SII-SWORD/CoKE huggingface dataset:
Coenzyme PQQ synthesis protein E-like (PqqE-like)
Type: Family

This entry represents coenzyme PQQ biosynthesis protein E, which is a prototypical peptide-cyclising radical SAM enzyme. It links a Tyr to a Glu as the first step in the biosynthesis of pyrrolo-quinoline-quinone (coenzyme PQQ) from the precursor peptide PqqA. PQQ is required for some glucose dehydrogenases and alcohol dehydrogenases.

This entry also includes some other radical SAM enzymes, such as tungsten-containing aldehyde ferredoxin oxidoreductase cofactor-modifying protein, adoMet-dependent heme synthase and Fe-coproporphyrin III synthase .
Uncharacterised conserved protein UCP037429 (UCP037429)
Type: Family

There is currently no experimental data for members of this group or their homologues, nor do they exhibit features indicative of any function. Members of this entry are mainly found in proteobacteria.
Sensor histidine kinase LiaS/VraS (LiaS/VraS)
Type: Family

This entry represents signal transduction histidine kinases such as LiaS from Bacillus subtilis and VraS from Staphylococcus aureus. LiaS is a member of the two-component regulatory system LiaS (HK)/LiaR(RR), which is probably involved in response to a subset of cell wall-active antibiotics that interfere with the lipid II cycle in the cytoplasmic membrane (bacitracin, nisin, ramoplanin and vancomycin) . LiaS may also be involved in response to cationic antimicrobial peptides and secretion stress.
Signal transduction histidine kinase, NreB (Sig_transdc_His_kinase_NreB)
Type: Family

Two-component signal transduction systems enable bacteria to sense, respond, and adapt to a wide range of environments, stressors, and growth conditions . Some bacteria can contain up to as many as 200 two-component systems that need tight regulation to prevent unwanted cross-talk . These pathways have been adapted to response to a wide variety of stimuli, including nutrients, cellular redox state, changes in osmolarity, quorum signals, antibiotics, and more . Two-component systems are comprised of a sensor histidine kinase (HK) and its cognate response regulator (RR) . The HK catalyses its own auto-phosphorylation followed by the transfer of the phosphoryl group to the receiver domain on RR; phosphorylation of the RR usually activates an attached output domain, which can then effect changes in cellular physiology, often by regulating gene expression. Some HK are bifunctional, catalysing both the phosphorylation and dephosphorylation of their cognate RR. The input stimuli can regulate either the kinase or phosphatase activity of the bifunctional HK.

This entry represents signal transduction histidine kinases such as NreB. The nreABC (nitrogen regulation) operon encodes a two-component regulatory system that controls dissimilatory nitrate/nitrite reduction in response to oxygen in staphylococci. NreB is a cytosolic protein with four N-terminal cysteine residues, where both the cysteine cluster and iron ions are required for function .
Signal transduction histidine kinase, STH3221, predicted (Sig_transdc_His_kin_STH3221)
Type: Family

Two-component signal transduction systems enable bacteria to sense, respond, and adapt to a wide range of environments, stressors, and growth conditions . Some bacteria can contain up to as many as 200 two-component systems that need tight regulation to prevent unwanted cross-talk . These pathways have been adapted to response to a wide variety of stimuli, including nutrients, cellular redox state, changes in osmolarity, quorum signals, antibiotics, and more . Two-component systems are comprised of a sensor histidine kinase (HK) and its cognate response regulator (RR) . The HK catalyses its own auto-phosphorylation followed by the transfer of the phosphoryl group to the receiver domain on RR; phosphorylation of the RR usually activates an attached output domain, which can then effect changes in cellular physiology, often by regulating gene expression. Some HK are bifunctional, catalysing both the phosphorylation and dephosphorylation of their cognate RR. The input stimuli can regulate either the kinase or phosphatase activity of the bifunctional HK.

A variant of the two-component system is the phospho-relay system. Here a hybrid HK auto-phosphorylates and then transfers the phosphoryl group to an internal receiver domain, rather than to a separate RR protein. The phosphoryl group is then shuttled to histidine phosphotransferase (HPT) and subsequently to a terminal RR, which can evoke the desired response .

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 , and CheA, which plays a central role in the chemotaxis system . 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 (with bifunctional enzymes) the phosphotransfer from aspartyl phosphate back to ADP or to water . The kinase core has a unique fold, distinct from that of the Ser/Thr/Tyr kinase superfamily.

This entry represents proteins predicted to act as signal transduction histidine kinases, such as STH3221 from Symbiobacterium thermophilum.
Signal transduction histidine kinase, ChrS (Sig_transdc_His_kinase_ChrS)
Type: Family

Two-component signal transduction systems enable bacteria to sense, respond, and adapt to a wide range of environments, stressors, and growth conditions . Some bacteria can contain up to as many as 200 two-component systems that need tight regulation to prevent unwanted cross-talk . These pathways have been adapted to response to a wide variety of stimuli, including nutrients, cellular redox state, changes in osmolarity, quorum signals, antibiotics, and more . Two-component systems are comprised of a sensor histidine kinase (HK) and its cognate response regulator (RR) . The HK catalyses its own auto-phosphorylation followed by the transfer of the phosphoryl group to the receiver domain on RR; phosphorylation of the RR usually activates an attached output domain, which can then effect changes in cellular physiology, often by regulating gene expression. Some HK are bifunctional, catalysing both the phosphorylation and dephosphorylation of their cognate RR. The input stimuli can regulate either the kinase or phosphatase activity of the bifunctional HK.

A variant of the two-component system is the phospho-relay system. Here a hybrid HK auto-phosphorylates and then transfers the phosphoryl group to an internal receiver domain, rather than to a separate RR protein. The phosphoryl group is then shuttled to histidine phosphotransferase (HPT) and subsequently to a terminal RR, which can evoke the desired response .

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 , and CheA, which plays a central role in the chemotaxis system . 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 (with bifunctional enzymes) the phosphotransfer from aspartyl phosphate back to ADP or to water . The kinase core has a unique fold, distinct from that of the Ser/Thr/Tyr kinase superfamily.

This entry represents signal transduction histidine kinases such as ChrS.
Signal transduction histidine kinase, hybrid-type, BC3207, predicted (Sig_transdc_His_kin_hyb_BC3207)
Type: Family

This entry represents predicted hybrid signal transduction histidine kinases, BC3207 type.

Two-component signal transduction systems enable bacteria to sense, respond, and adapt to a wide range of environments, stressors, and growth conditions . Some bacteria can contain up to as many as 200 two-component systems that need tight regulation to prevent unwanted cross-talk . These pathways have been adapted to response to a wide variety of stimuli, including nutrients, cellular redox state, changes in osmolarity, quorum signals, antibiotics, and more . Two-component systems are comprised of a sensor histidine kinase (HK) and its cognate response regulator (RR) . The HK catalyses its own auto-phosphorylation followed by the transfer of the phosphoryl group to the receiver domain on RR; phosphorylation of the RR usually activates an attached output domain, which can then effect changes in cellular physiology, often by regulating gene expression. Some HK are bifunctional, catalysing both the phosphorylation and dephosphorylation of their cognate RR. The input stimuli can regulate either the kinase or phosphatase activity of the bifunctional HK.

A variant of the two-component system is the phospho-relay system. Here a hybrid HK auto-phosphorylates and then transfers the phosphoryl group to an internal receiver domain, rather than to a separate RR protein. The phosphoryl group is then shuttled to histidine phosphotransferase (HPT) and subsequently to a terminal RR, which can evoke the desired response .

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 , and CheA, which plays a central role in the chemotaxis system . 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 (with bifunctional enzymes) the phosphotransfer from aspartyl phosphate back to ADP or to water . The kinase core has a unique fold, distinct from that of the Ser/Thr/Tyr kinase superfamily.
Mitochondrial translation factor Atp22 (Atp22)
Type: Family

This entry represents the mitochondrial translation factor Atp22, which is specific for subunit 6 of the mitochondrial ATPase . Atp22 is a component of the mitochondrial inner membrane required for the expression of the CF(0) component of the ATPase .
Uncharacterised conserved protein UCP037442, alpha/beta hydrolase, RSp0795 (UCP037442_abhydr)
Type: Family

This group represents a predicted alpha/beta hydrolase, RSp0795 type.
Alpha/beta hydrolase, predicted (Abhydr)
Type: Family

This group represents a predicted alpha/beta hydrolase.
Actin patch protein 1 (APP1)
Type: Family

This entry includes phosphatidate phosphatase App1 from budding yeasts. It is a Mg2+-dependent phosphatidate (PA) phosphatase which catalyses the dephosphorylation of PA to yield diacylglycerol. It may play a role in vesicular trafficking through its PAP activity at cortical actin patches .
Uncharacterised conserved protein UCP037465, zinc finger protein, AF1427 (UCP037465_Znf)
Type: Family

This group represents a predicted zinc finger protein, AF1427 type.
Clathrin heavy chain linker domain-containing protein 1 (CLHC1)
Type: Family

This group represents a clathrin heavy chain-related protein.
Peptidase S54, rhomboid, metazoan (Peptidase_S54_rhomboid_met)
Type: Family

This entry represents metazoan rhomboid proteins (

), integral membrane proteins thought to be involved in regulated intra-membrane proteolysis and the subsequent release of functional polypeptides from their membrane anchors . Rhomboid proteins cleave type-1 transmembrane domains using a catalytic triad composed of serine, histidine and asparagine contributed by different transmembrane domains. These proteins belong to the S54 peptidase family of proteins.
Cytochrome b561 and DOMON domain-containing protein (UCP037471)
Type: Family

This entry represents a group of DOMON domain (named after DOpamine beta-MOnooxygenase N-terminal domain) containing proteins from plants. They also contain a cytochrome b561 domain C-terminal to the DOMON domain. DOMON domain could bind catecholamines and thereby could regulate the cytochrome b561 domain function. Proteins in this family may act as a catecholamine-responsive trans-membrane electron transporter .
5-methyltetrahydrofolate-homocysteine S-methyltransferase, bacterial (MetH_bac)
Type: Family

This group represents a bacterial form of the 5-methyltetrahydrofolate-homocysteine S-methyltransferase MetH.
Hermansky-Pudlak syndrome 3 protein (HPS3)
Type: Family

The Hermansky-Pudlak syndrome 3 protein, also known as BLOC-2 complex member HPS3, is involved in early stages of melanosome biogenesis and maturation . Hermansky-Pudlak syndrome 3 (HPS3) is a form of Hermansky-Pudlak syndrome, a genetically heterogeneous autosomal recessive disorder characterised by oculocutaneous albinism, bleeding due to platelet storage pool deficiency, and lysosomal storage defects .
BLOC-2 complex, Hps6 subunit (BLOC-2_complex_Hps6_subunit)
Type: Family

Lysosome-related organelles comprise a group of specialised intracellular compartments that include melanosomes and platelet dense granules in mammals and eye pigment granules in insects. Hermansky-Pudlak syndrome (HPS) is a disorder of lysosome-related organelle biogenesis. Genes associated with HPS encode subunits of three complexes that are known as biogenesis of lysosome-related organelles complex (BLOC)-1, -2 and -3 . There are eight known HPS proteins of the BLOCs ]. Organelles affected in HPS include the melanosome, resulting in hypopigmentation, and the platelet delta (dense) granule, resulting in prolonged bleeding times.

HPS in humans or mice is caused by mutations in any of 15 genes, five of which encode subunits BLOC-1. BLOC-1 and BLOC-2 act sequentially in the same pathway. Melanosome maturation requires at least two cargo transport pathways directly from early endosomes to melanosomes. One pathway mediated by AP-3, and one pathway mediated by BLOC-1 and BLOC-2 . The adaptor protein AP-3 complex is a component of the cellular machinery that controls protein sorting from endosomes to lysosomes and melanosomes. BLOC-1 interacts physically and functionally with AP-3 to facilitate the trafficking of a known AP-3 cargo, CD63, and of tyrosinase-related protein 1 (Tyrp1). BLOC-1 also interacts with BLOC-2 to facilitate Tyrp1 trafficking by a mechanism apparently independent of AP-3 function. Both BLOC-1 and -2 predominantly localise to early endosome-associated tubules .

Complex-2 (BLOC-2) contains the HPS3, HPS5 and HPS6 proteins as subunits. Fibroblasts deficient in the BLOC-2 subunits HPS3 or HPS6 have normal basal secretion function of the lysosomal enzyme beta-hexosaminidase .

This entry includes BLOC-2 complex, Hps6 subunit, which may regulate the synthesis and function of lysosomes and of highly specialized organelles . It acts as cargo adapter for the dynein-dynactin motor complex to mediate the transport of lysosomes from the cell periphery to the perinuclear region. Hsp6 facilitates retrograde lysosomal trafficking by linking the motor complex to lysosomes, and perinuclear positioning of lysosomes is crucial for the delivery of endocytic cargos to lysosomes, for lysosome maturation and function .
Peptidoglycan GlcNAc deacetylase (Peptidoglycan_deacetylase)
Type: Family

This entry represents peptidoglycan GlcNAc deacetylases, including Peptidoglycan-N-acetylglucosamine deacetylase (PgdA) from Streptococcus pneumoniae, which confers host lysozyme resistance and contributes to pneumococcal virulence . Structural analysis from S. pneumoniae revealed that PGDA is a metalloenzyme using a His-His-Asp zinc-binding triad with a nearby aspartic acid and histidine acting as the catalytic base and acid, respectively . This entry also includes Peptidoglycan-N-acetylmuramic acid deacetylase PdaC from Bacillus subtilis, which has high amino acid sequence similarity with Streptococcus pneumoniae PgdA .
Sulphite reductase, assimilatory (Sulphite_reductase_assimil)
Type: Family

This group represents a sulphite reductase, assimilatory type.
DUF34/NIF3, bacteria (DUF34/NIF3_bac)
Type: Family

This family represents DUF34/metal-binding proteins (previously known as GTP cyclohydrolase 1 type 2) from bacteria.

This entry includes the DUF34/metal-binding protein/NIF3 proteins, which are widely distributed across superkingdoms. They were previously annotated as GTP cyclohydrolase 1 type 2 and, recently, through a comprehensive literature review and integrative bioinformatic analyses it was revealed that annotations for these members are misleading as they were based on a single set of in vitro results examining the NIF3 homolog of Helicobacter pylori . Actually, they have varied phenotypes with the unifying functional role as metal-binding proteins .

NIF3 interacts with the yeast transcriptional coactivator Ngg1p which is part of the ADA complex, the exact function of this interaction is unknown .
DUF34/NIF3, animal (DUF34/NIF3_animal)
Type: Family

This entry represents DUF34/metal-binding proteins (also referred to as NIF3-like protein 1) from animals. They share protein sequence similarity with budding yeast NIF3, which interacts with the yeast transcriptional coactivator Ngg1p that is part of the ADA complex .

This entry includes the DUF34/metal-binding protein/NIF3 proteins, which are widely distributed across superkingdoms. They were previously annotated as GTP cyclohydrolase 1 type 2 and, recently, through a comprehensive literature review and integrative bioinformatic analyses it was revealed that annotations for these members are misleading as they were based on a single set of in vitro results examining the NIF3 homologue of Helicobacter pylori . Actually, they have varied phenotypes with the unifying functional role as metal-binding proteins .
Predicted hydrolase of the HAD superfamily, SPs0319-type (HAD_SPs0319-typ)
Type: Family

This group represents a predicted hydrolase of the HAD superfamily, SPs0319-type (

).
Opine oxidase, subunit A/hydrogen cyanide synthase, subunit B (Opine_Oxase_asu/HCN_bsu)
Type: Family

This entry represents subunit A of opine oxidase, which is involved in the oxidative cleavage of octopine into L-arginine and pyruvate during octopine degradation as part of opine metabolism in bacteria. Opine oxidase exists as a heterodimer of one subunit A and one subunit B.
Cell shape-determining protein MreD, predicted (Cell_shape_determin_MreD_prd)
Type: Family

The MreD (murein formation D) protein is involved in bacterial cell shape determination. Most rod-shaped bacteria depend on MreB and RodA to achieve either a rod shape or some other non-spherical morphology such as coil or stalk formation. MreD is encoded in an operon with MreB, and often with RodA and PBP-2 as well. It is highly hydrophobic (therefore somewhat low-complexity) and highly divergent, and therefore cannot always be identified on the basis of sequence similarity.

This group represents predicted MreD proteins found primarily in Clostridium and Treponema species.
Betaine-homocysteine S-methyltransferase, BHMT (Betaine-hCys_S-MeTrfase_BHMT)
Type: Family

Betaine-homocysteine methyltransferase (BHMT) is involved in the regulation of homocysteine metabolism. It converts betaine and homocysteine to dimethylglycine and methionine, respectively. This reaction is also required for the irreversible oxidation of choline. BHMT requires a thiol reducing agent for its activity. The catalytic zinc of BHMT is bound by three thiolates and one hydroxyl group. A disulphide bond is formed between two of the three zinc-binding ligands when BHMT is inactive .

BHMT regulates homocysteine levels in the liver. The BHMT/betaine system directly protects hepatocytes from homocysteine-induced injury, but not tunicamycin-induced injury, including an endoplasmic reticulum stress response, lipid accumulation, and cell death. It also has a generalized effect on liver lipids by inducing ApoB expression and increasing S-adenosylmethionine/S-adenosylhomocysteine . However, the peripheral metabolism of homocysteine protects the liver without the direct action of BHMT in the liver .

The human betaine-homocysteine methyltransferase-2 is also a zinc metalloenzyme that uses S-methylmethionine (SMM) as a methyl donor for the methylation of homocysteine. Unlike the highly homologous BHMT, BHMT-2 cannot use betaine as a substrate .

This entry also includes homocysteine S-methyltransferase (

), which converts S-adenosylmethionine to methionine ; selenocysteine methyltransferase (

), which methylates DL-and L-selenocysteine, DL-homocysteine, and DL-and L-cysteine ; and S-methylmethionine--homocysteine S-methyltransferase BHMT2 (also

), which converts converts homocysteine to methionine .
Nucleoside-triphosphatase, alveolata (NTPase_alveloata)
Type: Family

This entry represents nucleoside-triphosphatase (

) from parasites such as Toxoplasma gondii . This enzyme acts as a heterotetramer. It is secreted and has been detected in host cell parasitophorous vacuoles, where it may perform an important processing step in the conversion of high energy nucleotides prior to uptake by the parasite. NTPAse-II has a specific activity 4.5-fold lower than NTPAse-I in hydrolysis of ATP. The primary difference between these isozymes lies in their ability to hydrolyse nucleoside triphosphate versus diphosphate substrates. While NTPAse-II hydrolyses ATP to ADP and ADP to AMP at almost the same rate, NTPAse-I hydrolyses ADP to AMP at a much slower rate (0.7% of the rate for ATP).
Multidomain scavenger receptor-like protein PxSR (Scavenger_rcpt_PxSR)
Type: Family

This group represents a multidomain scavenger receptor-like protein only found in Apicomplexa parasites. PxSR from the malaria parasite has not only a role in sporogonic development, it may also have a multiplicity of functions .
Rab geranylgeranyltransferase complex component A (Mrs6)
Type: Family

This group represents the substrate-binding subunit (component A) of the Rab geranylgeranyltransferase (GGTase) complex from fungi .