SII-SWORD/CoKE huggingface dataset:
Ribosomal RNA adenine dimethylase (rRNA_adenine_dimethylase)
Type: Family

The bacterial enzyme KsgA catalyses the transfer of a total of four methyl groups from S-adenosyl-l-methionine (S-AdoMet) to two adjacent adenosine bases in 16S rRNA. This enzyme and the resulting modified adenosine bases appear to be conserved in all species of eubacteria, eukaryotes, and archaea, and in eukaryotic organelles. Bacterial resistance to the aminoglycoside antibiotic kasugamycin involves inactivation of KsgA and resulting loss of the dimethylations, with modest consequences to the overall fitness of the organism . In contrast, the yeast ortholog, Dim1, is essential. In Saccharomyces cerevisiae (Baker's yeast), and presumably in other eukaryotes, the enzyme performs a vital role in pre-rRNA processing in addition to its methylating activity . Another orthologue is the eukaryotic transcription factor B (TFB), which has a second function; this enzyme is a nuclear-encoded mitochondrial transcription factor and is essential for mitochondrial gene expression . The best conserved region in these enzymes is located in the N-terminal section and corresponds to a region that is probably involved in S-adenosyl methionine (SAM) binding domain.
Bicarbonate transporter-like, transmembrane domain (HCO3_transpt-like_TM_dom)
Type: Domain

Bicarbonate (HCO
3
-
) transport mechanisms are the principal regulators of pH in animal cells. Such transport also plays a vital role in acid-base movements in the stomach, pancreas, intestine, kidney, reproductive organs and the central nervous system. Functional studies have suggested four different HCO
3
-
transport modes. Anion exchanger proteins exchange HCO
3
-
for Cl
-
in a reversible, electroneutral manner . Na
+
/HCO
3
-
co-transport proteins mediate the coupled movement of Na
+
and HCO
3
-
across plasma membranes, often in an electrogenic manner . Na
+
driven Cl
-
/HCO
3
-
exchange and K
+
/HCO
3
-
exchange activities have also been detected in certain cell types, although the molecular identities of the proteins responsible remain to be determined.

Sequence analysis of the two families of HCO
3
-
transporters that have been cloned to date (the anion exchangers and Na
+
/HCO
3
-
co-transporters) reveals that they are homologous. This is not entirely unexpected, given that they both transport HCO
3
-
and are inhibited by a class of pharmacological agents called disulphonic stilbenes . They share around ~25-30% sequence identity, which is distributed along their entire sequence length, and have similar predicted membrane topologies, suggesting they have ~10 transmembrane (TM) domains.

This entry represents transmembrane segments of bicarbonate transporters and related proteins.

In animals, this domain is found at the C terminus of many bicarbonate and similar multifunctional transporters. The crystal structure of Band 3 anion transport protein, the founding member of the solute carrier 4 (SLC4) family of bicarbonate transporters, has been solved. This protein functions both as a transporter that mediates electroneutral anion exchange across the cell membrane and as a structural protein .

Boron transporters from plants and yeast comprise only transmembrane segments, confirmed by the solved structures . In plants, boron is essential for maintaining the integrity of cell walls; this transporter mediates boron translocation from roots to shoots under boron limitation . Boron transporter 1 from Saccharomyces cerevisiae protects yeast cells from boron toxicity and is involved in the trafficking of proteins to the vacuole. The mechanism of its activity seems to be consistent with this described for other members of the family .
Sec-independent protein translocase TatC, archaeal (TatC_arc)
Type: Family

This entry represents the TatC translocase component of the Sec-independent protein translocation system in archaeal species. This system is responsible for translocation of folded proteins, often with bound cofactors across the periplasmic membrane .
Oxygen-dependent choline dehydrogenase (BetA)
Type: Family

Choline dehydrogenase catalyses the conversion of exogenously supplied choline into the intermediate glycine betaine aldehyde, as part of a two-step oxidative reaction leading to the formation of osmoprotectant betaine. This enzymatic system can be found in both Gram-positive and Gram-negative bacteria. As in Escherichia coli , Staphylococcus xylosus , and Rhizobium meliloti (Sinorhizobium meliloti) , this enzyme is found associated in a transcriptionally co-induced gene cluster with betaine aldehyde dehydrogenase, the second catalytic enzyme in this reaction. Other Gram-positive organisms have been shown to employ a different enzymatic system, utilising a soluble choline oxidase or type III alcohol dehydrogenase instead of choline dehydrogenase .
This enzyme is a member of the GMC oxidoreductase family, sharing a common evolutionary origin and enzymatic reaction with alcohol dehydrogenase . Out grouping from this model, Caulobacter crescentus (Caulobacter vibrioides) shares sequence homology with choline dehydrogenase, yet other genes participating in this enzymatic reaction have not currently been identified.
Aspartate-semialdehyde dehydrogenase, gamma-type (Asp_ADH_gamma-type)
Type: Family

Bacteria, plants and fungi metabolise aspartic acid to produce four amino acids -lysine, threonine, methionine and isoleucine -in a series of reactions known as the aspartate pathway. Additionally, several important metabolic intermediates are produced by these reactions, such as diaminopimelic acid, an essential component of bacterial cell wall biosynthesis, and dipicolinic acid, which is involved in sporulation in Gram-positive bacteria. Members of the animal kingdom do not posses this pathway and must therefore acquire these essential amino acids through their diet. Research into improving the metabolic flux through this pathway has the potential to increase the yield of the essential amino acids in important crops, thus improving their nutritional value. Additionally, since the enzymes are not present in animals, inhibitors of them are promising targets for the development of novel antibiotics and herbicides. For more information see .

Aspartate-semialdehyde dehydrogenase (

), the second enzyme in the aspartate pathway, converts aspartyl phosphate to aspartate-semialdehyde, the branch point intermediate between the lysine and threonine/methionine pathways. Based on sequence alignments, the aspartate-semialdehyde dehydrogenase family appears to have at least three distinct subfamilies. Most studies have been performed on enzymes isolated from Gram-negative bacteria . The N-terminal domain forms the active site and NADP-binding pocket, while C-terminal domain is primarily involved in hydrophobic intersubunit contacts. The catalytic mechanism involves the formation of a covalent thioester acyl-enzyme intermediate mediated through nucleophilic attack by an active site cysteine residue on the substrate aspartyl phosphate. Release of inorganic phosphate is followed by hydride transfer from NADPH to yield the product. The recently described archaeal structure suggests that the two subgroups of aspartate semi-aldehyde dehydrogenase share similar structures and have an identical catalytic mechanism, despite their relatively low sequence identity . Unlike the bacterial enzymes, the archaeal enzyme utilised both NAD and NADP as cofactor.

This entry represents a subfamily of aspartate semialdehyde dehydrogenases found mostly, though not exclusively, in proteobacteria.
Ferredoxin 2Fe-2S type, proteobacteria (Fdx_isc)
Type: Family

At least three types of Fe-S cluster-biosynthesis systems are known: NIF, ISC and SUF . This family consists of proteobacterial ferredoxins associated with and essential to the ISC (iron-sulfur cluster) system of 2Fe-2S cluster assembly . This family is closely related to (but excludes) eukaryotic (mitochondrial) adrenodoxins, which are ferredoxins involved in electron transfer to P450 cytochromes.
NADH ubiquinone oxidoreductase, F subunit (NADH-UbQ_OxRdtase_suF)
Type: Family

This entry describes the F subunit of complexes that resemble NADH-quinone oxidoreductases. The electron acceptor is a quinone, ubiquinone, in mitochondria and most bacteria, including Escherichia coli, where the recommended gene symbol is nuoF. This family does not have any members in chloroplast or cyanobacteria, where the quinone may be plastoquinone and NADH may be replaced by NADPH, nor in Methanosarcina, where NADH is replaced by F420H2.
NADH-ubiquinone oxidoreductase 51kDa subunit, FMN-binding domain (Nuo51_FMN-bd)
Type: Domain

This entry represents the FMN-binding domain of NADH-ubiquinone oxidoreductase 51kDa subunit from NADH:ubiquinone oxidoreductase.

Among the many polypeptide subunits that make up complex I, there is one with a molecular weight of 51kDa (in mammals), which is the second largest subunit of complex I . The 51kDa subunit, as the corresponding bacterial subunit (Nqo1 in Thermus and NuoF in E. coli) , contains the NADH-binding site, the primary electron acceptor FMN-binding site, and a 4Fe-4S cluster .
Rel homology domain, DNA-binding domain (RHD_DNA_bind_dom)
Type: Domain

The Rel homology domain (RHD) is found in a family of eukaryotic transcription factors, which includes NF-kappaB, Dorsal, Relish, NFAT, among others. The RHD is composed of two structural domains that grip the DNA in the major groove: the N-terminal DNA binding domain and the C-terminal domain, which has an immunoglobulin-like fold (See

). This entry represents the N-terminal DNA binding domain, whose specificity domain resembles the core domain of the p53 transcription factor, and contains a recognition loop that interacts with DNA bases. The C-terminal dimerisation domain contains the site for interaction with I-kappaB .
AbgT, Proteobacteria (AbgT_Proteobac)
Type: Family

AbgT catalyzes the concentration-dependent uptake of p-aminobenzoyl-glutamate (PABA-GLU) into cells. This allows accumulation of PABA-GLU to a concentration enabling AbgAB to catalyze cleavage into p-aminobenzoate and glutamate .

This entry represents a clade of AbgT proteins from Proteobacteria.
Nickel/cobalt transporter, high-affinity (Ni/Co_transpt_high_affinity)
Type: Family

High affinity nickel transporters are involved in the incorporation of nickel into H2-uptake hydrogenase and urease enzymes and are essential for the expression of catalytically active hydrogenase and urease. Ion uptake is dependent on proton motive force. HoxN in Ralstonia eutropha (Alcaligenes eutrophus) is thought to be an integral membrane protein with seven transmembrane helices . The transporter RcnA has been implicated in Ni(II) and Co(II) detoxification in E. coli, probably through efflux .
SUF system FeS cluster assembly, SufD (SUF_FeS_clus_asmbl_SufD)
Type: Family

Iron-sulphur (FeS) clusters are important cofactors for numerous proteins involved in electron transfer, in redox and non-redox catalysis, in gene regulation, and as sensors of oxygen and iron. These functions depend on the various FeS cluster prosthetic groups, the most common being [2Fe-2S] and [4Fe-4S] . FeS cluster assembly is a complex process involving the mobilisation of Fe and S atoms from storage sources, their assembly into [Fe-S] form, their transport to specific cellular locations, and their transfer to recipient apoproteins. So far in bacteria, three FeS assembly machineries have been identified that are capable of synthesising all types of [Fe-S] clusters: ISC (iron-sulphur cluster), SUF (sulphur assimilation), and NIF (nitrogen fixation) systems.

The ISC system is conserved in eubacteria and eukaryotes (mitochondria) and has broad specificity, targeting general FeS proteins . It is encoded by the isc operon (iscRSUA-hscBA-fdx-iscX). IscS is a cysteine desulphurase, which obtains S from cysteine (converting it to alanine) and serves as a S donor for FeS cluster assembly. IscU and IscA act as scaffolds to accept S and Fe atoms, assembling clusters and transferring them to recipient apoproteins. HscA is a molecular chaperone and HscB is a co-chaperone. Fdx is a [2Fe-2S]-type ferredoxin. IscR is a transcription factor that regulates expression of the isc operon. IscX (also known as YfhJ) appears to interact with IscS and may function as an Fe donor during cluster assembly .

The SUF system is an alternative pathway to the ISC system that operates under iron starvation and oxidative stress. It is found in eubacteria, archaea and eukaryotes (plastids). The SUF system is encoded by the suf operon (sufABCDSE), and the six encoded proteins are arranged into two complexes (SufSE and SufBCD) and one protein (SufA). SufS is a pyridoxal-phosphate (PLP) protein displaying cysteine desulphurase activity. SufE acts as a scaffold protein that accepts S from SufS and donates it to SufA . SufC is an ATPase with an unorthodox ATP-binding cassette (ABC)-like component. SufA is homologous to IscA , acting as a scaffold protein in which Fe and S atoms are assembled into [FeS] cluster forms, which can then easily be transferred to apoprotein targets.

In the NIF system, NifS and NifU are required for the formation of metalloclusters of nitrogenase in Azotobacter vinelandii, and other organisms, as well as in the maturation of other FeS proteins. Nitrogenase catalyses the fixation of nitrogen. It contains a complex cluster, the FeMo cofactor, which contains molybdenum, Fe and S. NifS is a cysteine desulphurase. NifU binds one Fe atom at its N-terminal, assembling an FeS cluster that is transferred to nitrogenase apoproteins . Nif proteins involved in the formation of FeS clusters can also be found in organisms that do not fix nitrogen .

This entry represents SufD proteins that form part of the SufBCD complex in the SUF system. No specific functions have been assigned to these proteins.
Restriction endonuclease, type II, BglI (Restrct_endonuc_II_BglI)
Type: Domain

This entry represents the structural domain of restriction endonuclease BglI . BglI recognises GCCNNNNNGGC and cleave after N-4.
DEAD/DEAH-box helicase domain (DEAD/DEAH_box_helicase_dom)
Type: Domain

This entry represents the DNA-binding domain at the N-terminal in DEAD/DEAH box helicase and related proteins. This domain also contains motif III (S-A-T) which was proposed to participate in linking ATPase and helicase activities.

DEAD-box and DEAH-box RNA helicases are essential enzymes involved in the unwinding of nucleic acids, playing critical roles in RNA metabolism. The DEAD-box helicases, exemplified by the translation initiation factor eIF4A, are RNA-dependent ATPases that act as RNA helicases in conjunction with eIF4B. These proteins participate in a wide range of processes including nuclear transcription, pre-mRNA splicing, ribosome biogenesis, nucleocytoplasmic transport, translation, RNA decay and organellar gene expression. In contrast, DEAH-box helicases are primarily involved in pre-mRNA splicing and function as ATP-dependent RNA helicases .
Peptidase M41, FtsH extracellular (Pept_M41_FtsH_extracell)
Type: Domain

This domain is found in the FtsH family of proteins that include FtsH a membrane-bound ATP-dependent protease universally conserved in prokaryotes . The FtsH peptidases, which belong to MEROPS peptidase family M41 (clan MA(E)), efficiently degrade proteins that have a low thermodynamic stability - e.g. they lack robust unfoldase activity. This feature may be key and implies that this could be a criterion for degrading a protein. In Oenococcus oeni (Leuconostoc oenos) FtsH is involved in protection against environmental stress , and shows increased expression under heat or osmotic stress. These two lines of evidence suggest that it is a fundamental prokaryotic self-protection mechanism that checks if proteins are correctly folded. The precise function of this N-terminal region is unclear.

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 .
3-hydroxyisobutyrate dehydrogenase (HIBADH)
Type: Family

3-hydroxyisobutyrate dehydrogenase is an enzyme that catalyzes the NAD+-dependent oxidation of 3-hydroxyisobutyrate to methylmalonate semialdehyde of the valine catabolism pathway.

In Pseudomonas aeruginosa, 3-hydroxyisobutyrate dehydrogenase (mmsB) is co-induced with methylmalonate-semialdehyde dehydrogenase (mmsA) when grown on medium containing valine as the sole carbon source. The positive transcriptional regulator of this operon (mmsR) is located upstream of these genes and has been identified as a member of the XylS/AraC family of transcriptional regulators .
Riboflavin-specific deaminase, C-terminal (RibD_C)
Type: Domain

Eubacterial riboflavin-specific deaminases have a zinc-binding domain,

, toward the N terminus and this domain toward the C terminus. Yeast HTP reductase, a riboflavin-biosynthetic enzyme, and several archaeal proteins related to riboflavin biosynthesis consist only of this domain and lack the zinc-binding domain.
NTP pyrophosphohydrolase MazG (NTP_PyrPHydrolase_MazG)
Type: Family

Nucleoside triphosphate pyrophosphohydrolase MazG is a regulator of oxidative stress and nutritional stress responses . In Thermotoga maritima, it has both nucleoside triphosphate pyrophosphohydrolase and pyrophosphatase activities .
Tellurite resistance protein TehA/malic acid transport protein (TehA/Mae1)
Type: Family

This entry includes TehA from Escherichia coli and Malic acid transport protein (Mae1) from Schizosaccharomyces pombe. TehA has been implicated in resistance to tellurite . It has proflavin and ethidium efflux activity . Mae1 functions in the uptake of malate and other dicarboxylates by a proton symport mechanism. These proteins exhibit 10 putative transmembrane a-helical spanners (TMSs).
Translocation protein Sec62, ascomycota (Sec62_asco)
Type: Family

Members of the NSCC2 family have been sequenced from various fungal and animal species including Saccharomyces cerevisiae, Drosophila melanogaster and Homo sapiens. These proteins are the Sec62 proteins, believed to be associated with the Sec61 and Sec63 constituents of the general protein secretary systems of yeast microsomes. They are also the non-selective cation (NS) channels of the mammalian cytoplasmic membrane. The yeast Sec62 protein has been shown to be essential for cell growth. The mammalian NS channel proteins have been implicated in platelet derived growth factor(PGDF) dependent single channel current in fibroblasts. These channels are essentially closed in serum deprived tissue-culture cells and are specifically opened by exposure to PDGF. These channels are reported to exhibit equal selectivity for Na+, K+ and Cs+ with low permeability to Ca2+, and no permeability to anions.

This family of Sec62 proteins is found mainly in Ascomycota.
Hydroxymethylglutaryl-CoA synthase, prokaryotic (HMG_CoA_synthase_prok)
Type: Family

Hydroxymethylglutaryl-CoA synthase (

) catalyses the condensation of acetyl-CoA with acetoacetyl-CoA to produce HMG-CoA and CoA, the second reaction in the mevalonate-dependent isoprenoid biosynthesis pathway. HMG-CoA synthase contains an important catalytic cysteine residue that acts as a nucleophile in the first step of the reaction: the acetylation of the enzyme by acetyl-CoA (its first substrate) to produce an acetyl-enzyme thioester, releasing the reduced coenzyme A. The subsequent nucleophilic attack on acetoacetyl-CoA (its second substrate) leads to the formation of HMG-CoA .

HMG-CoA synthase occurs in eukaryotes, archaea and certain bacteria . In vertebrates, there are two isozymes located in different subcellular compartments: a cytosolic form that is the starting point of the mevalonate pathway (leads to cholesterol and other sterolic and isoprenoid compounds), and a mitochondrial form responsible for ketone body biosynthesis. HMG-CoA is also found in other eukaryotes such as insects, plants and fungi . In bacteria, isoprenoid precursors are generally synthesised via an alternative, non-mevalonate pathway, however a number of Gram-positive pathogens utilise a mevalonate pathway involving HMG-CoA synthase that is parallel to that found in eukaryotes .

This entry represents HMG-CoA synthase enzymes found in a limited spectrum of mostly Gram-positive bacteria, which make isopentenyl pyrophosphate (IPP) via the mevalonate pathway.
V-ATPase proteolipid subunit C, eukaryotic (ATPase_proteolipid_su_C_euk)
Type: Family

Transmembrane ATPases are membrane-bound enzyme complexes/ion transporters that use ATP hydrolysis to drive the transport of protons across a membrane. Some transmembrane ATPases also work in reverse, harnessing the energy from a proton gradient, using the flux of ions across the membrane via the ATPase proton channel to drive the synthesis of ATP.

V-ATPases (also known as V1V0-ATPase or vacuolar ATPase) are found in the eukaryotic endomembrane system, and in the plasma membrane of prokaryotes and certain specialised eukaryotic cells. V-ATPases hydrolyse ATP to drive a proton pump, and are involved in a variety of vital intra-and inter-cellular processes such as receptor mediated endocytosis, protein trafficking, active transport of metabolites, homeostasis and neurotransmitter release . V-ATPases are composed of two linked complexes: the V1 complex (subunits A-H) contains the catalytic core that hydrolyses ATP, while the V0 complex (subunits a, c, c', c'', d) forms the membrane-spanning pore. V-ATPases may have an additional role in membrane fusion through binding to t-SNARE proteins .

This entry represents the 16kDa proteolipid subunit c that is part of the V0 complex of V-ATPase in eukaryotes, and includes members from diverse groups such as fungi, plants and parasites. The three proteolipid subunits (c, c' and c'') that form part of the proton-conducting pore, each contain a buried glutamic acid residue that is essential for proton transport, and together they form a hexameric ring spanning the membrane .
Glutamate--cysteine ligase, plant-type (Glut_cys_lig_pln_type)
Type: Family

These sequences represent one of two highly dissimilar forms of glutamate--cysteine ligase (gamma-glutamylcysteine synthetase), an enzyme of glutathione biosynthesis. The other group is represented by

. This form is found in plants (with a probable transit peptide), root nodule and other bacteria, but not Escherichia coli and closely related species.