SII-SWORD/CoKE huggingface dataset:
BssD/PflA/YjjW (BssD/PflA/YjjW)
Type: Family

This group of enzymes are activating enzymes (activases) and include:

Pyruvate formate-lyase-activating enzyme (PflA,

), which activates pyruvate formate-lyase under anaerobic conditions using S-adenosylmethionine and reduced flavodoxin as cosubstrates .

4-hydroxyphenylacetate decarboxylase activating enzyme (HpdA), which activates 4-hydroxyphenylacetate decarboxylase under anaerobic conditions .

Benzylsuccinate synthase activating enzyme (BssD), which activates benzylsuccinate synthase under anaerobic conditions using S-adenosylmethionine and reduced flavodoxin as cosubstrates .

Choline trimethylamine-lyase activating enzyme (CutD), which activates choline trimethylamine-lyase CutC under anaerobic conditions .

Putative glycyl-radical enzyme activating enzyme YjjW.

Trans-4-hydroxy-L-proline dehydratase activating enzyme PflE .

Isethionate sulfite-lyase activating enzyme IslB .
Glutathione S-transferase Theta, N-terminal (GST_N_Theta)
Type: Domain

GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. Cytosolic GSTs from mammals can be divided into four distinct classes: Alpha, Mu, Pi and Theta. The GST fold contains an N-terminal TRX-fold domain and a C-terminal α helical domain, with an active site located in a cleft between the two domains .

Mammalian class Theta GSTs show poor GSH conjugating activity towards the standard substrates, CDNB and ethacrynic acid, differentiating them from other mammalian GSTs . GSTT1-1 shows similar cataytic activity as bacterial DCM dehalogenase, catalyzing the GSH-dependent hydrolytic dehalogenation of dihalomethanes. This is an essential process in methylotrophic bacteria to enable them to use chloromethane and DCM as sole carbon and energy sources. The presence of polymorphisms in human GSTT1-1 and its relationship to the onset of diseases including cancer is subject of many studies . Human GSTT2-2 exhibits a highly specific sulfatase activity, catalyzing the cleavage of sulfate ions from aralkyl sufate esters, but not from aryl or alkyl sulfate esters .

This entry represents the N-terminal domain found in class Theta glutathione S-transferases (GSTs). Proteins containing this domain also include bacterial dichloromethane (DCM) dehalogenase.
Glutathione S-transferase Theta, C-terminal (GST_C_Theta)
Type: Domain

This entry represents the C-terminal domain found in class Theta GSTs. Proteins containing this domain also include bacterial dichloromethane (DCM) dehalogenase.

GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. Cytosolic GSTs from mammals can be divided into four distinct classes: Alpha, Mu, Pi and Theta. The GST fold contains an N-terminal TRX-fold domain and a C-terminal α helical domain, with an active site located in a cleft between the two domains .

Mammalian class Theta GSTs show poor GSH conjugating activity towards the standard substrates, CDNB and ethacrynic acid, differentiating them from other mammalian GSTs . GSTT1-1 shows similar cataytic activity as bacterial DCM dehalogenase, catalyzing the GSH-dependent hydrolytic dehalogenation of dihalomethanes. This is an essential process in methylotrophic bacteria to enable them to use chloromethane and DCM as sole carbon and energy sources. The presence of polymorphisms in human GSTT1-1 and its relationship to the onset of diseases including cancer is subject of many studies . Human GSTT2-2 exhibits a highly specific sulfatase activity, catalyzing the cleavage of sulfate ions from aralkyl sufate esters, but not from aryl or alkyl sulfate esters .
CTD small RNA polymerase II polypeptide A phosphatase-like (RNA_Pol_CTD_Phosphatase)
Type: Family

CTD phosphatases catalyse the dephosphorylation of the C-terminal domain of the largest RNA polymerase (RNAP) II subunit. This promotes the activity of RNA polymerase II. Small CTD phosphatases (SCPs) preferentially catalyse the dephosphorylation of Ser5 within the consensus repeat , whereas yeast Fcp1 dephosphorylates Ser2 and Ser5 . Structurally characterised enzymes in this group have the C0 cap type (only small inserts seen at either of the two points of cap insertion) .

This entry also matches the Phosphatase Herzog which is a prion-like protein found in Drosophila melanogaster, a membrane-associated phosphatase controlling embryonic patterning .
Glutathione transferase family (Glutathione_S-Trfase)
Type: Family

In eukaryotes, glutathione S-transferases (GSTs) participate in the detoxification of reactive electrophilic compounds by catalysing their conjugation to glutathione. The GST domain is also found in S-crystallins from squid, and proteins with no known GST activity, such as eukaryotic elongation factors 1-gamma and the HSP26 family of stress-related proteins, which include auxin-regulated proteins in plants and stringent starvation proteins in Escherichia coli. The major lens polypeptide of Cephalopoda is also a GST .

Bacterial GSTs of known function often have a specific, growth-supporting role in biodegradative metabolism: epoxide ring opening and tetrachlorohydroquinone reductive dehalogenation are two examples of the reactions catalysed by these bacterial GSTs. Some regulatory proteins, like the stringent starvation proteins, also belong to the GST family . GST seems to be absent from Archaea in which gamma-glutamylcysteine substitute to glutathione as major thiol.

Soluble GSTs activate glutathione (GSH) to GS-. In many GSTs, this is accomplished by a Tyr at H-bonding distance from the sulphur of GSH. These enzymes catalyse nucleophilic attack by reduced glutathione (GSH) on nonpolar compounds that contain an electrophilic carbon, nitrogen, or sulphur atom .

Glutathione S-transferases form homodimers, but in eukaryotes can also form heterodimers of the A1 and A2 or YC1 and YC2 subunits. The homodimeric enzymes display a conserved structural fold, with each monomer composed of two distinct domains . The N-terminal domain forms a thioredoxin-like fold that binds the glutathione moiety, while the C-terminal domain contains several hydrophobic α-helices that specifically bind hydrophobic substrates.
Chondrochloren A methyltransferase (CndI-like) (CndI-like)
Type: Family

Vitamin B12 dependent methylation of an sp3-hybridised carbon in chondrochloren B biosynthesis . The enzymes in this family have a non-canonical SAM/[Fe4S4] binding motif.
Gentamicin C-6' methyltransferase (GenK-like) (GenK-like)
Type: Family

Responsible for the methylation of gentamicin at the C6 position. It has recently been shown that GenK (

) acts at the X2 Branch Point and is essential for the production of G418 and Gentamicins C2a, C2, and C1. It also acts (with the same function) at the A and A2 branch points .
GTPase Obg (GTPase_Obg)
Type: Family

Proteins in this entry are uncharacterised. Protein Obg from the spirochaete bacterium Brachyspira hyodysenteriae is thought to be a GTPase that binds GTP and GDP.
Protein MJ0674-like (MJ0674-like)
Type: Family

Proteins in this entry are uncharacterised but contain a single [4Fe-4S] cluster, with the metal thought to be co-ordinated by three cysteines and an exchangeable S-adenosyl-L-methionine. This entry includes protein MJ0674 from the archaean Methanocaldococcus jannaschii.
Protein MJ0683-like (MJ0683-like)
Type: Family

Proteins in this entry possess the radical SAM domain. Included in this entry are the uncharacterised proteins MJ0683 (from Methanocaldococcus jannaschii), MT2655 and Rv2578c (from Mycobacterium tuberculosis), Mb2609c (from Mycobacterium bovis) and ORF301 (from Acidianus two-tailed virus). Also included in this entry is the radical SAM Nalpha-GlyT isomerase from Pseudomonas phage M6 which isomerizes 5-N-alpha-glycinylthymidine (Nalpha-GlyT) into 5-Calpha-glycinylthymidine (Calpha-GlyT) as a step in the pathway leading to thymidine hypermodifications in the viral genome; these modifications may prevent degradation of viral genome by the host restriction-modification antiviral defense system .
Protein MJ0021-like (MJ0021-like)
Type: Family

This entry represents a subgroup of radical SAM proteins, including protein MJ0021 from the archaean Methanocaldococcus jannaschii. Their function is not clear.
Protein MJ0103-like (MJ0103-like)
Type: Family

This entry includes uncharacterised proteins from archaea that contain a Radical SAM domain, including protein MJ0103 from Methanocaldococcus jannaschii.
RNF26, C3HC5-type zinc finger (RNF26_mRING-HC-C3HC5)
Type: Domain

RNF26 is an E3 ubiquitin ligase that temporally regulates virus-triggered type I interferon induction by increasing the stability of Mediator of IRF3 activation, MITA, also known as STING, through K11-linked polyubiquitination of MITA after viral infection and promoting degradation of IRF3, another important component required for virus-triggered interferon induction . Although RNF26 substrates of ubiquitination remain unclear at present, RNF26 upregulation in gastric cancer might be implicated in carcinogenesis through dysregulation of growth regulators .

RNF26 contains an N-terminal leucine zipper domain and a C-terminal modified C3HC5-type RING-HC finger, which is distinguished from typical C3HC4 RING-HC finger due to the existence of the additional cysteine residue in the middle portion of the RING finger domain .
Thioredoxin domain-containing protein 16 (TXNDC16)
Type: Family

TXNDC genes are members of the thioredoxin superfamily and were shown to play a role in redox homeostasis, protein folding, electron transfer, and also acting as cellular adapters. However, the function of TXDNC16 is still not clear. They have been identified as a meningioma-associated antigen .
Leucine-rich repeat-containing protein 56 (LRRC56)
Type: Family

The function of leucine-rich repeat-containing protein 56 (LRRC56) from vertebrates is not clear. However, its homologue in Chlamydomonas, also known as ODA8, is a conserved flagellar protein with a role in formation and transport of mature dynein complexes during flagellar assembly . LRRC56 from Trypanosoma brucei brucei is required for the assembly of dynein arms in the distal portion of flagellum axoneme .
Transforming growth factor beta regulator 1 (TBRG1)
Type: Family

TBRG1, also known as NIAM (nuclear interactor of ARF and Mdm2), is a p53 activator that causes a G1 phase cell cycle arrest, and collaborates with ARF in an additive fashion to suppress proliferation . NIAM has also been shown to associate with chromatin-associated protein and bind to Tip60 .
Fatty acid-binding protein homologue 1/2/3/4 (Lbp1-4)
Type: Family

This entry represents a group of fatty acid-binding protein homologues from roundworms. They may play a role in sequestering potentially toxic fatty acids and their peroxidation products, or may be involved in the maintenance of the impermeable lipid layer of the eggshell .
KRBA1 (KRBA1)
Type: Family

KRBA1 contains a short repeating motif with conserved sequence of residues, SSPLxxLxxCLK. Its function is still not clear.
RAB6A-GEF complex partner protein 1 (Ric1)
Type: Family

Ric1 is part of the RIC1-RGP1 complex that acts as a guanine nucleotide exchange factor (GEF) for Rab6 GTPase, which is important for normal Golgi structure and function .
Fatty acyl-AMP ligase /fatty acyl-CoA ligase (FAAL/FAAC)
Type: Family

Fatty acyl-AMP ligase (FAAL) belongs to the class I adenylate forming enzyme family and is homologous to fatty acyl-coenzyme A (CoA) ligases (FACLs). However, FAALs produce only the acyl adenylate and are unable to perform the thioester-forming reaction, while FACLs perform a two-step catalytic reaction; AMP ligation followed by CoA ligation using ATP and CoA as cofactors. FAALs have insertion motifs between the N-terminal and C-terminal subdomains that distinguish them from the FACLs. This insertion motif precludes the binding of CoA, thus preventing CoA ligation. It has been suggested that the acyl adenylates serve as substrates for multifunctional polyketide synthases to permit synthesis of complex lipids such as phthiocerol dimycocerosate, sulfolipids, mycolic acids, and mycobactin .

FAAL sequences are also found at the N terminus of non-ribosomal peptide synthetases, large modular enzymes that catalyse synthesis of important peptide products .
Zinc finger ZZ-type and EF-hand domain-containing protein 1 (ZZEF1)
Type: Family

This group of proteins is found in animals and includes Zinc finger ZZ-type and EF-hand domain-containing protein 1 (ZZEF1). ZZEF1 is a histone H3 reader which may act as a transcriptional coactivator for KLF6 and KLF9 transcription factors .
RING finger protein 208, HC type RING finger (RNF208_RING-HC)
Type: Domain

RNF208 is an E3 ubiquitin-protein ligase whose activity can be modulated by S-nitrosylation. It contains a C3HC4-type RING-HC finger .
WD repeat-containing protein 41 (WDR41)
Type: Family

WDR41 is the non-catalytic component of the C9orf72-SMCR8 complex, a complex that has guanine nucleotide exchange factor (GEF) activity and regulates autophagy . This complex also acts as a negative regulator of autophagy initiation by interacting with the ULK1/ATG1 kinase complex and inhibiting its protein kinase activity . WDR41 plays an essential role in C9orf72 lysosome recruitment, which is important for lysosomal responses to changes in acid availability . WDR41 also interacts with PQLC2, a lysosomal cationic amino acid transporter that serves as a sensor that responds to scarcity of its substrates by recruiting C9orf72-SMCR8-WDR41 complex to the surface of lysosomes .
Protein Esc1, basic helix-loop-helix-zipper domain (Esc1_bHLHzip)
Type: Domain

Esc1 from fission yeasts is involved in the sexual differentiation process .

This entry represents the basic helix-loop-helix-zipper (bHLHzip) domain of ESC1.
U4/U6.U5 small nuclear ribonucleoprotein component Snu23 (Snu23)
Type: Family

Pre-mRNA splicing is an important step in eukaryotic gene expression. Yeasts and humans share a common set of core spliceosomal proteins that are evolutionarily conserved such as B complex proteins Snu23 (known as ZMAT2 in humans), Prp38 and MFAP1 . This entry represents Snu23. Its structure has been revealed .
Laa1/Sip1/HEATR5 (Laa1/Sip1/HEATR5)
Type: Family

This entry includes Laa1 from budding yeasts, Sip1 from fission yeasts, HEATR5A/B from animals. Laa1 is an AP-1 accessory protein that play an important role for AP-1 localization . Sip1 interacts with F-box protein 6 and is essential for endocytosis and cytokinesis in fission yeast . The function of HTR5A/B is not clear.
PINK1, protein kinase domain (PINK1_STKc)
Type: Domain

PINK1 is a mitochondrial serine/threonine kinase that acts as a sensor of mitochondrial damage . It phosphorylates ubiquitin (Ub) and the Ub-like domain (UBL) of the E3 Ub ligase parkin at Ser65. The phosphorylation of Ub and the parkin UBL facilitates the transition from the autoinhibition state to the catalytically active state in parkin . Upon mitochondrial damage, PINK1 accumulates on the outer mitochondrial membrane (OMM), where it may recruit and activate Parkin . PINK1 has also been shown to phosphorylate Miro, a component of the primary motor/adaptor complex that anchors kinesin to the mitochondrial surface. The phosphorylation of Miro activates proteasomal degradation of Miro in a Parkin-dependent manner .
Outer dynein arm-docking complex subunit 4 (ODAD4)
Type: Family

ODAD4 (also known as TTC25) is a subunit of the outer dynein arm (ODA) docking complex (DC). Mutations of the TTC25 gene cause an ODA-DC defect involving severely reduced ciliary motility and classical symptoms of PCD (primary ciliary dyskinesia), as well as randomization of left-right body asymmetry in humans and mice .
Developmental regulatory protein WetA (WetA)
Type: Family

This entry represents WetA and related proteins mostly from fungi. BrlA, abaA and wetA are pivotal regulators of conidiophore development and conidium maturation. They act individually and together to regulate their own expression and that of numerous other sporulation-specific genes . WetA is responsible for activating a set of genes whose products make up the final two conidial wall layers or direct their assembly and, through this activity, is responsible for acquisition of spore dormancy .
Lunapark family (Lnp)
Type: Family

Lunapark (Lnp) is an endoplasmic reticulum (ER)-shaping membrane protein named after its conserved L-N-P-A-R-K peptide motif. It may serve as a curvature-stabilizing protein within tubular three-way junctions of the ER . Mutations in the Lnp gene has been linked to neurodevelopmental syndrome .
GCSF/MGF (GCSF/MGF)
Type: Family

This family includes granulocyte colony-stimulating factor (GCSF) and myelomonocytic growth factor (MGF). GCSF acts in hematopoiesis by affecting the production, differentiation and function of 2 related white cell groups in the blood . MGF also acts in hematopoiesis, stimulating proliferation and colony formation of normal and transformed avian cells of the myeloid lineage .
Coiled-coil domain-containing protein 144A/B/C (C144A/B/C)
Type: Family

This entry includes human coiled-coil domain-containing protein 144A/B/C (C144A/B/C). C144A may play a role in preventing the formation of kidney stones through inhibition of calcium oxalate monohydrate (COM) crystallization, attenuating COM-induced apoptotic injury to renal epithelial cells . C144A may also exhibit antilithiatic (preventing the formation of kidney stones) activity through crystal binding, hindering the crystal attachment to renal epithelial cells, a prerequisite to initiate inflammatory response .
Uncharacterized protein C10orf67-like (C10orf67-like)
Type: Family

This entry represents a group of animal proteins, including C10orf67 from human.
Uncharacterized protein C19orf44-like (C19orf44-like)
Type: Family

This entry includes C19orf44 and related proteins. Their function is not clear.
BTB/POZ domain-containing protein 8, BTB/POZ domain 1 (BTBD8_BTB_POZ_1)
Type: Domain

BTB/POZ domain-containing protein 8 (also known as AP2-interacting clathrin-endocytosis protein (APache)), is involved in synaptic vesicle trafficking, neuronal development, and synaptic plasticity .

This entry represents the first BTB (Broad-Complex, Tramtrack and Bric a brac)/POZ (poxvirus and zinc finger) domain found in BTBD8,
Importin beta family (Importin_beta)
Type: Family

This family consists of the karyopherins importin-beta and transportin. Importin subunit beta-1 forms a complex with an importin alpha subunit. The importin complex is required for nuclear protein import. Importins bind to NLSs in their protein cargos to transport them through the nuclear pore into the nucleus .

Transportin-1 and -2 also function in nuclear import . Transportin-1 was first identified as the import factor for the heterogeneous ribonucleoprotein A1 (hnRNP A1) .

The subfamily of proteins known as RanBP6 (Ran-binding protein 6) are part of this family .
Squalene monooxygenase (Squalene_monox)
Type: Family

Squalene is a precursor for the synthesis of sterols in eukaryotes. Squalene monooxygenase, also called squalene epoxidase, catalyzes the first oxygenation step in sterol biosynthesis and is a rate-limiting enzyme in this pathway. In Saccharomyces cerevisiae, squalene is the first precursor dedicated to ergosterol biosynthesis . Squalene monooxygenase is regulated both transcriptionally and post-translationally . It is involved in tumorigenesis .
Storkhead-box protein 1/2 (STOX1/2)
Type: Family

Storkhead-box proteins are winged-helix transcription factors. STOX1 and STOX2 have been linked to pre-eclampsia . STOX has been shown to regulate nitroso-redox balance and mitochondrial homeostasis .
BMERB domain-containing protein 1 (BMERB)
Type: Family

This entry includes human C16orf45 and related proteins. Their function is not clear.
Uncharacterized protein T25E4.2-like (T25E4.2-like)
Type: Family

This entry represents a group of proteins from nematoda, including T25E4.2 from C. elegans.
Protein lin-15B-like (Lin-15B-like)
Type: Family

This entry represents a group of proteins from Rhabditida, including Lin-15B from C. elegans. Lin-15B is a negative regulator of a tyrosine kinase signaling pathway . It negatively regulates vulval development .
MnmG, N-terminal domain (MnmG_N)
Type: Domain

MnmG (also known as GidA) is a tRNA modification enzyme found in bacteria and mitochondria. MnmG forms a complex with MnmE which is involved in the formation of methyluridine derivatives at the wobble uridine base in some tRNAs .

This domain is also found in the MnmG paralogue TrmFo, a folate/FAD-dependent methyltransferase that catalyzes the methylation of the C5-uridine 54 in the T-loop of tRNAs of most Gram-positive bacteria and some Gram-negative bacteria . TrmFO lacks a C-terminal helical domain present in MnmG .

This entry represents the N-terminal domain of MnmG and related domains. This domain does not include the C-terminal region of MnmG, which contains a sterile alpha motif domain and is responsible for tRNA-protein and protein-protein interactions including association with MnmE .
TREX component Tex1/THOC3 (Tex1/THOC3)
Type: Family

This entry includes Tex1 from budding yeasts and THOC3 from animals and plants. Tex1/THOC is part of the TREX complex involved in mRNA export. TREX complex is thought to couple mRNA transcription, processing and nuclear export. It specifically associates with spliced mRNA and not with unspliced pre-mRNA . The THOC1-THOC2-THOC3 core complex alone is sufficient to bind export factor NXF1-NXT1 and promote ATPase activity of DDX39B .
Synphilin-1 (SNCAIP)
Type: Family

Synphilin-1 interacts with and is ubiquitylated by the E3 ubiquitin ligase SIAH. It also interacs with PINK1 and is recruited to the mitochondria where promotes PINK1-dependent mitophagy. Synphilin-1, SIAH-1 and PINK1 seem to constitute a new mitophagy pathway .

Synphilin-1 is an alpha-synuclein-interacting protein that promotes the formation of inclusion bodies . Alternative splicing gives rise to at least eight synphilin-1 isoforms . Among them, synphilin-1A is an aggregation-prone protein that causes neuronal toxicity . Synphilin-1A has been linked to Parkinson's disease .
26S Proteasome non-ATPase regulatory subunit 12/COP9 signalosome complex subunit 4 (PSMD12/CSN4)
Type: Family

The 26S proteasome consists of a 20S proteolytic core particle (CP) and a 19S regulatory particle (RP). The RP can be further divided into two subcomplexes, the base that directly associates with the CP and a peripheral lid. The RP lid is structurally similar to the COP9 signalosome (CSN). The core CSN subunits (CSN4/5/7/6) show a remarkable one-to-one sequence correspondence with those of the RP lid (RPN5/11/9/8), suggesting a common ancestry and architecture .

This family includes the 26S Proteasome non-ATPase regulatory subunit 12 (PSMD12 or RPN5), a component of the 26S proteasome lid , and the COP9 signalosome subunit 4 .
Mesoderm induction early response protein/metastasis-associated protein (MIER/MTA)
Type: Family

MTA (metastasis-associated) proteins, including MTA1-3, are transcriptional co-repressors that function in histone deacetylation and are involved in the NuRD complex. Nevertheless, MTA1 and MTA2 have been shown to deacetylate non-histone proteins, such as p53. The expression of MTA proteins have been linked to human cancers .

Mesoderm induction early response proteins (MIER1-3) are ELM2-SANT domain-containing proteins. MIER1 functions as a transcriptional repressor through its ability to recruit HDAC1/2 activity. The function of MIER2 and MIER3 is not clear .