SII-SWORD/CoKE huggingface dataset:
Salt-Inducible kinase, catalytic domain (SIK)
Type: Domain

SIKs are serine/threonine kinasse that are part of a complex network that regulates Na,K-ATPase to maintain sodium homeostasis and blood pressure . Vertebrates contain three forms of SIKs (SIK1-3) from three distinct genes, which display tissue-specific effects. SIK1, also called SNF1LK, controls steroidogenic enzyme production in adrenocortical cells . In the brain, both SIK1 and SIK2 regulate energy metabolism . SIK2, also called QIK or SNF1LK2, is involved in the regulation of gluconeogenesis in the liver and lipogenesis in adipose tissues, where it phosphorylates the insulin receptor substrate-1 . In the liver, SIK3 (also called QSK) regulates cholesterol and bile acid metabolism . In addition, SIK2 plays an important role in the initiation of mitosis and regulates the localization of C-Nap1, a centrosome linker protein .
Maternal embryonic leucine zipper kinase, catalytic domain (MELK)
Type: Domain

MELK (Maternal Embryonic Leucine zipper Kinase) is a cell cycle dependent protein which functions in cytokinesis, cell cycle, apoptosis, cell proliferation, and mRNA processing . It is found upregulated in many types of cancer cells, playing an indispensable role in cancer cell survival. It makes an attractive target in the design of inhibitors for use in the treatment of a wide range of human cancer .
Serine/threonine-protein kinase Kin4/ppk1, catalytic domain (STK_Kin4/ppk1)
Type: Domain

Saccharomyces cerevisiae Kin4 is a central component of the spindle position checkpoint (SPOC), which monitors spindle position and regulates the mitotic exit network (MEN) . Kin4 associates with spindle pole bodies in mother cells to inhibit MEN signaling and delay mitosis until the anaphase nucleus is properly positioned along the mother-bud axis. Kin4 activity is regulated by both the bud neck-associated kinase Elm1 and protein phosphatase 2A .

The fission yeast homologue is known as ppk1 .
Protein kinase B gamma, catalytic domain (Akt3)
Type: Domain

Protein kinase B gamma (PKB-gamma), also known as AKT3, is one of three closely related serine/threonine-protein kinases: AKT1/alpha, AKT2/beta and AKT3/gamma. PKBs contain an N-terminal pleckstrin homology (PH) domain and a C-terminal catalytic domain . PKB-gamma is predominantly expressed in neuronal tissues. Mice deficient in PKB-gamma show a reduction in brain weight due to the decreases in cell size and cell number . PKB-gamma has also been shown to be upregulated in estrogen-deficient breast cancer cells, androgen-independent prostate cancer cells, and primary ovarian tumours . It acts as a key mediator in the genesis of ovarian cancer .
Protein kinase B alpha, catalytic domain (Akt1)
Type: Domain

Protein kinase B alpha (PKB-alpha), also known as AKT1, is one of three closely related serine/threonine-protein kinases: AKT1/alpha, AKT2/beta and AKT3/gamma. PKBs contain an N-terminal pleckstrin homology (PH) domain and a C-terminal catalytic domain . PKB-alpha is predominantly expressed in endothelial cells. It is critical for the regulation of angiogenesis and the maintenance of vascular integrity . It also plays a role in adipocyte differentiation . Mice deficient in PKB-alpha exhibit perinatal morbidity, growth retardation, reduction in body weight accompanied by reduced sizes of multiple organs, and enhanced apoptosis in some cell types. PKB-alpha activity has been reported to be frequently elevated in breast and prostate cancers . In some cancer cells, PKB-alpha may act as a suppressor of metastasis .
Protein Kinase B beta, catalytic domain (Akt2)
Type: Domain

Protein kinase B beta (PKB-beta), also known as AKT2, is one of three closely related serine/threonine-protein kinases: AKT1/alpha, AKT2/beta and AKT3/gamma. PKBs contain an N-terminal pleckstrin homology (PH) domain and a C-terminal catalytic domain . PKB-beta is the predominant PKB isoform expressed in insulin-responsive tissues. It plays a critical role in the regulation of glucose homeostasis . It is also implicated in muscle cell differentiation . Mice deficient in PKB-beta display normal growth weights but exhibit severe insulin resistance and diabetes, accompanied by lipoatrophy and B-cell failure .
DNA-directed RNA polymerase subunit RpoC1 (RNApol_RpoC1)
Type: Family

DNA-directed RNA polymerases

(also known as DNA-dependent RNA polymerases) are responsible for the polymerisation of ribonucleotides into a sequence complementary to the template DNA. In eukaryotes, there are three different forms of DNA-directed RNA polymerases transcribing different sets of genes. Most RNA polymerases are multimeric enzymes and are composed of a variable number of subunits. The core RNA polymerase complex consists of five subunits (two alpha, one beta, one beta-prime and one omega) and is sufficient for transcription elongation and termination but is unable to initiate transcription. Transcription initiation from promoter elements requires a sixth, dissociable subunit called a sigma factor, which reversibly associates with the core RNA polymerase complex to form a holoenzyme . The core RNA polymerase complex forms a "crab claw"-like structure with an internal channel running along the full length . The key functional sites of the enzyme, as defined by mutational and cross-linking analysis, are located on the inner wall of this channel.

RNA synthesis follows after the attachment of RNA polymerase to a specific site, the promoter, on the template DNA strand. The RNA synthesis process continues until a termination sequence is reached. The RNA product, which is synthesised in the 5' to 3' direction, is known as the primary transcript.

Eukaryotic nuclei contain three distinct types of RNA polymerases that differ in the RNA they synthesise:

RNA polymerase I: located in the nucleoli, synthesises precursors of most ribosomal RNAs.

RNA polymerase II: occurs in the nucleoplasm, synthesises mRNA precursors.

RNA polymerase III: also occurs in the nucleoplasm, synthesises the precursors of 5S ribosomal RNA, the tRNAs, and a variety of other small nuclear and cytosolic RNAs.

Eukaryotic cells are also known to contain separate mitochondrial and chloroplast RNA polymerases. Eukaryotic RNA polymerases, whose molecular masses vary in size from 500 to 700kDa, contain two non-identical large (>100kDa) subunits and an array of up to 12 different small (less than 50kDa) subunits.

This family includes the cyanobaterial DNA-dependent RNA polymerase gamma subunit (RpoC1) and the equivalent subunit in plastids and chloroplasts, that is designated beta'. Chloroplasts have inherited a multisubunit RNA polymerase from their cyanobacterial ancestor. Core subunits alpha, beta, beta' and beta'' are encoded by the rpoA, rpoB, rpoC1 and rpoC2 genes in the plastid genome .
ATP synthase, F0 complex, subunit b' (ATP_synth_b')
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.

F-ATPases (also known as ATP synthases, F1F0-ATPase, or H(+)-transporting two-sector ATPase) (

) are composed of two linked complexes: the F1 ATPase complex is the catalytic core and is composed of 5 subunits (alpha, beta, gamma, delta, epsilon), while the F0 ATPase complex is the membrane-embedded proton channel that is composed of at least 3 subunits (A-C), with additional subunits in mitochondria. Both the F1 and F0 complexes are rotary motors that are coupled back-to-back. In the F1 complex, the central gamma subunit forms the rotor inside the cylinder made of the α(3)β(3) subunits, while in the F0 complex, the ring-shaped C subunits forms the rotor. The two rotors rotate in opposite directions, but the F0 rotor is usually stronger, using the force from the proton gradient to push the F1 rotor in reverse in order to drive ATP synthesis . These ATPases can also work in reverse in bacteria, hydrolysing ATP to create a proton gradient.

This entry represents subunit b' from the F0 complex in F-ATPases found in chloroplasts and in cyanobacteria. The b subunits are part of the peripheral stalk that links the F1 and F0 complexes together, and which acts as a stator to prevent certain subunits from rotating with the central rotary element. The peripheral stalk differs in subunit composition between mitochondrial, chloroplast and bacterial F-ATPases. In bacterial and chloroplast F-ATPases, the peripheral stalk is composed of one copy of the delta subunit (homologous to OSCP in mitochondria), and two copies of subunit b in bacteria, or one copy each of subunits b and b' in chloroplasts and photosynthetic bacteria . The b' subunit is a diverged and duplicated form of b found in plants and photosynthetic bacteria.
tRNA N6-adenosine threonylcarbamoyltransferase Kae1, archaeal/eukaryotic (Kae1_archaea_euk)
Type: Family

The KEOPS/EKC complex is a tRNA modification complex involved in the biosynthesis of N6-threonylcarbamoyladenosine (t6A), a universally conserved tRNA modification found on ANN-codon recognizing tRNAs . In archaea and eukaryotes, KEOPS is composed of Kae1, a highly conserved protein present in bacteria, archaea and eukaryotes, kinase PRPK/Bud32, and three additional polypeptides (Pcc1, Cgi121, and Gon7) .

The first characterised member of the Kae1/TsaD family was annotated as Gcp for O-sialoglycoprotein endopeptidase , but this activity could not be confirmed . Later, its homologue, Kae1 from Pyrococcus abyssi, has been shown to have DNA-binding properties and apurinic-endonuclease activity . Members of this family have since been studied in yeast, archaea and bacteria resulting in sometimes conflicting data, several proposed functions and annotations but no definitive characterisation. For instance, some members have been linked to DNA maintenance in bacteria and mitochondria and transcription regulation and telomere homeostasis in eukaryotes , but their function remained unclear. Recent research indicates that this family is involved in the biosynthesis of N6-threonylcarbamoyl adenosine, a universal modification found at position 37 of tRNAs that read codons beginning with adenine .
Isochorismate synthase MenF (MenF)
Type: Family

Isochorismate synthase (

) catalyses the conversion of chorismate to isochorismate, the first step in the biosynthesis of both the respiratory chain component menaquinone (MK, vitamin K2) and phylloquinone (vitamin K1). In bacteria, isochorismate is a precursor of siderophores enterobactin (via the 2,3-dihydroxybenzoate (DHB) precursor) , amonabactins and salicylic acid . Most aerobic bacteria secrete siderophores to facilitate iron acquisition . Siderophores are iron-chelating agents which are low molecular weight compounds that specifically bind ferric iron and mediate iron uptake into the cell by recognition of specific membrane receptor proteins and transport systems. In plants, isochorismate synthase is required for defence against pathogens. Salicylic acid synthesised via the pathway using isochorismate synthase is responsible for both local and systemic acquired resistance in plants .

In Escherichia coli and Bacillus subtilis, two distinct isochorismate synthase isoenzymes, MenF and EntC /DhbC , are known to be involved in MK and siderophore biosynthesis pathways, respectively . MenF and EntC are differentially regulated and isochorismate synthesised by EntC is mainly channelled into enterobactin synthesis, whereas isochorismate synthesised by MenF is mainly channelled into menaquinone synthesis .

The catalytic/chorismate binding domain characteristic of members of this group is related to other chorismate binding enzymes : component I of anthranilate synthase, para-aminobenzoate synthase, and aminodeoxychorismate synthase (please see

).

There is a significant heterogeneity in the length and sequence of the N-terminal region of members of this group. Partially on the basis of the N-terminal region, the group can be divided into subfamilies, with the enzymes involved in DHB (enterobactin precursor) biosynthesis (EntC/DhbC/VibC) forming a distinct subfamily, and the enzymes involved in MK biosynthesis (MenF) forming two groups (E. coli and B. subtilis types).

This family represents MenF both from E. coli and B. subtilis.
Cytidylyltransferase IspD/TarI (IspD/TarI)
Type: Family

This family consists of cytidylyltransferases IspD and TarI and close homologues.

2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase (IspD) catalyses the formation of 4-diphosphocytidyl-2-C-methyl-D-erythritol from CTP and 2-C-methyl-D-erythritol 4-phosphate (MEP) in the deoxyxylulose pathway of isopentenyl diphosphate (IPP) biosynthesis . This mevalonate independent pathway that utilizes pyruvate and glyceraldehydes 3-phosphate as starting materials for production of IPP occurs in a variety of bacteria, archaea and plant cells, but is absent in mammals. The isoprenoid pathway is a well known target for anti-infective drug development . In about twenty percent of bacterial genomes, this protein occurs as IspDF, a bifunctional fusion protein.

Ribitol-5-phosphate cytidylyltransferase (TarI) is required for the synthesis of activated ribitol via the wall teichoic acid biosynthesis pathway. The enzyme catalyzes the transfer of the cytidylyl group of CTP to D-ribitol 5-phosphate to form CDP-ribitol .

The human IspD (known as D-ribitol-5-phosphate cytidylyltransferase or isoprenoid synthase domain-containing protein) shows a canonical N-terminal cytidyltransferase domain linked to a C-terminal domain that is absent in cytidyltransferase homologues. It has cytidyltransferase activity toward pentose phosphates, including ribulose 5-phosphate, ribose 5-phosphate, and ribitol 5-phosphate. It is implicated in dystroglycan O-mannosylation .

D-fructose-6-phosphate cytidylyltransferase catalyses the formation of CDP-6-d-fructose from cytidine triphosphate and d-fructose-6-phosphate and is involved in the biosynthesis of capsular polysaccharides . It could also utilise other sugar donors such as D-fructose-1-phosphate, D-glucose-6-phosphate, alpha-D-glucose-1-phosphate or D-glucitol-6-phosphate .
Terpene cyclase-like 2 (Terpene_cyclase-like_2)
Type: Family

Characterised enzymes in the terpene cyclase like 2 family include sesquiterpene cyclases, such as epi-isozizaene synthase and pentalenene synthase, as well as 2-methylisoborneol synthase, which processes a naturally occurring noncanonical isoprenoid substrate . As with other enzymes with the 'terpenoid synthase fold', they have two conserved metal binding motifs, proposed to coordinate Mg2 ion-bridged binding of the diphosphate moiety of FPP to the enzymes. Metal-triggered substrate ionisation initiates catalysis, and the α-barrel active site serves as a template to channel and stabilise the conformations of reactive carbocation intermediates through a complex cyclisation cascade. These enzymes function in the monomeric form and are found mostly in fungi, bacteria and some plant species .
Elongator complex protein 3-like (ELP3-like)
Type: Family

The elongator complex is a major component of the RNA polymerase II (RNAPII) holoenzyme responsible for transcriptional elongation. It binds to both naked and nucleosomal DNA, can acetylate both core and nucleosomal histones, and is involved in chromatin remodelling . It acetylates histones H3, preferentially at 'Lys-14', and H4, preferentially at 'Lys-8'. ELP3 is required for the complex integrity and for the association of the complex with nascent RNA transcript. ELP3 is thought to act as a highly conserved histone acetyltransferase (HAT) capable of acetylating core histones in vitro, however, it is clearly a multi-domain protein. The HAT activity is thought to be present only in the C-terminal GNAT domain (histone acyltransferase domain). Recent work suggests that both the histone acetyltransferase and radical S-adenosylmethionine domains are essential for function, although the exact role of the Radical SAM domain is still unclear. The radical SAM domain is important for the structural integrity of the protein complex, and in yeast (previously demonstrated) . However, an alternative may be that ELP3 binds and cleave SAM, as seen in the archaean
M. jannaschii
. It has also been shown in previous studies that the mouse ELP3 does not require the histone acyltransferase domain for zygotic paternal genome demethylation .

The archaeal protein which is the homologue of the third subunit of the eukaryotic elongator complex (Elp3), catalyses the tRNA wobble uridine modification at C5: the same reaction as the eukaryotic elongator complex. The proposed mechanism of action by Elp3 represents an unprecedented chemistry performed on acetyl-CoA in which the methyl group of the acetly-CoA is activated by the 5'-deoxyadenosyl radical. This then adds to the uridine of tRNA .

Some bacterial ELP3 homologues are known as tRNA uridine(34) acetyltransferase .

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Lysis inhibition accessory protein rIII (Linr3)
Type: Family

Lysis inhibition (LIN) accessory protein rIII is thought to inhibit cell lysis by binding to the cytoplasmic part of holin T, stabilizing the holin-antiholin complex and preventing lysis by blocking the hole-forming function of the T holin .
Endolysin T7 type (Endolysin_T7_type)
Type: Family

This family includes endolysin, a bacteriophage T7 protein which has amidase activity and is able to degrade host peptidoglycans. It is important for release of virus particles from the infected bacterial cell and acts together with holin and spanin to bring about cell lysis. Endolysin hydrolyzes the link between N-acetylmuramoyl residues and L-amino acid residues in certain cell-wall glycopeptides . Endolysin also inhibits the viral RNA polymerase and plays an important role in the switch between viral transcription and genome replication .
Endolysin T4 type (Endolysin_T4_type)
Type: Family

This family includes endolysin, a lysozyme from bacteriophage T4 and its relatives. Endolysin is required for host cell lysis, and degrades the cross-links in the bacterial cell wall following on from pore formation in the cell membrane by holin and spanin . Endolysin specifically hydrolyses the (1->4)-beta-linkages between N-acetylmuramic acid and N-acetyl-D-glucosamine residues in the peptidoglycan and between N-acetyl-D-glucosamine residues in chitodextrins . Host cell lysis is required for released of virus particles from the cell.

This entry also includes SAR-endolysins. Canonical phage lysozymes accumulate fully folded and enzymatically active in the cytoplasm. In contrast, SAR-endolysins are first secreted as enzymatically inactive enzymes anchored to the membrane by the N-terminal SAR domain 2 . This functional regulation is essential to avoid premature lysis of the infected host .
Endolysin lambda type (Endolysin_lambda_type)
Type: Family

This family includes endolysin from bacteriophage lambda and its relatives. Endolysin is a lysozyme that hydrolyses the (1->4)-beta-glycosidic linkage between N-acetylmuramic acid (MurNAc) and N-acetylglucosamine (GlcNAc) residues in the bacterial cell wall peptidoglycan . Endolysin and the cell membrane pore-forming proteins holin and spanin act together to bring about host cell lysis and release of virus particles .
Diadenylate cyclase CdaS (CdaS)
Type: Family

Diadenylate cyclase catalyses the condensation of 2 ATP molecules into cyclic di-AMP (c-di-AMP), a signaling compound secreted into the host's cytosol by bacterial pathogens, such as Listeria monocytogenes. This compound triggers the cytosolic surveillance pathway (CSP), a host pathway of innate immunity . Apart from a role in the establishment of bacterial infection, c-di-AMP seems to be involved in coordinating bacterial growth, cell wall stability, and responses to stress .

This family includes the sporulation-specific diadenylate cyclase CdaS from Bacillus . CdaS contains an N-terminal domain that consists of two α-helices and a C-terminal catalytically active diadenylate cyclase (DAC) domain. The cyclic di-AMP formed by CdaS is required for efficient germination .
Ribosome hibernation promoting factor, long/plastid (HPF_long/plastid)
Type: Family

Bacteria dimerize pairs of 70S ribosomes into inactive 100S ribosomes during the stationary phase and when exposed to certain stresses, a process that is called ribosome hibernation. Hibernating ribosomes are formed by the activity of one or more highly conserved proteins. In Gammaproteobacteria two proteins are involved in this process, ribosome modulation factor (RMF) and hibernation promoting factor (HPF), while most Gram-positive bacteria produce a single, longer HPF protein .

This family includes the long form of the HPF proteins and the functional homologue PSRP1, a ribosome-binding factor from chloroplasts .
Baseplate wedge protein gp10 (BP10_T4)
Type: Family

The members of this family are similar to gene product 10 (gp10) of bacteriophage T4. gp10 is a peripheral baseplate protein that is part of the tail fibre network . It functions as a molecular lever that rotates and extends the hinged short tail fibres to facilitate cell attachment .
Antiholin T4 type (RI_T4)
Type: Family

Antiholins (also known as RI) are bacteriophage proteins that inhibit lysis of host cells by interacting and inhibiting holin, the protein that forms micropores in the host bacterial cell membrane . Antiholin prevents holin forming homo-oligomers . Antiholin has an N-terminal signal anchor release (SAR) domain which not only directs itself to the periplasm , but also targets itself for degradation by the host serine peptidase DegP .
Baseplate wedge protein gp7 (GP7_T4)
Type: Family

This family includes baseplate wedge protein gp7 (gp7) from bacteriophage T4 and its relatives. Contractile tail bacteriophages use a multiprotein tubular apparatus resembling a coiled spring wound round a rigid tube to attach to and penetrate host cell membranes. The structure known as the baseplate replays the contraction signal to the sheath . gp7 is an intermediate (or inner) baseplate protein involved in tail assembly . It also forms a complex with gp25 and two molecules of gp6 which is involved in sheath contraction .
Baseplate wedge protein gp6 (GP6_T4)
Type: Family

This family includes baseplate wedge protein gp6 (gp6) from bacteriophage T4 and its relatives. Contractile tail bacteriophages use a multiprotein tubular apparatus resembling a coiled spring wound round a rigid tube to attach to and penetrate host cell membranes. The structure known as the baseplate replays the contraction signal to the sheath . gp6 is located next to the tail tube and is an intermediate (or inner) baseplate protein involved in tail assembly . Two molecules of gp6 form a complex with gp25 and gp7 which is involved sheath contraction .
DNA-directed DNA polymerase T7 (DPOL_T7)
Type: Family

This entry includes the DNA-directed DNA polymerase from bacteriophage T7 and its relatives. The polymerase has two activities, DNA synthesis (polymerase) and an exonucleolytic activity that degrades single-stranded DNA in the 3'-5' direction . The polymerase binds to host thioredoxin which increases the rate of dNTP incorporation , and binds to DNA helicase gp4 to co-ordinate nucleotide polymerization with unwinding of the DNA .
Diadenylate cyclase CdaA (CdaA)
Type: Family

Diadenylate cyclase catalyses the condensation of 2 ATP molecules into cyclic di-AMP (c-di-AMP), a signaling compound secreted into the host's cytosol by bacterial pathogens, such as Listeria monocytogenes. This compound triggers the cytosolic surveillance pathway (CSP), a host pathway of innate immunity . Apart from a role in the establishment of bacterial infection, c-di-AMP seems to be involved in coordinating bacterial growth, cell wall stability, and responses to stress .

Most bacteria possess one diadenylate cyclase (DAC) enzyme (CdaA, also called YbbP and DacA), while Bacillus subtilis has two additional DACs (CdaS, also called YojJ and DacB) and DisA . This entry includes CdaA from B.subtilis, which produces the c-di-AMP required for cell wall homeostasis but harmful in excess .