SII-SWORD/CoKE huggingface dataset:
[NiFe]-hydrogenase maturation factor, HypX/HoxX type (NiFe-hyd_mat_HypX/HoxX)
Type: Family

[NiFe] hydrogenases function in H2 metabolism in a variety of microorganisms, enabling them to use H2 as a source of reducing equivalent under aerobic and anaerobic conditions [NiFe] hydrogenases consist of two subunits, hydrogenase large and hydrogenase small. The large subunit contains the binuclear [NiFe] active site, while the small subunit binds at least one [4Fe-4S] cluster .

The large subunit of [NiFe]-hydrogenase--as well as other nickel metalloenzymes--is synthesized as a precursor devoid of the metalloenzyme active site. This precursor then undergoes a complex post-translational maturation process that requires a number of accessory proteins .

Members of this family, which includes HypX and HoxX, have been shown to be involved in this process , and have been proposed to participate in the generation and transport of the CO and CN ligands . Interestingly, HypX/HoxX is not present in all hydrogen-metabolizing bacteria. Furthermore, hypX deletion mutants have a reduced but detectable level of hydrogenase activity .

Members of this group have an unusual domain combination: an N-terminal formyl transferase domain and a C-terminal enoyl-CoA hydratase/isomerase domain. So far, no enzymatic reaction is known to combine N
10
-formyltetrahydrofolate as a C1 donor and acyl-CoA as a substrate .

For more information about maturation factors/accessory proteins known to be involved in CN/CO delivery, please see

, which describes HypF.
Protein of unknown function DUF1462 (DUF1462)
Type: Family

There are currently no experimental data for members of this group of bacterial proteins or their homologues. A crystal structure of

revealed a thioredoxin-like fold, its core consisting of three layers α/β/α.
Diol dehydratase-reactivating factor large subunit (DDRA)
Type: Family

Members of this family are the large (alpha) subunit of the alpha-2/beta-2 tetrameric enzyme that reactivates B12-dependent trimeric diol dehydratases (1,2-propanediol dehydratase, glycerol dehydratase). Note that the beta subunit of the reactivase is homologous to the beta (medium) subunit of the diol dehydratase. The reactivase catalyzes the exchange of chemically inactivated B-12 for active B12. This entry excludes homologues from Mycobacterium (e.g. M. smegmatis), where the several paralogous forms of the dehydratase occur and are exceptional also by not being found in a carboxysome-like microcompartment .
Diol/glycerol dehydratase reactivating factor, small subunit (Diol/glycerol_deHydtase_re_ssu)
Type: Family

Diol dehydratase (propanediol dehydratase) and glycerol dehydratase undergo concomitant, irreversible inactivation by glycerol during catalysis . This inactivation is mechanism-based and involves cleavage of the Co-C bond of the cobalamin cofactor, coenzyme B12 (AdoCbl), forming 5 -deoxyadenosine and a modified coenzyme . Irreversible inactivation of the enzyme results from tight binding to the modified, inactive cobalamin .

The glycerol-inactivated enzyme undergoes rapid reactivation in the presence of free AdoCbl, ATP, and Mg
2+
(or Mn
2+
) . Reactivation is mediated by a complex of two proteins: a large subunit (DdrA/PduG,

) and a small subunit (DdrB/PduH) .

The two subunits of the reactivating factor for glycerol dehydratase have been shown to form a tight complex that serves to reactivate the glycerol-inactivated holoenzyme, as well as O
2
-inactivated holoenzyme in vitro . It is believed that this reactivating factor replaces an enzyme-bound, adenine-lacking inactive cobalamin with a free, adenine-containing active cobalamin .

PduG and PduH, part of the propanediol utilization
pdu
operon, are believed to have a similar function in the reactivation of propanediol dehydratase. PduG was also proposed, on the basis of genetic tests, to be a cobalamin adenosyltransferase involved in the conversion of inactive cobalamin (B12) to AdoCbl . However, this function has since been shown to belong to another protein, PduO .
Bacterial microcompartment shell protein, EutL/PduB type (EutL_PduB)
Type: Family

This entry represents Bacterial microcompartment shell protein EutL/PduB predominantly found in Proteobacteria and Firmicutes. Both proteins are components of the BMC shell. EutL is involved in ethanolamine degradation , while PduB is responsible for 1,2-propanediol (1,2-PD) degradation .

Bacterial microcompartments (BCMs) function as organelles by sequestering particular metabolic processes within the cell. The shells of varied microcompartments are built primarily from small proteins belonging to the BMC domain family.
Corrinoid adenosyltransferase EutT (AdoTrfase_EutT)
Type: Family

ATP:cob(I)alamin (or ATP:corrinoid) adenosyltransferases (

), catalyse the conversion of cobalamin (vitamin B12) into its coenzyme form, adenosylcobalamin (AdoCbl)or coenzyme B12 . AdoCbl contains an adenosyl moiety liganded to the cobalt ion of cobalamin via a covalent Co-C bond. AdoCbl is required as a cofactor for the activity of certain enzymes.

ATP:cob(I)alamin adenosyltransferases are classed into three groups: CobA-type , EutT-type and PduO-type . Each of the three enzyme types appears to be specialised for particular AdoCbl-dependent enzymes or for the de novo synthesis AdoCbl. PduO and EutT are distantly related, sharing short conserved motifs, while CobA is evolutionarily unrelated and is an example of convergent evolution.

This entry represents Corrinoid adenosyltransferase EutT and similar proteins predominantly found in Gammaproteobacteria. They convert cyanocobalamin (CN-B12) to adenosylcobalamin (AdoCbl), the inducer of the eut operon . Bacteria that harbour the ethanolamine utilization pathway can use ethanolamine a source of carbon and nitrogen .
Uncharacterised protein family YjbK (Uncharacterised_YjbK)
Type: Family

Detailed sequence analysis shows that members of this family are distantly related to thermophilic adenylate cyclases (class 2) (

) and mammalian thiamine triphosphatases, and belong to the CYTH domain superfamily . It has been predicted that CYTH domain proteins may play a central role in the interface between nucleotide and polyphosphate metabolism . Based on the conservation of catalytic residues, it has been predicted that CYTH domains are likely to chelate two divalent cations, and exhibit a reaction mechanism that is dependent on two metal ions, analogous to nucleotide cyclases, polymerases and certain phosphoesterases . It has also been suggested that the experimentally characterised members of the CYTH domain superfamily, namely adenylyl cyclase and thiamine triphosphatase, are secondary derivatives of proteins that performed an ancient role in polyphosphate and nucleotide metabolism .
Microcystin LR degradation protein MlrC (MlrC)
Type: Family

Proteins in this entry are involved in degradation of the cyanobacterial heptapeptide hepatotoxin microcystin LR, and are encoded in the mlr gene cluster . MlrC from Sphingomonas wittichii (strain RW1 / DSM 6014 / JCM 10273) is believed to mediate the last step of peptidolytic degradation of the tetrapeptide. It is suspected to be a metallopeptidase based on homology to known peptidases and its inhibition by metal chelators. The proteins encoded by the mlr cluster may be involved in cell wall peptidoglycan cycling and subsequently act fortuitously in hydrolysis of microcystin LR.
Uncharacterised conserved protein UCP014484, transmembrane (UCP014484_TM)
Type: Family

There are currently no experimental data for members of this group or their homologues. However, these proteins are predicted to contain three or more transmembrane segments.
PhoPQ-activated pathogenicity-related protein, PqaA type (PhoPQ-act_pathogen-rel_PqaA)
Type: Family

Proteins in this entry are believed to play a role in virulence/pathogenicity in Salmonella. Salmonella typhi PqaA has been shown to be activated by PhoP/Q two-component regulatory system, which regulates many virulence genes . It has been also shown to confer resistance to antimicrobial peptides (melittin) . Members of this family are predicted to belong to the alpha/beta hydrolase domain superfamily.
Protein of unknown function DUF1269, membrane associated (DUF1269_membrane)
Type: Family

There are currently no experimental data for members of this group or their homologues. However, these proteins are predicted to contain two or more transmembrane segments.
Virion core protein, vaccinia E11L type (Virion_core)
Type: Family

This family consists of several Chordopoxvirus E11 proteins. The E11 gene of vaccinia virus encodes a 15kDa polypeptide also known as Core protein OPG073. Mutations in the E11 gene makes the virus temperature-sensitive due to either the fact that virus infectivity requires a threshold level of active E11 protein or that E11 function is conditionally essential .
Knr4/Smi1 family (Knr4/Smi1)
Type: Family

This entry includes a group of fungal proteins that are involved in cell wall biosynthesis, including Smi1 from S. cerevisiae and Cot2 from Neurospora crassa. Smi1 (also known as Knr4) is involved in the regulation of cell wall assembly and 1,3-beta-glucan synthesis, possibly through the transcriptional regulation of cell wall glucan and chitin synthesis . Cot2 is required for (1,3) beta-glucan synthase activity and cell wall formation .
Predicted archaeal flagellar protein C (FlaC_arc)
Type: Family

Members of this family are encoded by archaeal flagellar operons, and are therefore predicted to be involved in archaeal flagellar assembly, but their specific role is unknown . In several archaea, the flagellin genes are followed immediately by the genes encoding flagellar accessory proteins flaCDEFGHIJ. They may have a role in translocation, secretion, or assembly of the flagellum. FlaC has been shown to be membrane-associated.

Archaeal flagella, found in all the main groupings of archaea, differ from eubacterial flagella in both structure and composition, although some archaeal flagellar proteins show similarity to the eubacterial proteins involved in the pilus biogenesis/type II and IV secretory pathways .
Nucleotidase, putative (Nucleotidase_putative)
Type: Family

These proteins, which are annotated as putative nucleotidases, contain a domain that is distantly related to HAD-like hydrolase domain, and belong to the SCOP HAD-like hydrolase domain superfamily.
Histone-lysine N-methyltransferase, H3 lysine-37 specific (SET7_MeTrfase)
Type: Family

This entry includes SET7, an histone lysine methyltransferase that specifically mono-, di-, and trimethylates 'Lys-37' of histone H3 . In S. pombe, SET7 regulates sporulation .
Mosquitocidal toxin (Mtx2_tox)
Type: Family

This group represents a mosquitocidal toxin.
Epsilon toxin (Epsilon_toxin)
Type: Family

This group represents an epsilon toxin .
Activating signal cointegrator 1 complex subunit 1 (ASCC1)
Type: Family

ASCC1, also called ASC-1 complex subunit p50, or Trip4 complex subunit p50, plays a role in DNA damage repair as component of the ASCC complex which consists of ASCC1, ASCC2 and ASCC3 subunits (p50, p100 and p200, respectively) . It is part of the ASC-1 complex that enhances NF-kappa-B, SRF and AP1 transactivation . In cells responding to gastrin-activated paracrine signals, it is involved in the induction of SERPINB2 expression by gastrin . ASCC1 may also play a role in the development of neuromuscular junction .

This protein has an RNA-binding KH domain fused to a 2H RNA-phosphoesterase and modulates the ASCC3 helicase recruitment to the ASCC complex during alkylation damage.

This entry also includes some uncharacterised proteins from fungi, such as the ASCC1 orthologue from S.pombe, C15D4.13c.
Type VI secretion system accessory component TagJ (TagJ)
Type: Family

This entry includes TagJ (also known as HsiE1), which is an accessory component of the bacterial type VI secretion system (T6SS). It plays a role in the interaction between ClpV and the TssC/TssB sheath .

The type VI secretion system (T6SS), also known as CIS contractile injection system , is a supra-molecular bacterial complex that resembles phage tails. It is a toxin delivery systems which fires toxins into target cells upon contraction of its TssBC sheath . Thirteen essential core proteins are conserved in all T6SSs: the membrane associated complex TssJ-TssL-TssM, the baseplate proteins TssE, TssF, TssG, and TssK, the bacteriophage-related puncturing complex composed of the tube (Hcp), the tip/puncturing device VgrG, and the contractile sheath structure (TssB and TssC). Finally, the starfish-shaped dodecameric protein, TssA, limits contractile sheath polymerization at its distal part when TagA captures TssA .
Methylthioribose kinase (Methylthioribose_kinase)
Type: Family

Members of this family are 5-methylthioribose kinases (

) that catalyse phosphorylation of 5-methylthioribose (MTR), a step in the recycling of methionine from 5'-methylthioadenosine, a co-product of polyamine biosynthesis. The preceding step of methylthioadenosine (MTA) hydrolysis to MTR is catalysed by 5'-methylthioadenosine/S-adenosylhomocysteine (MTA/AdoHcy) nucleosidase.

Bacillus subtilis protein MtnK (formerly YkrT) and Klebsiella pneumoniae protein MtrK have been experimentally characterised. K. pneumoniae MtrK expression is regulated by methionine .

As this enzyme is absent in mammals, it has been considered a target for rational drug design.
Protein of unknown function DUF1129 (DUF1129)
Type: Family

There are currently no experimental data for members of this group or their homologues. However, these proteins contain predicted integral membrane proteins (with several transmembrane segments).
TIM-barrel domain, IGPS-like (TIM-br_IGPS-like)
Type: Domain

This domain is likely to have a TIM barrel fold, related to IGPS (indole-3-glycerol-phosphate synthase). Interestingly, this novel domain also exists as an N-terminal domain of a putative sigma
54
-dependent transcriptional activator. Because sigma
54
dependent activators typically have a three-domain structure: the variable N-terminal regulatory (activation) domain involved in signal recognition/receiving, the central AAA-type ATPase domain, and the DNA-binding domain, the domain described by this entry may be predicted to play a role in signal recognition/receiving and signal transduction. However this has not been experimentally validated.
Virulence factor SrfB (Virulence_factor_SrfB)
Type: Family

This entry represents proteins of unknown function. It has been shown in Salmonella enterica that
srfB
is one of the genes activated by the global signal transduction/regulatory system SsrA/B . This activation takes place within eukaryotic cells. The activated genes include pathogenicity island 2 (SPI-2) genes and at least 10 other genes (
srfB
is one of them) which are believed to be horizontally acquired, and to be involved in virulence/pathogenicity .
Predicted HD phosphohydrolase (HD_phosphohydro)
Type: Family

There are currently no experimental data for members of this group or their homologues. However, members of this family contain a version of the HDc domain (metal-dependent phosphohydrolases with conserved "HD" motif), indicating possible phosphohydrolase activity.
Bacteriophytochrome, CheY-like (Bactrphtchr_CheY)
Type: Family

This entry contains bacteriophytochromes, or BphPs (light-regulated signal transduction histidine kinases) with the receiver (CheY-like) domain fused at the C terminus.

Phytochrome dimeric photoreceptors regulate growth and development by sensing ambient light . Apart from phytochromes in photosynthetic organisms, phytochrome-like photoreceptors have been found in several nonphotosynthetic organisms, including in the heterotrophic eubacteria Deinococcus radiodurans and Pseudomonas aeruginosa,

]. These homodimeric photoreceptors sense red light (R) and far-red light (FR) through photointerconversion between two stable conformations, a R-absorbing Pr form and a FR-absorbing Pfr form .

Phytochromes in general contain a signature N-terminal chromophore-binding region (CBD) that includes GAF and PHY domains, both of which are essential for autocatalytically binding bilin chromophores. A C-terminal module is involved in signal transduction and homodimerisation, and is different in different groups of phytochromes. Phytochromes are divided into three groups: plant phys, cyanobacterial phys (Cphs), and bacteriophytochrome photoreceptors (BphPs) .

The BphPs are common among photosynthetic and nonphotosynthetic Eubacteria and present in some fungi . They act as photoregulated kinases that presumably initiate the phosphorelay cascade by phosphotransfer to an associated response regulator (RR). In some cases, the receiver (CheY-like) domain of this RR is fused to the C-terminal end of the BphP (such hybrid proteins are in this entry).

Like Cphs, BphPs often contain the canonical two-component histidine kinase motif and act as histidine kinases in vitro. The main distinction is that they use the bilin biliverdin (BV) as the chromophore . Included in the CBD are the positionally conserved cysteine (Cys-20 and Cys-13) and histidine (His-250 and His-248) residues that could serve as the chromophore-binding site, by using either a thiolether or Schiff-base-type linkage, respectively .
Probable bifunctional tRNA threonylcarbamoyladenosine biosynthesis protein (tRNA_threonyl_synthase/kinase)
Type: Family

This entry describes a probable bifunctional tRNA threonylcarbamoyladenosine biosynthesis protein. Its N-termanal domain is homologous to the Kae1/YgjD family, which is involved in tRNA threonylcarbamoyladenosine biosynthesis . Its C-terminal region contains a serine/threonine protein kinase domain (STYKS) and is homologous to Bud32. Kae1 and Bud32 are two components of the the KEOPS/EKC complex, which has been implicated in transcription, telomere maintenance and chromosome segregation . In this archaeal family, it seems that the Kae1 and Bud32 orthologues are fused.
Corrinoid adenosyltransferase PduO (PduO)
Type: Family

ATP:cob(I)alamin (or ATP:corrinoid) adenosyltransferases (

), catalyse the conversion of cobalamin (vitamin B12) into its coenzyme form, adenosylcobalamin (AdoCbl)or coenzyme B12 . AdoCbl contains an adenosyl moiety liganded to the cobalt ion of cobalamin via a covalent Co-C bond. AdoCbl is required as a cofactor for the activity of certain enzymes.

ATP:cob(I)alamin adenosyltransferases are classed into three groups: CobA-type , EutT-type and PduO-type . Each of the three enzyme types appears to be specialised for particular AdoCbl-dependent enzymes or for the de novo synthesis AdoCbl. PduO and EutT are distantly related, sharing short conserved motifs, while CobA is evolutionarily unrelated and is an example of convergent evolution.

This entry represents bacterial Corrinoid adenosyltransferase PduO, which functions to convert inactive cobalamin to adenosylcobalamin (AdoCbl) for 1,2-propanediol degradation . Members of this family catalyse one of the steps in this process of assimilation of the exogenous inactive cobalamin . Cobalamin-dependent 1,2-propanediol utilization and glycerol utilization pathways both require AdoCbl for AdoCbl-dependent diol or glycerol dehydratases. PduO is encoded by the propanediol utilization pdu operon.

Proteins identified in this entry contain two domains, N- and C-terminal domains, both of which occur in a stand-alone forms. Therefore, PduO and other proteins have been suggested to be bifunctional enzymes that catalyse sequential steps in the adenosylation pathway, namely, the reduction of cob(II)alamin to cob(I)alamin and the adenosylation of cob(I)alamin . The N-terminal domain is responsible for the ATP:cob(I)alamin adenosyltransferase activity . The C-terminal domain is predicted to have a different enzymatic activity involving the same process: biosynthesis of an active AdoCbl cofactor.
Adenomatous polyposis coli protein repeat (APC_rpt)
Type: Repeat

This short region is found repeated in the mid region of the adenomatous polyposis proteins (APCs). In the human protein many cancer-linked SNPs are found near the first three occurrences of the motif. These repeats bind beta-catenin .
SAMP (SAMP)
Type: Repeat

This short region is found repeated in the mid region of the adenomatous polyposis proteins (APCs). This motif binds axin .
Bacteriophage head completion protein GpL (Phage_head_completion_GpL)
Type: Family

This entry represents the head completion protein GpL found in bacteriophages and prophages. GpL allows the completion of filled heads by rendering newly packaged DNA in the heads resistant to DNase. The protein is thought to bind to DNA filled capsids .
Penaeidin (Penaeidin)
Type: Family

This family consists of several isoforms of the penaeidin protein, which is specific to shrimps. Penaeidins, a unique family of antimicrobial peptides (AMPs) with both proline and cysteine-rich domains, were initially identified in the hemolymph of the Pacific white shrimp, Penaeus vannamei .
Zea mays MURB-like (Zea_mays_MuDR)
Type: Family

This family consists of several Zea mays (Maize) specific MURB-like proteins. The transposition of Mu elements underlying Mutator activity in maize requires a transcriptionally active MuDR element. Despite variation in MuDR copy number and RNA levels in Mutator lines, transposition events are consistently late in plant development, and Mu excision frequencies are similar .
Capsid scaffolding protein GpO (Capsid_scaffold_GpO)
Type: Family

The bacteriophage P2 capsid is formed by multiple copies of the capsid protein GpN. The scaffolding protein GpO, which is essential for the assembly of this capsid, consists of an N-terminal serine protease domain and a C-terminal scaffolding domain . During capsid assembly, GpO interacts with GpN via the N-terminal domain, while the C-terminal domain plays an essential role as a scaffold. When capsid assembly is complete the C-terminal domain of GpO is cleaved autocatalytically. Cleavage of GpN to its mature form by the remaining N-terminal domain then completes the maturation process.
AgrD, cyclic lactone autoinducer peptide (AgrD)
Type: Family

Members of this family of short peptides are precursors to thiolactone (unless Cys is replaced by Ser) cyclic autoinducer peptides, used in quorum-sensing systems in Gram-positive bacteria. The best characterised is the AgrD precursor, processed by the AgrB protein. Nearby proteins regularly encountered include a histidine kinase and a response regulator .

The agr locus was initially described in Staphylococcus aureus as an element controlling the production of exoproteins implicated in virulence. Its pattern of action has been shown to be complex, upregulating certain extracellular toxins and enzymes expressed post-exponentially and repressing some exponential-phase surface components. AgrD encodes the precursor of the autoinducing peptide (AIP).The AIP derived from AgrD by the action of AgrB interacts with AgrC in the membrane to activate AgrA, which upregulates transcription both from promoter P2, amplifying the response, and from P3, initiating the production of a novel effector: RNAIII. In S. aureus, delta-hemolysin is the only translation product of RNA III and is not involved in the regulatory functions of the transcript, which is therefore the primary agent for modulating the expression of other operons controlled by agr .