SII-SWORD/CoKE huggingface dataset:
UPF0166 (UPF0166)
Type: Family

UPF0166 protein family includes TM_0021 from Thermotoga maritima (

) and other proteins predominantly found in bacteria but also in some archaea. TM_0021 is a putative PII-like signaling protein thought to be involved in the regulation of the nitrogen status in this organism. The protein adopts a trimeric assembly. Each monomer folds into an α+β sandwich with a four-stranded antiparallel β-sheet packed against two antiparallel α-helices resembling a ferredoxin-like fold, with a short β-hairpin inserted before the first α-helix .
Protein of unknown function DUF192 (DUF192)
Type: Family

This entry describes proteins of unknown function.
Ribonucleotide reductase regulator NrdR-like (RNR_NrdR-like)
Type: Family

Ribonucleotide reductases (RNRs) are essential enzymes which catalyse the reduction of ribonucleotides to their respective deoxyribonucleotides, thus providing the precursors necessary for DNA synthesis .

Proteins in this entry are orthologues of the novel transcriptional regulator NrdR (

) from Streptomyces coelicolor. This protein negatively regulates the expression of the RNR genes in this organism . NrdR, like all proteins in this entry, contains an ATP-cone domain which may regulate DNA-binding activity by sensing deoxyribonucleotides , though since this domain resembles the allosteric effector region of some RNRs it has also been suggested that it may allow NrdR to directly modulate the activity of some reductases, in addition to its function as a transcriptional regulator .

NrdR-type proteins have been detected in a large number of bacterial genomes . They are encoded only once in any particular genome and are usually clustered near RNR genes or genes involved in chromosome replication. Currently, only a single archaeon Natronomonas pharaonis (strain DSM 2160/ATCC 35678) has been shown to encode one of these proteins.
DegV (DegV)
Type: Family

This family of proteins is related to DegV of Bacillus subtilis and includes paralogous sets in several species (B. subtilis, Deinococcus radiodurans, Mycoplasma pneumoniae) that are closer in percent identity to each other than to most homologues from other species. This suggests both recent paralogy and diversity of function.
DNA recombination RmuC (DNA_recombination_RmuC)
Type: Family

This protein contains several bacterial RmuC DNA recombination proteins. The function of the RMUC protein is unknown but it is suspected that it is either a structural protein that protects DNA against nuclease action, or is itself involved in DNA cleavage at the regions of DNA secondary structures . Proteins in this family are predicted to contain a central endonuclease-like fold domain, surrounded by coiled coils, consistent with a direct role in DNA cleavage .
GTP cyclohydrolase FolE2/MptA (GTP_cyclohydrolase_FolE2/MptA)
Type: Family

This is a family of prokaryotic/archaeal proteins with type I GTP cyclohydrolase activity. GTP cyclohydrolase I is the first enzyme of the de novo tetrahydrofolate biosynthetic pathway present in bacteria, fungi, and plants, and encoded in Escherichia coli by the folE gene . FolE is Zinc 2+ dependent .

In bacteria GTP cyclohydrolase FolE2 converts GTP to 7,8-dihydroneopterin triphosphate ; while in the archaea GTP cyclohydrolase MptA converts GTP to 7,8-dihydro-D-neopterin 2',3'-cyclic phosphate, the first intermediate in the biosynthesis of coenzyme methanopterin .
Sporulation regulator WhiA (Sporulation_regulator_WhiA)
Type: Family

This entry describes a family of DNA-binding proteins widely conserved in Gram-positive bacteria, and occasionally occurring elsewhere, such as in Thermotoga .

The family includes the sporulation regulator WhiA, which is required for expression of the ParB partioning protein during sporogenesis , as well as the uncharacterised protein MG103, found in mycoplasma.
L-lactate permease (Lactate_perm)
Type: Family

This entry represents a family of L-lactate permeases . This family also includes GlcA, a permease for glycolate which is structurally and functionally similar to L-lactate permease and can also transport L-lactate and D-lactate .
Adenosylcobinamide-GDP ribazoletransferase (CobS)
Type: Family

Cobalamin (vitamin B12) is a structurally complex cofactor, consisting of a modified tetrapyrrole with a centrally chelated cobalt. Cobalamin is usually found in one of two biologically active forms: methylcobalamin and adocobalamin. Most prokaryotes, as well as animals, have cobalamin-dependent enzymes, whereas plants and fungi do not appear to use it. In bacteria and archaea, these include methionine synthase, ribonucleotide reductase, glutamate and methylmalonyl-CoA mutases, ethanolamine ammonia lyase, and diol dehydratase . In mammals, cobalamin is obtained through the diet, and is required for methionine synthase and methylmalonyl-CoA mutase .

This entry represents the CobS protein, which joins adenosylcobinamide-GDP and alpha-ribazole to generate adenosylcobalamin (Ado-cobalamin) and also synthesizes adenosylcobalamin 5'-phosphate from adenosylcobinamide-GDP and alpha-ribazole 5'-phosphate . It catalyses the reactions:

Adenosylcobinamide-GDP + alpha-ribazole = GMP + adenosylcobalamin

Adenosylcobinamide-GDP + alpha-ribazole 5'-phosphate = GMP + adenosylcobalamin 5'-phosphate

The protein product from these catalyses is associated with a large complex of proteins and is induced by cobinamide. CobS is involved in part III of cobalamin biosynthesis, one of the late steps in adenosylcobalamin synthesis that, together with CobU, CobT, and CobC proteins, defines the nucleotide loop assembly pathway .
ATP-grasp fold, PylC-type (ATP-grasp_PylC-type)
Type: Domain

The ATP-grasp fold is one of several distinct ATP-binding folds, and is found in enzymes that catalyze the formation of amide bonds, catalyzing the ATP-dependent ligation of a carboxylate-containing molecule to an amino or thiol group-containing molecule . This fold is found in many different enzyme families, including various peptide synthetases, biotin carboxylase, synapsin, succinyl-CoA synthetase, pyruvate phosphate dikinase, and glutathione synthetase, amongst others . These enzymes contribute predominantly to macromolecular synthesis, using ATP-hydrolysis to activate their substrates.
Domain of unknown function DUF202 (DUF202)
Type: Domain

This entry describes a domain of unknown function found in bacterial inner membrane proteins and yeast vacuolar transporter chaperones.
Fe-S metabolism associated domain, SufE-like (Fe-S_metab-assoc_dom)
Type: Domain

This entry represents the core domain of SufE and related proteins. This domain of SufE shows strong structural similarity to IscU, and the sulfur-acceptor site in SufE coincides with the location of the cysteine residues mediating Fe-S cluster assembly in IscU. Thus, a conserved core structure is implicated in mediating the interactions of both SufE and IscU with the mutually homologous cysteine desulfurase enzymes present in their respective operons .
Putative manganese efflux pump (Mntp/YtaF)
Type: Family

MntP is a family of bacterial proteins with a signal peptide and four transmembrane domains. It is a putative manganese efflux pump, since deletion of the gene leads to profound manganese sensitivity and elevated intracellular manganese levels in bacteria. Manganese is a highly important trace nutrient for organisms from bacteria to humans, and acts as an important element in the defence against oxidative stress and as an enzyme cofactor .
Glycerol-3-phosphate acyltransferase, PlsY (G3P_acylTferase_PlsY)
Type: Family

PlsY is a glycerol-3-phosphate acyltransferase (GPAT) (

) that catalyses the transfer of an acyl group from acyl-ACP to glycerol-3-phosphate to form lysophosphatidic acid (LPA) . During this process, PlsY utilises a novel acyl-donor, acyl-phosphate produced by PlsX. In some bacteria, the PlsX/Y system plays a major part at the initial stage of glycerolipid synthesis . However, in E. coli, the other GPAT, PlsB (described in

) is also involved in this process .
Fido domain (Fido)
Type: Domain

This globular domain is named fido after the Fic and Doc proteins where it is found. It is approximately 125 to 150 residues long, and is present in proteins from all kingdoms of life , including:

Fic (filamentation induced by cAMP) from diverse bacteria. It contains a longer insert in the fido domain.

Doc (death on curing) proteins from phage P1 and several bacteria. All these proteins contain a minimal stand-alone version of the fido domain.

HypE (Huntingtin associated protein E) from animal. In humans, HypE is thought to interact with Huntingtin, one of the major proteins in the Huntington's disease protein interaction network. Proteins related to HypE are also found in several bacteria and some archaea. HypE proteins contain a longer insert in their fido domain and are typically multidomain proteins.

Type IV secretion system effector AnkX from Legionella.

VopS, a type III secretion system effector from Vibrio that causes eukaryotic cell cytotoxicity.

IbpA (virulence factor p76) from Haemophilus somnus. It includes an N-terminal haemagglutination activity domain, two fido domains and a peptidase C58 domain.

BepA, an anti-apoptotic bacterial effector protein, which is a type IV secretion system substrate.

The fido domain of Vibrio VopS covalently modifies Rho GTPase threonine with AMP to inhibit downstream signaling events in host cells. The AMPylation activity extends to a eukaryotic fido domain in Drosophila fic homologue CG9523. AMPylation represents a newly discovered posttranslational modification used to stably modify proteins with AMP. This signaling mechanism is predicted to be functionally similar to other posttranslation modifications such as phosphorylation, SUMOylation or acetylation, because the added moiety changes the activity of the modified protein. The covalent attachment of AMP by a phosphodiester bond is predicted to be reversible and is bulky enough to provide a docking site for a putative AMP binding domain .

The fido domain contains a central motif conserved in most sequences (H-x-F-x-[DE]-[AG]-N-[GK]-R), with the motif His contributing to fic AMPylation. The fido domain adopts an α-helical fold, arranged as a six-helix up and down bundle .
F420-non-reducing hydrogenase iron-sulfur subunit D (MvhD/FlpD)
Type: Domain

This entry represents the F420-non-reducing hydrogenase iron-sulfur subunit D from Archaeoglobus profundus, MvhD , which is part of a complex that provides reducing equivalents for heterodisulfide reductase , and from Methanobacterium thermoautotrophicum, known as FlpD . No specific functions have been assigned to the delta subunit.

This domain is also found at the C terminus of AhdrA1, a subunit of the ferredoxin:CoB-CoM heterodisulfide reductase, an enzyme complex that catalyzes the reversible reduction of CoM-S-S-CoB to the thiol-coenzymes H-S-CoM (coenzyme M) and H-S-CoB (coenzyme B) .
Formylmethanofuran dehydrogenase, subunit E domain (FmdEsu_dom)
Type: Domain

This entry represents a domain found in subunit E of formylmethanofuran dehydrogenase (FmdE). It appears to be related to the Tubulin/FtsZ 2-layer sandwich domain.

Formylmethanofuran dehydrogenases (

), found in methanogenic archaea, are molybdenum or tungsten iron-sulphur proteins containing a pterin dinucleotide cofactor. Formylmethanofuran dehydrogenase catalyses the reversible reduction of CO
2
and methanofuran via N-carboxymethanofuran (carbamate) to N-formylmethanofuran, the first and second steps in methanogenesis from CO
2
. There are two isoenzymes of formylmethanofuran dehydrogenase: a tungsten-containing isoenzyme (Fwd) and a molybdenum-containing isoenzyme (Fmd). The tungsten isoenzyme is constitutively transcribed, whereas transcription of the molybdenum operon is induced by molybdate .
S-ribosylhomocysteinase (LuxS) (S-ribosylhomocysteinase)
Type: Family

In bacteria, the regulation of gene expression in response to changes in cell density is called quorum sensing. Quorum-sensing bacteria produce, release, and respond to hormone-like molecules (autoinducers) that accumulate in the external environment as the cell population grows. For example, enteric bacteria use quorum sensing to regulate several traits that allow them to establish and maintain infection in their host, including motility, biofilm formation, and virulence-specific genes . The LuxS/AI-2 system is one of several quorum sensing mechanisms. AI-2 (autoinducer-2) is a signalling molecule that functions in interspecies communication by regulating niche-specific genes with diverse functions in various bacteria, often in response to population density. LuxS (S-ribosylhomocysteinase;

) is an autoinducer-production protein that has a metabolic function as a component of the activated methyl cycle. LuxS converts S-ribosylhomocysteine to homocysteine and 4,5-dihydroxy-2,3-pentanedione (DPD); DPD can then spontaneously cyclise to active AI-2 . LuxS is a homodimeric iron-dependent metalloenzyme containing two identical tetrahedral metal-binding sites similar to those found in peptidases and amidases .
Nitrate reductase, gamma subunit (Nitrate_red_gam)
Type: Family

The nitrate reductase enzyme (

) is composed of three subunits; an alpha, a beta and two gamma. It is the second nitrate reductase enzyme which it can substitute for the NRA enzyme in Escherichia coli allowing it to use nitrate as an electron acceptor during anoerobic respiration .

Nitrate reductase gamma subunit resembles cytochrome b and transfers electrons from quinones to the beta subunit .
Phosphatidylserine decarboxylase-related (PS_Dcarbxylase)
Type: Family

Phosphatidylserine decarboxylase plays a pivotal role in the synthesis of phospholipid by the mitochondria. The substrate phosphatidylserine is synthesized extramitochondrially and must be translocated to the mitochondria prior to decarboxylation .
Phosphatidylserine decarboxylases

is responsible for conversion of phosphatidylserine to phosphatidylethanolamine and plays a central role in the biosynthesis of aminophospholipids .

This family also includes L-tryptophan decarboxylase from the mushroom Psilocybe cubensis, which is required for the biosynthesis of the psychotropic agent psilocybin. This enzyme catalyses the first step in the biosynthetic pathway, converting L-tryptophan to tryptamine .
TauD/TfdA-like domain (TauD/TfdA-like)
Type: Domain

This domain is found in TauD/TfdA taurine catabolism dioxygenases. The Escherichia coli tauD gene is required for the utilisation of taurine (2-aminoethanesulphonic acid) as a sulphur source and is expressed only under conditions of sulphate starvation. TauD is an alpha-ketoglutarate-dependent dioxygenase catalysing the oxygenolytic release of sulphite from taurine . The 2,4-dichlorophenoxyacetic acid/alpha-ketoglutarate dioxygenase from Burkholderia sp. (strain RASC) also belongs to this family . TfdA from Ralstonia eutropha (Alcaligenes eutrophus) is a 2,4-D monooxygenase .

This domain is also found in gamma-butyrobetaine hydroxylase (GBBH), the enzyme responsible for the biosynthesis of L-carnitine, a key molecule of fatty acid metabolism. The GBBH monomer consists of this catalytic double-stranded β-helix (DBSH) domain, which is found in all 2-ketoglutarate (2KG) oxygenases, and a smaller N-terminal domain .
Potassium-transporting ATPase C chain (KdpC)
Type: Family

Kdp is a high affinity ATP-driven K+ transport system in Escherichia coli. It is a membrane complex (KdpFABC) composed of four subunits, KdpA, KdpB, KdpC and KdpF, although KdpF is not present in some species . It maintains intracellular homeostasis, cell shape and turgor under potassium-limiting conditions. KdpA is the K+-transporting subunit of this complex, while KdpB is a P-type ATPase that provides the energy for K+ transport. Both subunits are joined by KdpC, a probable catalytic chaperone and KdpF, that may stabilize the complex. KdpC and KdpF have single transmembrane helices and no known homologues outside of Kdp .

This family represents the KdpC subunit from KdpFABC complex.
1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXP_reductoisomerase)
Type: Family

1-deoxy-D-xylulose 5-phosphate reductoisomerase synthesises 2-C-methyl-D-erythritol 4-phosphate from 1-deoxy-D-xylulose 5-phosphate in a single step by intramolecular rearrangement and reduction and is responsible for terpenoid biosynthesis in some organisms . In Arabidopsis thaliana 1-deoxy-D-xylulose 5-phosphate reductoisomerase is the first committed enzyme of the non-mevalonate pathway for isoprenoid biosynthesis. The enzyme requires Mn2+, Co2+ or Mg2+ for activity, with the first being most effective.

The structure of this enzyme has been solved, showing the protein forms a dimeric assembly and contains a metal ion in the active site .
Paired amphipathic helix (PAH)
Type: Repeat

This entry represents the paired amphipathic helix (PAH) repeat. Sin3 proteins have at least three PAH domains (PAH1, PAH2, and PAH3) . They are components of a co-repressor complex that silences transcription, playing important roles in the transition between proliferation and differentiation. Sin3 proteins are recruited to the DNA by various DNA-binding transcription factors such as the Mad family of repressors, Mnt/Rox, PLZF, MeCP2, p53, REST/NRSF, MNFbeta, Sp1, TGIF and Ume6 . Sin3 acts as a scaffold protein that in turn recruits histone-binding proteins RbAp46/RbAp48 and histone deacetylases HDAC1/HDAC2, which deacetylate the core histones resulting in a repressed state of the chromatin . The PAH domains are protein-protein interaction domains through which Sin3 fulfils its role as a scaffold. The PAH2 domain of Sin3 can interact with a wide range of unrelated and structurally diverse transcription factors that bind using different interaction motifs. For example, the Sin3 PAH2 domain can interact with the unrelated Mad and HBP1 factors using alternative interaction motifs that involve binding in opposite helical orientations .
CP12 domain (CP12_dom)
Type: Domain

This entry represents an uncharacterised domain found in calvin cycle protein CP12 and other proteins. This domain is sometimes found in association cystathionine-beta-synthase domains.

CP12 is a chloroplast protein that regulates the Calvin cycle responsible for CO2 assimilation . Oxidized CP12 forms a supramolecular complex with two key Calvin cycle enzymes, GAPDH (glyceraldehyde-3-phosphate dehydrogenase) and PRK (phosphoribulokinase), down-regulating their activity. It also interacts with other enzymes such as aldolase and malate dehydrogenase .
Undecaprenyl-diphosphatase UppP (UppP)
Type: Family

This is a family of small, highly hydrophobic proteins. Over-expression of this protein in Escherichia coli is associated with bacitracin resistance , and the protein was originally proposed to be an undecaprenol kinase called bacA. BacA protein, however, does not show undecaprenol phosphokinase activity . It is now known to be an undecaprenyl pyrophosphate phosphatase (

) and is renamed UppP. It is not the only protein associated with bacitracin resistance .
Colicin V production, CvpA (Colicin-V_CvpA)
Type: Family

Colicin V is a small extracellular protein toxin which kills sensitive cells by disrupting their membrane potential . Colicin V is produced from large low-copy plasmids and requires four plasmid genes for synthesis export and immunity [

3034857). The cvaC gene is the structural gene for colicin V and cvaA and cvaB are required for processing and export of the toxin through the inner and outer membranes cvi confers immunity to the host cell. There are several stages at which host factors could play a role in colicin V production and mutations that alter any of these functions should result in lowered levels of extracellular colicin V

].

Colicin V production protein is required in Escherichia coli for colicin V production from plasmid pColV-K30 . This entry represent the CvpA protein, which is involved in colicin V production. It is coded for by the cvpA gene, which is found upstream of the purF gene in the purF operon .
S-adenosylmethionine decarboxylase family, prokaryotic (AdoMetDC_fam_prok)
Type: Family

Polyamines such as spermidine and spermine are essential for cellular growth under most conditions, being implicated in a large number of cellular processes including DNA, RNA and protein synthesis. S-adenosylmethionine decarboxylase (AdoMetDC) plays an essential regulatory role in the polyamine biosynthetic pathway by generating the n-propylamine residue required for the synthesis of spermidine and spermine from putrescein . Unlike many amino acid decarboxylases AdoMetDC uses a covalently bound pyruvate residue as a cofactor rather than the more common pyridoxal 5'-phosphate. These proteins can be divided into two main groups which show little sequence similarity either to each other, or to other pyruvoyl-dependent amino acid decarboxylases: class I enzymes found in bacteria and archaea, and class II enzymes found in eukaryotes. In both groups the active enzyme is generated by the post-translational autocatalytic cleavage of a precursor protein. This cleavage generates the pyruvate precursor from an internal serine residue and results in the formation of two non-identical subunits termed alpha and beta which form the active enzyme .

This entry represents the prokaryotic AdoMetDC family, which includes S-adenosylmethionine decarboxylase and arginine decarboxylase proenzymes .
tRNA wybutosine-synthesizing protein (tRNA_yW-synthesising)
Type: Domain

The methyltransferase TYW3 (tRNA-yW- synthesising protein 3) has been identified in yeast to be involved in wybutosine (yW) biosynthesis . yW is a complexly modified guanosine residue that contains a tricyclic base and is found at the 3'-position adjacent the anticodon of phenylalanine tRNA. TYW3 is an N-4 methylase that methylates yW-86 to yield yW-72 in an Ado-Met-dependent manner .
Epoxyqueuosine reductase QueH (QueH)
Type: Family

QueH has been predicted to be an epoxyqueuosine reductase that catalyzes the conversion of epoxyqueuosine (oQ) to queuosine (Q), which is a hypermodified base found in the wobble positions of tRNA(Asp), tRNA(Asn), tRNA(His) and tRNA(Tyr) .
Pirin, N-terminal domain (Pirin_N_dom)
Type: Domain

Eukaryotic pirins are highly conserved nuclear proteins that may function as transcriptional regulators with a role in apoptosis . Prokaryotic homologues have also been identified. Both bacterial and human pirins have been shown to possess quercetinase activity , although this is not universally true for all family members - YhaK (

), for example, displays no such enzymatic activity .

Pirin is composed of two structurally similar domains arranged face to face. Although the two domains are similar, the C-terminal domain of pirin differs from the N-terminal domain as it does not contain a metal binding site and its sequence does not contain the conserved metal-coordinating residues .

Pirin is considered a member of the cupin superfamily on the basis of primary sequence and structural similarity. The presence of a metal binding site in the N-terminal β-barrel of pirin, may be significant in its interaction with Bcl-3 and nuclear factor I (NFI) and role in regulating NF-kappaB transcription factor activity .

This entry represents the Pirin N-terminal domain.