SII-SWORD/CoKE huggingface dataset:
NADH:ubiquinone oxidoreductase-like, 20kDa subunit (NADH_UbQ_OxRdtase-like_20kDa)
Type: Domain

This entry represents a Rossmann fold-type domain found in NADH:ubiquinone oxidoreductase 20kDa subunit, [NiFe] hydrogenase small subunit and coenzyme F420 hydrogenase subunit gamma.

NADH:ubiquinone oxidoreductase (complex I) (

) is a respiratory-chain enzyme that catalyses the transfer of two electrons from NADH to ubiquinone in a reaction that is associated with proton translocation across the membrane (NADH + ubiquinone = NAD+ + ubiquinol) . Among the many polypeptide subunits that make up complex I, there is one with a molecular weight of 20kDa (in mammals) , which is a component of the iron-sulphur (IP) fragment of the enzyme. It seems to bind a 4Fe-4S iron-sulphur cluster.

The great majority of hydrogenases (H2ases) contain iron-sulfur clusters and two metal atoms at their active centre, Ni and Fe in the case of the [NiFe]-H2ases. They catalyse the reversible oxidation of hydrogen gas and play a central role in microbial energy metabolism; in addition to their role in fermentation and H2 respiration . The small subunit (chain A) contains the Fe4S4 clusters, whereas the large subunit (chain B) binds the binuclear NiFe active site .
NADH-ubiquinone oxidoreductase, 20 Kd subunit (NADH_UQ_OxRdtase_20Kd_su)
Type: Family

Among the many polypeptide subunits that make up complex I, there is one with a molecular weight of 20kDa (in mammals) , which is a component of the iron-sulphur (IP) fragment of the enzyme. It seems to bind a 4Fe-4S iron-sulphur cluster. The 20kDa subunit has been found to be nuclear encoded, as a precursor form with a transit peptide in mammals, and in Neurospora crassa. It is mitochondrial encoded in Paramecium (gene psbG) and chloroplast encoded in various higher plants (gene ndhK or psbG).
D-isomer specific 2-hydroxyacid dehydrogenase, catalytic domain (D-isomer_2_OHA_DH_cat_dom)
Type: Domain

A number of NAD-dependent 2-hydroxyacid dehydrogenases which seem to be specific for the D-isomer of their substrate have been shown to be functionally and structurally related. The catalytic domain contains a number of conserved charged residues which may play a role in the catalytic mechanism . The NAD-binding domain is described in

.
D-isomer specific 2-hydroxyacid dehydrogenase, NAD-binding domain (D-isomer_DH_NAD-bd)
Type: Domain

A number of NAD-dependent 2-hydroxyacid dehydrogenases which seem to be specific for the D-isomer of their substrate have been shown to be functionally and structurally related. All contain a glycine-rich region located in the central section of these enzymes, this region corresponds to the NAD-binding domain. This domain is inserted into the catalytic domain. The catalytic domain is described in (

).
Intein (INTEIN)
Type: Domain

Inteins, or protein introns, are parts of protein sequences that are post-translationally excised, their flanking regions (exteins) being spliced together to yield an additional protein product . This process is believed to be self-catalysed, apparently initiating at the C-terminal splice junction, where a conserved asparagine residue mediates the nucleophilic attack of the peptide bond between it and its neighbouring residue. Most inteins consist of two domains: One is involved in autocatalytic splicing, and the other is an endonuclease that is important in the spread of inteins .

Inteins are between 134 and 608 amino acids long, and they are found in members of all three domains of life: eukaryotes, bacteria, and archaea, although most frequently in archaea. Inteins are found in proteins with diverse functions, including metabolic enzymes, DNA and RNA polymerases, proteases, ribonucleotide reductases, and the vacuolar-type ATPase. However, enzymes involved in DNA replication and repair appear to dominate. Inteins are found in conserved regions of conserved proteins and can be regarded as parasitic genetic elements . Inteins are difficult to identify from sequence data because they lie in the same reading frame as the spliced protein and they are characterised by only a few short conserved motifs : two of these are similar to the nonapeptide LAGLIDADG, which is diagnostic of certain homing endonucleases (mutation of one such motif causes loss of endonuclease activity, but not of the protein splicing function); another includes the C' splice site, mutations in which disable protein function.
RND efflux pump, membrane fusion protein (RND_pump_MFP)
Type: Family

This entry represents a large family of polypeptides, the MFP (for membrane fusion protein) family. MFPs are a component of the RND family of transporters (RND refers to resistance, nodulation, and cell division). MFPs are proposed to span the periplasm in some way linking the inner and outer membranes . However, some members of this family are found in Gram-positive bacteria, where there is no outer membrane. MFPs are involved in the export of a variety of compounds, from drug molecules to large polypeptides, and are united by their similar overall structural organisation, combined with some conserved regions .
Secretion protein HlyD, conserved site (Secretion_HlyD_CS)
Type: Conserved_site

Gram-negative bacteria produce a number of proteins which are secreted into the growth medium by a mechanism that does not require a cleaved N-terminal signal sequence. These proteins, while having different functions, require the help of two or more proteins for their secretion across the cell envelope.

The secretion proteins are evolutionary related and consist of from 390 to 480 amino acid residues. They seem to be anchored in the inner membrane by a N-terminal transmembrane region. The C-terminal section of these proteins is the best conserved region.
Pseudouridine synthase, RsuA/RluA-like (PsdUridine_synth_RsuA/RluA)
Type: Domain

Pseudouridine synthases catalyse the isomerisation of uridine to pseudouridine (Psi) in a variety of RNA molecules, and may function as RNA chaperones. Pseudouridine is the most abundant modified nucleotide found in all cellular RNAs. There are four distinct families of pseudouridine synthases that share no global sequence similarity, but which do share the same fold of their catalytic domain(s) and uracil-binding site and are descended from a common molecular ancestor. The catalytic domain consists of two subdomains, each of which has an α+β structure that has some similarity to the ferredoxin-like fold (note: some pseudouridine synthases contain additional domains). The active site is the most conserved structural region of the superfamily and is located between the two homologous domains. These families are :

Pseudouridine synthase I, TruA.

Pseudouridine synthase II, TruB, which contains and additional C-terminal PUA domain.

Pseudouridine synthase RsuA. RluB, RluE and RluF are also part of this family.

Pseudouridine synthase RluA. TruC, RluC and RluD belong to this family.

Pseudouridine synthase TruD, which has a natural circular permutation in the catalytic domain, as well as an insertion of a family-specific α+β subdomain.

This entry represents several different pseudouridine synthases from family 3, including: RsuA (acts on small ribosomal subunit), RluA, RluB, RluC, RluD, RluE and RluF (act on large ribosomal subunit) and TruC .

RsuA from Escherichia coli catalyses formation of pseudouridine at position 516 in 16S rRNA during assembly of the 30S ribosomal subunit . RsuA consists of an N-terminal domain connected by an extended linker to the central and C-terminal domains. Uracil and UMP bind in a cleft between the central and C-terminal domains near the catalytic residue Asp 102. The N-terminal domain shows structural similarity to the ribosomal protein S4. Despite only 15% amino acid identity, the other two domains are structurally similar to those of the tRNA-specific psi-synthase TruA, including the position of the catalytic Asp. Our results suggest that all four families of pseudouridine synthases share the same fold of their catalytic domain(s) and uracil-binding site.

RluB, RluC, RluD, RluE and RluF are homologous enzymes which each convert specific uridine bases in E. coli ribosomal 23S RNA to pseudouridine:

RluB modifies uracil-2605.

RluC modifies uracil-955, U-2504, and U-2580.

RluD modifies uracil-1911, U-1915, and U-1917.

RluE modifies uracil-3457.

RluF modifies uracil-2604, and to a lesser extent U-2605.

RluD also possesses a second function related to proper assembly of the 50S ribosomal subunit that is independent of Psi-synthesis . Both RluC and RluD have an N-terminal S4 RNA binding domain. Despite the conserved topology shared by RluC and RluD, the surface shape and charge distribution are very different.
5'-Nucleotidase, conserved site (5'-Nucleotdase_CS)
Type: Conserved_site

5'-nucleotidases (

) are enzymes that catalyse the hydrolysis of phosphate esterified at carbon 5' of the ribose and deoxyribose portions of nucleotide molecules. 5'-nucleotidase is a ubiquitous enzyme found in a wide variety of species and which occurs in different cellular locations. All these proteins share regions of sequence similarity, the conserved sites represented in this entry are located in the N-terminal section of these enzymes and contain a perfectly conserved pentapeptide.
Glucosamine/galactosamine-6-phosphate isomerase (Glc/Gal-6P_isomerase)
Type: Domain

This domain is characteristic of the enzymes 6-phosphogluconolactonase (

), Glucosamine-6-phosphate isomerase (

), and Galactosamine-6-phosphate isomerase. 6-Phosphogluconolactonase is the enzyme responsible for the hydrolysis of 6-phosphogluconolactone to 6-phosphogluconate, the second step in the pentose phosphate pathway. Glucosamine-6-phosphate isomerase (or Glucosamine 6-phosphate deaminase) is the enzyme responsible for the conversion of D-glucosamine 6-phosphate into D-fructose 6-phosphate . It is the last specific step in the pathway for N-acetylglucosamine (GlcNAC) utilization in bacteria such as Escherichia coli (gene nagB) or in fungi such as Candida albicans (gene NAG1).
EB domain (EB_dom)
Type: Domain

The EB domain has no known function. It is found in several Caenorhabditis sp. and Drosophila sp. proteins. The domain contains 8 conserved cysteines that probably form four disulphide bridges and is found associated with kunitz domains

.
Cysteine-rich repeat (Cys_repeat_1)
Type: Repeat

This repeat, originally named as Worm-specific repeat type 1, is found in several Caenorhabditis elegans proteins, as well as some other eukaryotes. The region contains several conserved cysteines that probably form disulphide bridges and is often found associated with kunitz domains

that may function as serine peptidase inhibitors; these belong to MEROPS peptidase inhibitor family I2.
Quinate/shikimate 5-dehydrogenase/glutamyl-tRNA reductase (Shikm_DH/Glu-tRNA_Rdtase)
Type: Domain

This entry represents a domain found in shikimate and quinate dehydrogenases, as well as glutamyl-tRNA reductases.

Shikimate 5-dehydrogenase (

) catalyses the conversion of shikimate to 5-dehydroshikimate . This reaction is part of the shikimate pathway which is involved in the biosynthesis of aromatic amino acids . Quinate 5-dehydrogenase catalyses the conversion of quinate to 5-dehydroquinate. This reaction is part of the quinate pathway where quinic acid is exploited as a source of carbon in prokaryotes and microbial eukaryotes. Both the shikimate and quinate pathways share two common pathway metabolites, 3-dehydroquinate and dehydroshikimate.

Glutamyl-tRNA reductase (

) catalyses the first step of tetrapyrrole biosynthesis in plants, archaea and most bacteria. The dimeric enzyme has an unusual V-shaped architecture where each monomer consists of three domains linked by a long 'spinal' α-helix. The central catalytic domain specifically recognises the glutamate moiety of the substrate .
Cation/H+ exchanger, transmembrane domain (Cation/H_exchanger_TM)
Type: Domain

This entry represents the transmembrane region of a number of cation/proton exchangers, including Na+/H+ exchangers, K+/H+ exchangers and Na+(K+,Li+,Rb+)/H+ exchangers.

Sodium proton exchangers (NHEs) constitute a large family of integral membrane protein transporters that are responsible for the counter-transport of protons and sodium ions across lipid bilayers . These proteins are found in organisms across all domains of life. In archaea, bacteria, yeast and plants, these exchangers provide increased salt tolerance by removing sodium in exchanger for extracellular protons. In mammals they participate in the regulation of cell pH, volume, and intracellular sodium concentration, as well as for the reabsorption of NaCl across renal, intestinal, and other epithelia . Human NHE is also involved in heart disease, cell growth and in cell differentiation . The removal of intracellular protons in exchange for extracellular sodium effectively eliminates excess acid from actively metabolising cells. In mammalian cells, NHE activity is found in both the plasma membrane and inner mitochondrial membrane. To date, nine mammalian isoforms have been identified (designated NHE1-NHE9) . These exchangers are highly-regulated (glyco)phosphoproteins, which, based on their primary structure, appear to contain 10-12 membrane-spanning regions (M) at the N terminus and a large cytoplasmic region at the C terminus. The transmembrane regions M3-M12 share identity with other members of the family. The M6 and M7 regions are highly conserved. Thus, this is thought to be the region that is involved in the transport of sodium and hydrogen ions. The cytoplasmic region has little similarity throughout the family. There is some evidence that the exchangers may exist in the cell membrane as homodimers, but little is currently known about the mechanism of their antiport .
Josephin domain (Josephin)
Type: Domain

The Josephin domain is an eukaryotic protein module of about 180 residues, which occurs in stand-alone form in Josephin-like proteins, and as an amino- terminal domain associated with two or three copies of the ubiquitin- interacting motif (UIM) in ataxin 3-like proteins. Josephin domain-containing proteins function as de-ubiquitination enzymes . Although it has originally been proposed that the Josephin domain could be an all-α helical domain distantly related to ENTH and VHS domains involved in membrane trafficking and regulatory adaptor function , it is now believed that it is a mainly α helical cysteine-protease domain predicted to be active against ubiquitin chains or related substrates .

The Josephin domain contains two conserved histidines and one cysteine that is required for the ubiquitin protease activity and two ubiquitin-binding sites .

Some proteins known to contain a Josephin domain are:

Animal Machado-Joseph disease protein 1 (Ataxin 3). It interacts with key regulators (CBP, p300 and PCAF) of transcription and represses transcription.

Plant Machado-Joseph disease-like protein (MJD1a-like) (Ataxin 3 homologue).

Mammalian Josephin 1 and 2.

Drosophila melanogaster Josephin-like protein.

Arabidopsis thaliana Josephin-like protein.
Dihydroneopterin aldolase (Dihydroneopterin_aldolase)
Type: Family

Dihydroneopterin aldolase catalyzes the conversion of 7,8-dihydroneopterin to 6-hydroxymethyl-7,8-dihydropterin in the biosynthetic pathway of tetrahydrofolate. The enzyme form a homo-octamers. Aldolase can use L-threo-dihydroneopterin and D-erythro-dihydroneopterin as substrates for the formation of 6-hydroxymethyldihydropterin, but it can also catalyze the epimerization of carbon 2' of dihydroneopterin and dihydromonapterin at appreciable velocity .
Dihydroneopterin aldolase/epimerase domain (FolB_dom)
Type: Domain

Dihydroneopterin aldolase (DHNA or folB) catalyses the conversion of 7,8-dihydroneopterin to 6-hydroxymethyl-7,8-dihydropterin in the biosynthetic pathway of tetrahydrofolate . Folate derivatives are essential cofactors in the biosynthesis of purines, pyrimidines, and amino acids, as well as formyl-tRNA. Mammalian cells are able to utilize pre-formed folates after uptake by a carrier-mediated active transport system. Most microbes and plants lack this system and must synthesize folates de novo from guanosine triphosphate and DHNA is one enzyme in this pathway. In the opportunistic pathogen Pneumocystis carinii, dihydroneopterin aldolase function is expressed as the N-terminal portion of the multifunctional folic acid synthesis protein (Fas). This region encompasses two domains, FasA and FasB, which are 27% amino acid identical . FasA and FasB also share significant amino acid sequence similarity with bacterial dihydroneopterin aldolases.

This entry also includes 7,8-dihydroneopterin triphosphate epimerase domain (DHNTPE or folX). Though it is known that DHNTPE catalyzes the epimerization of dihydroneopterin triphosphate to dihydromonapterin triphosphate, the biological role of this enzyme is still unclear. It is hypothesized that it is not an essential protein since a folX knockout in E. coli has a normal phenotype and the fact that folX is not present in H. influenza . DHNA and DHNTPE have been shown to be able to compensate for the other's activity albeit at slower reaction rates . The functional enzyme for both is an octamer of identical subunits. Mammals lack many of the enzymes in the folate pathway including, DHNA and DHNTPE.

This region consists of two tandem sequences each homologous to folB and which form tetramers .
Cobalamin (vitamin B12)-binding domain (Cobalamin-bd)
Type: Domain

The cobalamin (vitamin B12) binding domain can bind two different forms of the cobalamin cofactor, with cobalt bonded either to a methyl group (methylcobalamin) or to 5'-deoxyadenosine (adenosylcobalamin). Cobalamin-binding domains are mainly found in two families of enzymes present in animals and prokaryotes, which perform distinct kinds of reactions at the cobalt-carbon bond. Enzymes that require methylcobalamin carry out methyl transfer reactions. Enzymes that require adenosylcobalamin catalyse reactions in which the first step is the cleavage of adenosylcobalamin to form cob(II)alamin and the 5'-deoxyadenosyl radical, and thus act as radical generators. In both types of enzymes the B12-binding domain uses a histidine to bind the cobalt atom of cobalamin cofactors. This histidine is embedded in a DXHXXG sequence, the most conserved primary sequence motif of the domain . Proteins containing the cobalamin-binding domain include:

Animal and prokaryotic methionine synthase (

), which catalyse the transfer of a methyl group from methyl-cobalamin to homocysteine, yielding enzyme-bound cob(I)alamin and methionine.

Animal and prokaryotic methylmalonyl-CoA mutase (

), which are involved in the degradation of several amino acids, odd-chain fatty acids and cholesterol via propionyl-CoA to the tricarboxylic acid cycle.

Prokaryotic lysine 5,6-aminomutase (

).

Prokaryotic glutamate mutase (

) .

Prokaryotic methyleneglutarate mutase (

).

Prokaryotic isobutyryl-CoA mutase (

).

The core structure of the cobalamin-binding domain is characterised by a five-stranded α/β (Rossmann) fold, which consists of 5 parallel β-sheets surrounded by 4-5 α-helices in three layers (α/β/α) . Upon binding cobalamin, important elements of the binding site appear to become structured, including an α-helix that forms on one side of the cleft accommodating the nucleotide 'tail' of the cofactor. In cobalamin, the cobalt atom can be either free (dmb-off) or bound to dimethylbenzimidazole (dmb-on) according to the pH. When bound to the cobalamin-binding domain, the dimethylbenzimidazole ligand is replaced by the active histidine (His-on) of the DXHXXG motif. The replacement of dimethylbenzimidazole by histidine allows switching between the catalytic and activation cycles . In methionine synthase the cobalamin cofactor is sandwiched between the cobalamin-binding domain and an approximately 90 residues N-terminal domain forming a helical bundle comprising two pairs of antiparallel helices .

In methionine synthase, there is a second, adjacent domain involved in cobalamin binding that forms a 4-helical bundle cap (

); in the conversion to the active conformation of this enzyme, the 4-helical cap rotates to allow the cobalamin cofactor to bind the activation domain (

) .
Methylmalonyl-CoA mutase, C-terminal (Acid_CoA_mut_C)
Type: Domain

This entry represents the C-terminal domain of eukaryotic and prokaryotic MUT enzymes. This domain covers the whole length of the protein in some members such as Glutamate mutase sigma subunit (GlmS), Fused isobutyryl-CoA mutase (IcmF, ) and Pivalyl-CoA mutase small subunit . It seems to have evolutionary relationship with with a coenzyme B12-dependent enzyme .

Methylmalonyl-CoA mutase (MUT

) catalyses a reversible isomerization between L-methylmalonyl-CoA and succinyl-CoA. The enzyme uses an adenosylcobalamin cofactor, highly conserved from bacteria to human . It may be a homodimer, as in mitochondria, or a heterodimer with partially homologous beta chain that does not bind the adenosylcobalamin cofactor, as in Propionibacterium freudenreichii . In human, it is an essential enzyme in propionate catabolism as it conducts metabolites from the breakdown of amino acids (valine, isoleucine, methionine, and threonine), odd-chain fatty acids, and the side chain of cholesterol into the tricarboxylic acid cycle. Defects in this enzyme causes methylmalonic aciduria (MMA) and is the site where most of the mutations have been found. Defects in one of several proteins (MMAA, MMAB, MMADHC) involved in the uptake, modification, and delivery of AdoCbl to the MUT enzyme for its activity also cause MMA . This metabolic disease may develop immediately after birth (early onset) with a severe metabolic crisis or later either with intermittent metabolic decompensations or with chronic progression manifesting as failure to thrive and developmental delay (late onset). Symptoms include severe ketoacidosis, feeding difficulties, lethargy, and hypotonia .
Short chain fatty acid transporter AtoE (SCFA_transpt_AtoE)
Type: Family

Members of this family may be short chain fatty acid transporters although there has been no experimental characterisation of this function.
Conserved hypothetical protein CHP00336 (CHP00366)
Type: Family

This is a family of conserved hypothetical proteins of no clearly defined function, although they may act as short chain fatty acid transporters.
Phosphopantetheine attachment site (Ppantetheine_attach_site)
Type: PTM

Phosphopantetheine (or pantetheine 4' phosphate) is the prosthetic group of acyl carrier proteins (ACP) in some multienzyme complexes where it serves as a 'swinging arm' for the attachment of activated fatty acid and amino-acid groups .

The amino-terminal region of the ACP proteins is well defined and consists of four α helices arranged in a right-handed bundle held together by interhelical hydrophobic interactions. The Asp-Ser-Leu (DSL) motif is conserved in all of the ACP sequences, and the 4'-PP prosthetic group is covalently linked via a phosphodiester bond to the serine residue. The DSL sequence is present at the amino terminus of helix II, a domain of the protein referred to as the recognition helix and which is responsible for the interaction of ACPs with the enzymes of type II fatty acid synthesis .
Ku70/Ku80, DNA-binding domain (DNA_bd_Ku70/Ku80)
Type: Domain

The Ku heterodimer (composed of Ku70 and Ku80) contributes to genomic integrity through its ability to bind DNA double-strand breaks and facilitate repair by the non-homologous end-joining pathway. This is the central DNA-binding β-barrel domain. This domain is found in both the Ku70 and Ku80 proteins that form a DNA binding heterodimer .