SII-SWORD/CoKE huggingface dataset:
Nicotinate-nucleotide-dimethylbenzimidazole phosphoribosyltransferase-like superfamily (Nict_dMeBzImd_PRibTrfase_sf)
Type: Homologous_superfamily

Nicotinate mononucleotide (NaMN):5,6-dimethylbenzimidazole (DMB) phosphoribosyltransferase (CobT) plays a central role in the synthesis of alpha-ribazole-5'-phosphate, an intermediate for the lower ligand of cobalamin . It is one of the enzymes of the anaerobic pathway of cobalamin biosynthesis, and one of the four proteins (CobU, CobT, CobC, and CobS) involved in the synthesis of the lower ligand and the assembly of the nucleotide loop .

Vitamin B
12
(cobalamin) is used as a cofactor in a number of enzyme-catalysed reactions in bacteria, archaea and eukaryotes . The biosynthetic pathway to adenosylcobalamin from its five-carbon precursor, 5-aminolaevulinic acid, can be divided into three sections: (1) the biosynthesis of uroporphyrinogen III from 5-aminolaevulinic acid; (2) the conversion of uroporphyrinogen III into the ring-contracted, deacylated intermediate precorrin 6 or cobalt-precorrin 6; and (3) the transformation of this intermediate to form adenosylcobalamin . Cobalamin is synthesised by bacteria and archaea via two alternative routes that differ primarily in the steps of section 2 that lead to the contraction of the macrocycle and excision of the extruded carbon molecule (and its attached methyl group) . One pathway (exemplified by Pseudomonas denitrificans) incorporates molecular oxygen into the macrocycle as a prerequisite to ring contraction, and has consequently been termed the aerobic pathway. The alternative, anaerobic, route (exemplified by Salmonella typhimurium) takes advantage of a chelated cobalt ion, in the absence of oxygen, to set the stage for ring contraction .

This entry represents bacterial- and archaeal-type nicotinate-nucleotide-dimethylbenzimidazole phosphoribosyltransferase enzymes involved in dimethylbenzimidazole synthesis, as well as a group of proteins of unknown function. This function is essential to
de novo
cobalamin (vitamin B12) production in bacteria.

The structure of CobT has a three layers (α/β/β) fold with parallel β-sheet of seven strands.
Propanediol/glycerol dehydratase, small subunit superfamily (Prodiol/glycerol_DeHase__sf_su)
Type: Homologous_superfamily

Diol dehydratase (

) and glycerol dehydratase (

) are two iso-functional enzymes that can each catalyse the conversion of 1,2-propanediol, 1,2-ethanediol and glycerol to the corresponding deoxy aldehydes (propionaldehyde, acetaldehyde and 3-hydroxypropionaldehyde, respectively). This reaction proceeds by a radical mechanism involving coenzyme B12 (adenosylcobalamin, AdoCbl) as an essential cofactor. Even though they catalyse the same reaction, these two enzymes (1) differ in their substrate preferences (diol dehydratase has a higher affinity for 1,2-propanediol and glycerol dehydratase for glycerol ); (2) they participate in different pathways (dihydroxyacetone [DHA] pathway for glycerol dehydratase and 1,2-propanediol degradation pathway for diol dehydratase); and (3) in those organisms where both enzymes are produced (such as Klebsiella and Citrobacter), the genes for them are independently regulated: glycerol dehydratase is induced when Klebsiella pneumoniae grows in glycerol-containing medium, whereas diol dehydratase is fully induced when it grows in propane-1,2-diol-containing medium, but only slightly in the glycerol medium .

Both diol dehydratase and glycerol dehydratase comprise three subunits: PduC/PduD/PduE or PddA/PddB/PddC for propanediol dehydratase, and GldA/Gld/B/GldC or DhaB/DhaC/DhaE for glycerol dehydratase. This entry represents the small subunit PduE/PddC/GldC/DhaE.

The structure of dehydratase consists of three helices.
Small/middle T-antigen superfamily (Papo_T_antigensf)
Type: Homologous_superfamily

This domain superfamily represents a conserved region in papovavirus small and middle T-antigens. It is found as the N-terminal domain in the small T-antigen, and is centrally located in the middle T-antigen .

The structure has an all-α zinc-binding fold with two zinc ion-binding sites with a common CxCxxC motif but different fourth ligands.
NAC domain superfamily (NAC_dom_sf)
Type: Homologous_superfamily

This entry represents the NAC domain superfamily.

The NAC domain (for Petunia hybrida (Petunia) NAM and for Arabidopsis ATAF1, ATAF2, and CUC2) is an N-terminal module of ~160 amino acids, which is found in proteins of the NAC family of plant-specific transcriptional regulators (no apical meristem (NAM) proteins) . NAC proteins are involved in developmental processes, including formation of the shoot apical meristem, floral organs and lateral shoots, as well as in plant hormonal control and defence. The NAC domain is accompanied by diverse C-terminal transcriptional activation domains. The NAC domain has been shown to be a DNA-binding domain (DBD) and a dimerization domain .

The NAC domain can be subdivided into five subdomains (A-E). Each subdomain is distinguishable by blocks of heterogeneous amino acids or gaps. While the NAC domains were rich in basic amino acids (R, K and H) as a whole, the distribution of positive and negative amino acids in each subdomain were unequal. Subdomains C and D are rich in basic amino acids but poor in acidic amino acids, while subdomain B contains a high proportion of acidic amino acids. Putative nuclear localization signals (NLS) have been detected in subdomains C and D . The DBD is contained within a 60 amino acid region located within subdomains D and E . The overall structure of the NAC domain monomer consists of a very twisted antiparallel β-sheet, which packs against an N-terminal α-helix on one side and one shorter helix on the other side surrounded by a few helical elements. The structure suggests that the NAC domain mediates dimerization through conserved interactions including a salt bridge, and DNA binding through the NAC dimer face rich in positive charges .
Quinolinate synthetase A superfamily (NadA_sf)
Type: Homologous_superfamily

Quinolinate synthetase catalyses the second step of the
de novo
biosynthetic pathway of pyridine nucleotide formation. In particular, quinolinate synthetase is involved in the condensation of dihydroxyacetone phosphate and iminoaspartate to form quinolinic acid . This synthesis requires two enzymes, an FAD-containing "B protein" and an "A protein". B protein converts L-aspartate to iminoaspartate. The A protein, NadA, converts iminoaspartate to quinolate. NadA harbours a [4Fe-4S] cluster .

The structure of NadA is composed of three similar domains related by pseudo threefold symmetry. Each domain has three layers (α/β/α) with parallel β sheet.
PTS system IIB component-like superfamily (PTS_EIIB-like_sf)
Type: Homologous_superfamily

The bacterial phosphoenolpyruvate: sugar phosphotransferase system (PTS) is a multi-protein system involved in the regulation of a variety of metabolic and transcriptional processes. The lactose/cellobiose-specific family are one of four structurally and functionally distinct group IIB PTS system cytoplasmic enzymes. The fold of IIB cellobiose shows similar structure to mammalian tyrosine phosphatases. This signature is often found downstream of

.

The PTS structure presents three layers (α/β/α) with parallel β-sheet of four strands.
Ataxin, AXH domain superfamily (Ataxin_AXH_dom_sf)
Type: Homologous_superfamily

Spinocerebellar ataxia type 1 is late-onset neurodegenerative diseases caused by the expansion of a CAG triplet repeat in the SCA1 gene. This results in the lengthening of a polyglutamine tract in the gene product ataxin-1 producing a toxic gain of function that results in neuronal death.
Signal transduction histidine kinase, dimerisation/phosphoacceptor domain superfamily (HisK_dim/P_sf)
Type: Homologous_superfamily

This entry represents the dimerisation and phosphoacceptor domain superfamily found in some histidine kinases. Signal transducing histidine kinases are the key elements in two-component signal transduction systems, which control complex processes such as the initiation of development in microorganisms . Examples of histidine kinases are EnvZ, which plays a central role in osmoregulation . Histidine kinases usually have an N-terminal ligand-binding domain and a C-terminal kinase domain, but other domains may also be present. The kinase domain is responsible for the autophosphorylation of the histidine with ATP, the phosphotransfer from the kinase to an aspartate of the response regulator, and the phosphotransfer from aspartyl phosphate back to ADP or to water . The homodimeric domain includes the site of histidine autophosphorylation and phosphate transfer reactions. The structure of the homodimeric domain comprises a closed, four-helical bundle with a left-handed twist, formed by two identical α-hairpin subunits.
Thymidylate synthase ThyX superfamily (Thymidylate_synthase_ThyX_sf)
Type: Homologous_superfamily

All cellular organisms need thymidylate (dTMP) for the replication of their chromosomes, as dTMP is required for the biosynthesis of dTTP, a building block of DNA. Cells can produce thymidylate either de novo from dUMP or incorporate thymidine using thymidine kinase. The de novo pathway of dTMP synthesis requires a specific enzyme, thymidylate synthase, which methylates dUMP at position 5 of the pyrimidine ring. There are two pathways for thymidylate synthesis, each utilising a different thymidylate synthase enzyme: ThyA (

) and ThyX (

) . Both enzymes convert dUMP to dTMP, but there is no sequence identity between the two enzymes, and their mechanisms of action differ . Only ThyX uses FAD as cofactor.

The well studied thyA proteins catalyse the reductive methylation reaction of dUMP, with methylenetetrahydrofolate (CH(2)H(4)folate) serving as one-carbon donor and as source of reductive power. On the other hand the thyX family of thymidylate synthases contains FAD that is tightly bound by a novel fold. FAD mediates hydride transfer from NADPH during catalysis. Consequently, in the reaction catalysed by thyX, CH(2)H(4)folate serves only as a carbon donor and tetrahydrofolate (and not dihydrofolate as in the case of thyA) is produced .
Cytochrome b6/f complex, subunit 5 superfamily (Cyt_6/f_cplx_su5_sf)
Type: Homologous_superfamily

This superfamily consists of cytochrome b6/f complex subunit 5 (PetG). The cytochrome bf complex, found in green plants, eukaryotic algae and cyanobacteria, connects photosystem I to photosystem II in the electron transport chain, functioning as a plastoquinol:plastocyanin/cytochrome c6 oxidoreductase . The purified complex from the unicellular alga Chlamydomonas reinhardtii contains seven subunits; namely four high molecular weight subunits (cytochrome f, Rieske iron-sulphur protein, cytochrome b6, and subunit IV) and three approximately miniproteins (PetG, PetL, and PetX) . Stoichiometry measurements are consistent with every subunit being present as two copies per b6/f dimer. The absence of PetG affects either the assembly or stability of the cytochrome bf complex in C. reinhardtii .
S-adenosylmethionine:tRNA ribosyltransferase-isomerase, QueA superfamily (QueA_sf)
Type: Homologous_superfamily

This entry represents the S-adenosylmethionine:tRNA ribosyltransferase-isomerase, QueA. Queuosine is a hypermodified nucleoside that usually occurs in the first position of the anticodon of tRNAs specifying the amino acids asparagine, aspartate, histidine, and tyrosine. The hypermodified nucleoside is found in bacteria and eukaryotes . Queuosine is synthesized
de novo
exclusively in bacteria; for eukaryotes the compound is a nutrient factor. Queuosine biosynthesis protein, or S-adenosylmethionine:tRNA-ribosyltransferase-isomerase (QueA) catalyses the formation of the 2,3-epoxy-4,5-dihydroxycyclopentane ring of the Q precursor epoxyqueuosine (oQ). S-adenosyl-L-methionine (AdoMet) reacts with 7-aminomethyl-7-deazaguanine of tRNA at position 34 to yield adenine, methionine, and a modified tRNA with oQ at position 34.

QueA consists of two domains: domain 1 has three layers (α/β/α)), while domain 2 is a closed β-barrel with Greek-key topology .
CarD-like/TRCF, RNAP-interacting domain superfamily (CarD-like/TRCF_RID_sf)
Type: Homologous_superfamily

This entry represents the RNA polymerase-interacting domain (RID) superfamily of transcription-repair-coupling factor (TRCF), CarD and CarD homologue in Myxococcus xanthus, called CdnL . CarD is a Myxococcus xanthus protein required for the activation of light- and starvation-inducible genes . Furthermore, CarD is widely distributed among bacteria and represents a distinct class of RNAP binding proteins that regulate transcription and essential processes. TRCF couples transcription and DNA repair in bacteria in which the RID domain is essential for the RNAP release function .

The structure of CarD presents a partly open barrel (tudor-like) topology. The last strand is interrupted by a turn of 3-10 helix.
OsmC/Ohr superfamily (OsmC/Ohrsf)
Type: Homologous_superfamily

This superfamily of peroxiredoxins includes osmotically inducible protein C (OsmC), a stress-induced protein found in Escherichia coli. This superfamily also contains organic hydroperoxide resistance protein (Ohr), that has a novel pattern of oxidative stress regulation.

The transcription of the osmC gene of E. coli is regulated as a function of the phase of growth and is induced during the late exponential phase when the growth rate slows before entry into stationary phase. The transcription is initiated by two overlapping promoters, osmCp1 and osmCp2 .

Ohr from Xanthomonas campestris pv. phaseoli is highly induced by organic hydroperoxides, weakly induced by H2O2, and not induced at all by a superoxide generator. OHR may be a new type of organic hydroperoxide detoxification protein .

The structure of OsmC present a swapped dimer of β(3)-α-β(2)-α(2)-β subunits fold with mixed β-sheet and buried helix.
Class V myosin, motor domain (MYSc_Myo5)
Type: Domain

Class V myosins have been shown to play a role in both membrane trafficking and RNA transport . There are two type V myosins in yeast, which appear to have nonoverlapping functions. In Schizosaccharomyces pombe Myo52 is involved in growth polarity and cytokinesis, whereas Myo51 is a component of the cytokinetic actin ring . Similarly, Saccharomyces cerevisiae Myo2 is essential for polarized growth, most likely through transport of secretory vesicles to the developing bud , while Myo4 has been proposed to transport a mRNA needed to repress mating type switching in daughter cells . Mice and humans possess three class V myosins (Myo5A, Myo5B, and Myo5C). Possible cargoes for myosin-V in mammals include melanosomes, synaptic vesicles and organelles in neurons . Mutations in myo5A cause Griscelli syndrome type-1 (GS1) and neuroectodermal melanolysosomal disease, or Elejalde disease .

This entry represents the motor (head) domain of class V myosins . The motor domain has ATPase activity and belongs to the larger group of P-loop NTPases.
Bifunctional nuclease superfamily (BFN_sf)
Type: Homologous_superfamily

The bifunctional nuclease (BFN) domain is specific to bacteria and plant organisms. It has both RNase and DNase activities .

The dimer of the BFN domain forms a wedge, each monomer being a basic triangular shape. The BFN domain is composed of an eight-stranded, distorted β-sheet consisting of a four-stranded, antiparallel β-sheet (B1, B2, B3, B8), and a four-stranded mixed β-sheet (B4, B5, B6, B7). The sheets are intercalated by three short α-helices (H1, H3, H4), while a longer α-helix (H2) forms the central core of the dimer interface .

Some proteins known to contain a BFN domain are listed below:

Thermotoga maritima TM0160, a conserved hypothetical protein.

Plant bifunctional nuclease in basal defense response (BBD) proteins, regulators in abscisic acid (ABA)-mediated defense responses.

This entry represents the BFN superfamily.
Dinitrogenase iron-molybdenum cofactor biosynthesis superfamily (DiNase_FeMo-co_biosyn_sf)
Type: Homologous_superfamily

This entry represents several Nif (B, X and Y) proteins, which are involved in the biosynthesis of the iron-molybdenum cofactor (FeMo-co) found in the dinitrogenase enzyme of the nitrogenase complex in nitrogen-fixing bacteria. The nitrogenase complex catalyses the reduction of atmospheric dinitrogen to ammonia, and is composed of an iron metalloprotein (dinitrogenase reductase; homodimer of NifH;

) and a Fe-Mo metalloprotein (dinitrogenase; heterotetramer of NifD and NifK;

). The pathway for the synthesis of the Fe-Mo cofactor involves several proteins, including NifB, NifE, NifH, NifN, NifQ, NifV and NifX. NifB appears to be an iron-sulphur source for FeMo-co biosynthesis, while NifX may be associated with the mature FeMo-co, in particular with the addition of homocitrate during the last step of biosynthesis . The NifX protein shows sequence similarity with the C terminus of NifB , as well as to the conserved protein MTH1175 from the archaeon Methanobacterium thermoautotrophicum, which displays a ribonuclease H-like motif of three layers, α/β/α, with a single mixed β-sheet .
Class VII myosin, motor domain (MYSc_Myo7)
Type: Domain

Class VII are monomeric myosins associated with functions in sensory systems such as vision and hearing . In Dictyostelium it has been shown that myosin VII is involved in phagocytosis and cell adhesion . Vertebrates have two class VII myosins (VIIa and VIIb) that are thought to play important roles in linking the actin cytoskeleton to adhesion receptors on the cell surface . Myosin VII isoforms have a conserved motor domain, 5 IQ motifs, and a tail with 2 MyTH4-FERM domains separated by an SH3 domain . The catalytic (head) domain has ATPase activity and belongs to the larger group of P-loop NTPases.
Carbon storage regulator superfamily (CsrA_sf)
Type: Homologous_superfamily

The RNA-binding protein CsrA (carbon storage regulator) is a new kind of global regulator, which facilitates specific mRNA decay . CsrA is entirely contained within a globular complex of approximately 18 CsrA-H6 subunits and a single RNA, CsrB. CsrA binds to the CsrB RNA molecule to form the Csr regulatory system which has a strong negative regulatory effect on glycogen biosynthesis, glyconeogenesis and glycogen catabolism and a positive regulatory effect on glycolysis .

The CsrA structure has a sandwich fold composed of ten strands in two sheets with intertwined dimer topology.
Tetrapyrrole biosynthesis, uroporphyrinogen III synthase superfamily (4pyrrol_syn_uPrphyn_synt_sf)
Type: Homologous_superfamily

This entry represents uroporphyrinogen III synthase (

) which functions during the second stage of tetrapyrrole biosynthesis. This enzyme catalyses the inversion of the final pyrrole unit (ring D) of the linear tetrapyrrole molecule, linking it to the first pyrrole unit (ring A), thereby generating a large macrocyclic structure called uroporphyrinogen III . The enzyme folds into two α/β domains connected by a β-ladder, the active site being located between the two domains . Congenital erythropoietic porphyria (CEP) is an autosomal recessive inborn error of metabolism that results from the markedly deficient activity of uroporphyrinogen III synthase .

Tetrapyrroles are large macrocyclic compounds derived from a common biosynthetic pathway . The end-product, uroporphyrinogen III, is used to synthesise a number of important molecules, including vitamin B12, haem, sirohaem, chlorophyll, coenzyme F430 and phytochromobilin .

The first stage in tetrapyrrole synthesis is the synthesis of 5-aminoaevulinic acid ALA via two possible routes: (1) condensation of succinyl CoA and glycine (C4 pathway) using ALA synthase (

), or (2) decarboxylation of glutamate (C5 pathway) via three different enzymes, glutamyl-tRNA synthetase (

) to charge a tRNA with glutamate, glutamyl-tRNA reductase (

) to reduce glutamyl-tRNA to glutamate-1-semialdehyde (GSA), and GSA aminotransferase (

) to catalyse a transamination reaction to produce ALA.

The second stage is to convert ALA to uroporphyrinogen III, the first macrocyclic tetrapyrrolic structure in the pathway. This is achieved by the action of three enzymes in one common pathway: porphobilinogen (PBG) synthase (or ALA dehydratase,

) to condense two ALA molecules to generate porphobilinogen; hydroxymethylbilane synthase (or PBG deaminase,

) to polymerise four PBG molecules into preuroporphyrinogen (tetrapyrrole structure); and uroporphyrinogen III synthase (

) to link two pyrrole units together (rings A and D) to yield uroporphyrinogen III.

Uroporphyrinogen III is the first branch point of the pathway. To synthesise cobalamin (vitamin B12), sirohaem, and coenzyme F430, uroporphyrinogen III needs to be converted into precorrin-2 by the action of uroporphyrinogen III methyltransferase (

). To synthesise haem and chlorophyll, uroporphyrinogen III needs to be decarboxylated into coproporphyrinogen III by the action of uroporphyrinogen III decarboxylase (

) .
Malate/L-sulfolactate/L-lactate dehydrogenase-like superfamily (Mal/L-sulfo/L-lacto_DH-like_sf)
Type: Homologous_superfamily

The malate dehydrogenase (MDH) of some extremophilies is more similar to the L-lactate dehydrogenases (L-LDH;

) from various sources than to other MDHs .

This superfamily consists of bacterial and archaeal malate/L-sulfolactate/L-lactate dehydrogenases and related proteins. The archaebacterial malate dehydrogenase (

,

) deviates from the eubacterial and eukaryotic enzymes having a low selectivity for the coenzyme (NAD(H) or NADP(H)) and catalysing the reduction of oxalacetate to malate more efficiently than the reverse reaction .

The structure of these dehydrogenases consists of three layers (α/β/α) composed of mixed sheet of seven strands, with strands 1, 6 and 7 antiparallel to the rest.
(2R)-phospho-3-sulpholactate synthase, ComA superfamily (ComA_synth_sf)
Type: Homologous_superfamily

Methanogenic archaea produce methane via the anaerobic reduction of acetate or single carbon compounds . Coenzyme M (CoM; 2-mercaptoethanesulphonic acid) serves as the terminal methyl carrier for this process. Previously thought to be unique to methanogenic archaea, CoM has also been found in methylotrophic bacteria.

Biosynthesis of CoM begins with the Michael addition of sulphite to phosphoenolpyruvate, forming 2-phospho-3-sulpholactate (PSL). This reaction is catalyzed by members of this family, PSL synthase (ComA) . Subsequently, PSL is dephosphorylated by phosphosulpholactate phosphatase (ComB) to form 3-sulpholactate , which is then converted to
3-sulphopyruvate by L-sulpholactate dehydrogenase (ComC;

) . Sulphopyruvate decarboxylase (ComDE;

) converts 3-sulphopyruvate to sulphoacetaldehyde . Reductive thiolation of sulphoacetaldehyde is the final step.

This entry also includes some proteins from plants and fungi, such as HEAT-STRESS-ASSOCIATED 32 from Arabidopsis .

The ComA structure has a TIM β/α-barrel fold with a parallel β-sheet.
Glu-tRNAGln amidotransferase superfamily, subunit C (Asp/Glu-ADT_sf_sub_c)
Type: Homologous_superfamily

This entry includes the C subunit of the bacterial/archaeal aspartyl/glutamyl-tRNA(Asn/Gln) amidotransferases (known as GatC) and eukaryotic Glu-tRNAGln amidotransferases.

Aspartyl/glutamyl-tRNA(Asn/Gln) amidotransferase ([ec:6.3.5.-]) allows the formation of correctly charged Asn-tRNA(Asn) or Gln-tRNA(Gln) through the transamidation of misacylated Asp-tRNA(Asn) or Glu-tRNA(Gln) in organisms which lack either or both of asparaginyl-tRNA or glutaminyl-tRNA synthetases. The reaction takes place in the presence of glutamine and ATP through an activated phospho-Asp-tRNA(Asn) or phospho-Glu-tRNA(Gln) . The enzyme is composed of three subunits: A (an amidase), B and C. It also exists in eukaryotes as a protein targeted to the mitochondria.

The heterotrimer GatABC is involved in converting Glu to Gln and/or Asp to Asn, when the amino acid is attached to the appropriate tRNA. In Lactobacillus, GatABC is responsible for producing tRNA(Gln). In Archaea, GatABC is responsible for producing tRNA(Asn), while GatDE is responsible for producing tRNA(Gln). In lineages that include Thermus, Chlamydia, or Acidithiobacillus, the GatABC complex catalyses both tRNA(Gln) and tRNA(Asn).