. They are related to Mg-dependent DNases and contain a TadD DNase domain. However, the similarity is not strong enough to confidently predict that these proteins are necessarily DNases and not some other type of metal-dependent hydrolase. Another related group is the TatD deoxyribonuclease family.

Members of this group may be distantly related to a large 3D fold-based domain superfamily of metalloenzymes . The description of this fold superfamily was based on an analysis of conservation patterns in three dimensions, and the discovery that the same active-site architecture occurs in a large set of enzymes involved primarily in nucleotide metabolism. The group is thought to include urease, dihydroorotase, allantoinase, hydantoinase, AMP-, adenine- and cytosine- deaminases, imidazolonepropionase, aryldialkylphosphatase, chlorohydrolase, formylmethanofuran dehydrogenase, and other enzymes .
Methanogenesis marker 6 protein (Methan_mark_6)
Type: Family

The exact functionof this protein unknown, but likely is linked to methanogenesis or a process closely connected to it.
Formylmethanofuran dehydrogenase, subunit A (Formylmethanofuran_DH_asu)
Type: Family

Formylmethanofuran dehydrogenase (

) is found in methanogenic and sulphate-reducing archaea. The enzyme contains molybdenum or tungsten, a molybdopterin guanine dinuceotide cofactor (MGD) and iron-sulphur clusters . It catalyses the reversible reduction of CO
2
and methanofuran via N-carboxymethanofuran (carbamate) to N-formylmethanofuran, the first and second steps in methanogenesis from CO
2
. This reaction is important for the reduction of CO
2
to methane, in autotrophic CO
2
fixation, and in CO
2
formation from reduced C
1
units . The synthesis of formylmethanofuran is crucial for the energy metabolism of archaea. Methanogenic archaea derives the energy for autrophic growth from the reduction of CO
2
with molecular hydrogen as the electron donor . The process of methanogenesis consists of a series of reduction reactions at which the one-carbon unit derived from CO
2
is bound to C
1
carriers.

There are two isoenzymes of formylmethanofuran dehydrogenase: a tungsten-containing isoenzyme (Fwd) and a molybdenum-containing isoenzyme (Fmd). The tungsten isoenzyme is constitutively transcribed, whereas transcription of the molybdenum operon is induced by molybdate . The archaean Methanobacterium thermoautotrophicum contains a 4-subunit (FwdA, FwdB, FwdC, FwdD) tungsten formylmethanofuran dehydrogenase and a 3-subunit (FmdA, FmdB, FmdC) molybdenum formylmethanofuran dehydrogenase .

This entry represents subunit A (FmdA and FwdA) of formylmethanofuran dehydrogenases. The other subunits are subunit B (

), subunit C (

), subunit D (

), subunit E (

), and subunit F. Some organisms also encode a fusion of the C and D subunits(

). Members of this entry share sequence similarity with the two highly conserved regions of dihydroorotase (

) (an amidohydrolase): the first is located at the N-terminal end and contains two histidine residues suggested to be involved in binding a zinc ion ; the second conserved region is at the C terminus .

In Methylobacterium extorquens, homologues of FmdA, FmdB and FmdC subunits were found and shown to copurify with a functional formyltransferase complex. However, there is no evidence that the complex catalyses the oxidation of formylmethanofuran .

Methanogenic bacteria and archea derive the energy for autotrophic growth from methanogenesis, the reduction of CO2 with molecular hydrogen as the electron donor. FMDH catalyzes the first step in methanogenesis, the formyl-methanofuran synthesis. In this step, CO2 is bound to methanofuran and subsequently reduced to the formyl state with electrons derived from hydrogen .
Uncharacterised conserved protein UCP006529, dinucleotide-utilising ThiF/HesA (UCP006529_dinclt)
Type: Family

Members of this group contain a divergent form of a domain based on the common NAD/FAD-binding fold. Its various forms are found in a wide range of enzymes, including ubiquitin-activating enzymes and NAD/FAD-dependent dehydrogenases and oxidases (

). Members are distantly related to the HesA/MoeB/ThiF group of NAD/FAD-binding fold enzymes.

Hmd co-occurring protein HcgE from Methanothermobacter marburgensis, an adenylyltransferase that forms AMP-guanylylpyridinol from ATP and guanylylpyridinol , also belongs to this protein family.
Uncharacterised conserved protein UCP006557 (UCP006557)
Type: Family

This family of hypothetical archaeal proteins has no known function.
Uncharacterised conserved protein UCP006563 (UCP006563)
Type: Family

There are currently no experimental data for members of this group or their homologues, nor do they exhibit features indicative of any function.
MTH0776-like (MTH0776-like)
Type: Family

This entry represents a family of archaeal proteins with an important role in methanogenesis, including MTH0776 from Methanobacterium thermoautotrophicum. This protein assume an α-β globular structure consisting of six β-strands and three α-helices forming the secondary structural topological arrangement of α1-β1-α2-β2-β3-β4-β5-β6-α3 .
Uncharacterised conserved protein UCP006598 (UCP006598)
Type: Family

There are currently no experimental data for members of this group or their homologues, nor do they exhibit features indicative of any function.
Uncharacterised conserved protein UCP006600 (UCP006600)
Type: Family

There are currently no experimental data for members of this group or their homologues, nor do they exhibit features indicative of any function. The structure of the Methanothermobacter thermautotrophicus (Methanobacterium thermoformicicum) protein has been determined but no evidence of the function is available yet.
Bacteriophage Mu, Probable terminase, large subunit gp28 (Phage_Mu_Gp28)
Type: Family

This entry represents Probable terminase, large subunit gp28 from the Bacteriophage Mu and similar proteins from tailed bacteriophages and prophages from Proteobacteria. Gp28 may be related to viral DNA translocation into empty capsids and act as an endonuclease that cuts the viral genome to initiate and to end a packaging reaction.
Alpha/beta-hydrolase family (Alpha/beta-hydrolase_fam)
Type: Family

This is a family of α/β hydrolases which may function as lipases. This domain is the catalytic domain and includes the catalytic triad and the GXSXG sequence motif which is a characteristic of these enzymes .
Uncharacterised conserved protein UCP009471 (UCP009471)
Type: Family

There are currently no experimental data for members of this group or their homologues, nor do they exhibit features indicative of any function.
Uncharacterised conserved protein UCP012281 (UCP012281)
Type: Family

There are currently no experimental data for members of this group or their homologues, nor do they exhibit features indicative of any function.
Formylmethanofuran dehydrogenase, subunit D (Formylmethanofuran_DH_dsu)
Type: Family

Formylmethanofuran dehydrogenase (

) is found in methanogenic and sulphate-reducing archaea. The enzyme contains molybdenum or tungsten, a molybdopterin guanine dinuceotide cofactor (MGD) and iron-sulphur clusters . It catalyses the reversible reduction of CO
2
and methanofuran via N-carboxymethanofuran (carbamate) to N-formylmethanofuran, the first and second steps in methanogenesis from CO
2
. This reaction is important for the reduction of CO
2
to methane, in autotrophic CO
2
fixation, and in CO
2
formation from reduced C
1
units . The synthesis of formylmethanofuran is crucial for the energy metabolism of archaea. Methanogenic archaea derives the energy for autrophic growth from the reduction of CO
2
with molecular hydrogen as the electron donor . The process of methanogenesis consists of a series of reduction reactions at which the one-carbon unit derived from CO
2
is bound to C
1
carriers.

There are two isoenzymes of formylmethanofuran dehydrogenase: a tungsten-containing isoenzyme (Fwd) and a molybdenum-containing isoenzyme (Fmd). The tungsten isoenzyme is constitutively transcribed, whereas transcription of the molybdenum operon is induced by molybdate . The archaean Methanobacterium thermoautotrophicum contains a 4-subunit (FwdA, FwdB, FwdC, FwdD) tungsten formylmethanofuran dehydrogenase and a 3-subunit (FmdA, FmdB, FmdC) molybdenum formylmethanofuran dehydrogenase .

This entry represents subunit D (FmdD and FwdD) of formylmethanofuran dehydrogenase. The other subunits are subunit A (

), subunit B (

), subunit C (

), subunit E (

), subunit F. Some organisms also encode a fusion of the C and D subunits (

).

Members of this entry contain a molybdopterin dinucleotide binding domain. This domain is found in various molybdopterin-containing oxidoreductases. It corresponds to the C-terminal domain IV of dimethyl sulphoxide (DMSO) reductase, which interacts with the 2-amino pyrimidone ring of both molybdopterin guanine dinucleotide molecules ; it is also found in formate dehydrogenase alpha subunit (

), nitrate reductase Nap large subunit and some other dehydrogenases.
CPxCG-like zinc finger protein (Znf_CPxCG-like)
Type: Family

This family includes small CPxCG-related zinc finger archaeal proteins, which are thought to bind DNA and to be potential transcriptional regulators. These zinc fingers are characterised by the specific CPxCG pattern (variants CPxCx and CxxCG) and a second Cys/His pattern potentially more general, being 7-40 residues apart from each other. This family includes Nif-regulating protein A (Q8PW88) which contains the patterns CxxCG and HxxxH (the latter is unique to this protein and located 24 residues away from the CxxCG motif) to form the zinc finger motif. It is a DNA-binding protein involved in nitrogen regulation as it enhances the transcription of the nitrogen fixation (nif) operon under nitrogen-limited conditions .
Inorganic triphosphatase NeuTTM/CthTTM-like (NeuTTM/CthTTM-like)
Type: Family

This entry includes bacterial CYTH-domain containing proteins such as NeuTTM (

) from Nitrosomonas europaea and CthTTM (

) from Clostridium thermocellum They both have a high PPPase activity (though CthTM was less specific) but neither had any significant adenylyl cyclase activity .

CYTH domain proteins act on triphosphorylated substrates and require at least one divalent metal cation for catalysis .
Pantoate kinase (PoK)
Type: Family

This group of enzymes belongs to the GHMP kinase domain superfamily. Pantoate kinase (PoK) works with phosphopantothenate synthetase (PPS) in the coenzyme A (CoA) biosynthesis pathway in the Archaea. It phosphorylates (R)-pantoate to form (R)-4-phosphopantoate in the CoA biosynthesis pathway .
Peptidase M6, unassigned InhA-related (Pept_M6_InhA-rel)
Type: Family

This group of proteins are related to the secreted virulence peptidase InhA (

) and along with InhA belong to MEROPS peptidase family M6 (immune inhibitor A, clan MA). On the basis of sequence similarity, and a conserved HEXXHXXGXXD motif, where the two histidines and the aspartate are zinc ligands and the glutamate is the catalytic residue it can be predicted that all members are peptidases.
LytTR transcriptional regulator with ABC transporter ATP-binding domain (LytTR_ABC)
Type: Family

Members of this group combine the N-terminal ATP-binding domain of the ABC transporter family and a C-terminal LytTR DNA-binding domain . Accordingly, these proteins are predicted to be involved in transcriptional regulation and signal transduction, but the exact regulatory role, mode of signal transduction, and type of signal transmitted are unknown .
Aconitase X (AcnX)
Type: Family

Distant sequence similarity and comparative genomic analysis shows aconitase X (AcnX) is a subfamily of aconitase enzymes . However, Aconitase X (corresponding gene known as LhpI) is a cis-3-hydroxy-L-proline dehydratase containing mononuclear Fe(III), but not the [4Fe-4S] cluster. Bacteria with the LhpI gene could degrade cis-3-hydroxy-L-proline as the sole carbon source .