SII-SWORD/CoKE huggingface dataset:
Protein of unknown function DUF92, TMEM19 (DUF92_TMEM19)
Type: Family

Many members of this family have no known function and are predicted to be integral membrane proteins.

One member of the family has been characterised as protein PGR (AtPGR). PGR is suggested to be a potential glucose-responsive regulator in carbohydrate metabolism in plants. This entry also includes protein VTE6, which is a Pphytyl-phosphate kinase catalyzing the conversion of phytyl-monophosphate to phytyl-diphosphate .
S-adenosylmethionine synthetase, archaea (S-AdoMet_synthetase_arc)
Type: Family

A highly diverged class of S-adenosylmethionine synthetases have been identified in the archaea. S-adenosylmethionine is the primary alkylating agent in all known organisms. ATP:L-methionine S-adenosyltransferase (MAT) catalyses the only known biosynthetic route to this central metabolite. Although the amino acid sequence of MAT is strongly conserved among bacteria and eukarya (see

) no homologues had been recognised in the completed genome sequences of any archaea. The identification of a second major class of MAT emphasises the long evolutionary history of the archaeal lineage and the structural diversity found even in crucial metabolic enzymes . Three bacterial genomes encode both the archaeal and eukaryotic/bacterial types of MAT .
Polysaccharide biosynthesis protein (Polysacc_synth)
Type: Family

Members of this family are integral membrane proteins , and many are implicated in the production of polysaccharide. The family includes RfbX part of the O antigen biosynthesis operon , and SpoVB from Bacillus subtilis (

), which is involved in spore cortex biosynthesis .
Stage II sporulation protein M-like (SpoIIM-like)
Type: Family

This entry represents a group of predicted integral membrane proteins, including Stage II sporulation protein M (spoIIM) from Bacillus subtilis (

).

SpoIIM is on e of four stage II sporulation proteins that is necessary for the forespore inside the mother-cell to be properly internalised through the breakdown of peptidoglycans trapped between the membranes of the septum separating the forespore and the mother-cell. The four proteins working in sequence are SpoIIB, SpoIIM, SpoIIP and SpoIID. D, M and P are in a complex with each other and the complex assembles in a hierarchical manner such that M, which serves as a membrane anchor, recruits P to the septum and P, in turn, recruits D to the septum .
Chorismate pyruvate-lyase Rv2949c-like (Rv2949c-like)
Type: Family

This entry includes chorismate pyruvate-lyase Rv2949c from Mycobacterium tuberculosis. It removes the pyruvyl group from chorismate to provide 4-hydroxybenzoate (4HB) . The chorismate pyruvate-lyase encoded by sll1797 in cyanobacteria Synechocystis sp. , has been shown to catalyse the initial and essential step in plastoquinone biosynthesis . In E. coli, the chorismate lyase (UbiC) catalyses the conversion of chorismate to p-hydroxybenzoate and pyruvate in the biosynthesis of ubiquinone as well .
Aspartate transcarbamylase regulatory subunit (Asp_carbamoylTrfase_reg)
Type: Family

Aspartate carbamoyltransferase (aspartate transcarbamylase, ATCase)

is an allosteric enzyme that plays a central role in the regulation of the pyrimidine pathway in bacteria. The holoenzyme is a dodecamer composed of six catalytic chains, each with an active site, and six regulatory chains lacking catalytic activity . The catalytic subunits exist as a dimer of catalytic trimers, (c3)2, while the regulatory subunits exist as a trimer of regulatory dimers, (r2)3, therefore the complete holoenzyme can be represented as (c3)2(r2)3. The association of the catalytic subunits c3 with the regulatory subunits r2 is responsible for the establishment of positive co-operativity between catalytic sites for the binding of aspartate and it dictates the pattern of allosteric response toward nucleotide effectors. ATCase from Escherichia coli is the most extensively studied allosteric enzyme . The crystal structure of the T-state, the T-state with CTP bound, the R-state with N-phosphonacetyl-L-aspartate (PALA) bound, and the R-state with phosphonoacetamide plus malonate bound have been used in interpreting kinetic and mutational studies.

A high-resolution structure of E. coli ATCase in the presence of PALA (a bisubstrate analog) allows a detailed description of the binding at the active site of the enzyme and allows a detailed model of the tetrahedral intermediate to be constructed. The entire regulatory chain has been traced showing that the N-terminal regions of the regulatory chains R1 and R6 are located in close proximity to each other and to the regulatory site. This portion of the molecule may be involved in the observed asymmetry between the regulatory binding sites as well as in the heterotropic response of the enzyme . The C-terminal domain of the regulatory chains have a rubredoxin-like zinc-bound fold.
Endonuclease dU (Endo_dU)
Type: Family

This entry includes Endonuclease dU (Endo_dU) from Archaeoglobus fulgidus (AF_1433,

) and similar proteins mainly found in archaea. Sequence and structure analysis to identify RNase H-like superfamily members, has clustered this family in endonuclease Clade V, thus suggesting endonuclease activity of these proteins . Endo_dU, which cleave the 3'-side of deoxyuridine (dU) on DNA substrates, shows a typical RNase H-like fold, with a core structure of five β-strands and three α-helices. It may participate in DNA repair . This family was formerly known as DUF99.
Fructose-1,6-bisphosphatase, class V (FBPase_V)
Type: Family

Fructose-1,6-bisphophatase (FBPase) catalyses the hydrolysis of D-fructose-1,6-bisphosphate (FBP) to D-fructose-6-phopshate (F6P) and orthophosphate, and is a key enzyme in gluconeogenesis . Three different groups of FBPases have been identified in eukaryotes and bacteria (FBPase I-III) . None of these groups have been found in archaea so far, though a new group of FBPases (FBPase IV) which also show inositol monophosphatase activity has recently been identified in archaea .

Proteins in this entry are though to represent a new group of FBPases (FBPase V) which are found in thermophilic archaea and a hyperthermophilic bacterium Aquifex aeolicus . The characterised members of this group show strict substrate specificity for FBP and are suggested to be the true FBPase in these organisms . A structural study suggests that FBPase V has a novel fold for a sugar phosphatase, forming a four-layer α-β-β-α sandwich, unlike the more usual five-layered α-β-α-β-α arrangement . The arrangement of the catalytic side chains and metal ligands was found to be consistent with the three-metal ion assisted catalysis mechanism proposed for other FBPases.
Archease (Archease)
Type: Family

The archease superfamily of proteins are represented in all three domains of life. Archease genes are generally located adjacent to genes encoding proteins involved in DNA or RNA processing and therefore have been predicted to be modulators or chaperones involved in DNA or RNA metabolism. Many of the roles of archeases remain to be established experimentally.

The function of one of the archeases from the hyperthermophile Pyrococcus abyssi has been determined. The gene encoding the archease (PAB1946) is located in a bicistronic operon immediately upstream from a second open reading frame (PAB1947), which encodes a tRNA m5C methyltransferase. The methyl transferase catalyses m5C formation at several cytosine's within tRNAs with preference for C49; the specificity of the methyltransferase reaction being increased by the archease. The archease protects the tRNA (cytosine-5-)-methyltransferase PAB1947 against aggregation and increases its specificity. The archease exists in monomeric and oligomeric states, with only the oligomeric forms able to bind the methyltransferase .

The function of this family of archeases as chaperones is supported by structural analysis of

from Methanobacterium thermoautotrophicum, which shows homology to heat shock protein 33, which is a chaperone protein that inhibits the aggregation of partially denatured proteins .
Nicotinate-nucleotide-dimethylbenzimidazole phosphoribosyltransferase, archaeal type (Nict_dMeBzImd_PRibTrfase_arc)
Type: Family

This entry represents the archaeal-type nicotinate-nucleotide-dimethylbenzimidazole phosphoribosyltransferases.

Nicotinate mononucleotide (NaMN):5,6-dimethylbenzimidazole (DMB) phosphoribosyltransferase (CobT) plays a central role in the synthesis of alpha-ribazole-5'-phosphate, an intermediate for the lower ligand of cobalamin . It is one of the enzymes of the anaerobic pathway of cobalamin biosynthesis, and one of the four proteins (CobU, CobT, CobC, and CobS) involved in the synthesis of the lower ligand and the assembly of the nucleotide loop .

Vitamin B
12
(cobalamin) is used as a cofactor in a number of enzyme-catalysed reactions in bacteria, archaea and eukaryotes . The biosynthetic pathway to adenosylcobalamin from its five-carbon precursor, 5-aminolaevulinic acid, can be divided into three sections: (1) the biosynthesis of uroporphyrinogen III from 5-aminolaevulinic acid; (2) the conversion of uroporphyrinogen III into the ring-contracted, deacylated intermediate precorrin 6 or cobalt-precorrin 6; and (3) the transformation of this intermediate to form adenosylcobalamin . Cobalamin is synthesised by bacteria and archaea via two alternative routes that differ primarily in the steps of section 2 that lead to the contraction of the macrocycle and excision of the extruded carbon molecule (and its attached methyl group) . One pathway (exemplified by Pseudomonas denitrificans) incorporates molecular oxygen into the macrocycle as a prerequisite to ring contraction, and has consequently been termed the aerobic pathway. The alternative, anaerobic, route (exemplified by Salmonella typhimurium) takes advantage of a chelated cobalt ion, in the absence of oxygen, to set the stage for ring contraction .
Adenosylcobinamide amidohydrolase, CbiZ (AdoCbi_amidolase)
Type: Family

This archaeal and prokaryotic protein family includes CbiZ, which converts adenosylcobinamide (AdoCbi) to adenosylcobyric acid (AdoCby), an intermediate of the de novo coenzyme B12 biosynthetic route .
Integral membrane protein EMC3/TMCO1-like (EMC3/TMCO1)
Type: Family

This entry represents a group of eukaryotic and archaeal proteins from the Oxa1 superfamily which includes a group of proteins that function in different contexts as transmembrane domains (TMD) insertases and/or as intramembrane chaperones to facilitate membrane protein folding and assembly . Eukaryotic members include EMC3, a subunit of the ER membrane protein complex (EMC) required for protein folding , and TMCO1, a component of the multi-pass translocon (MPT) complex that mediates insertion of multi-pass membrane proteins into the lipid bilayer of membranes . Previously, it has been reported that TMCO1 is a ER calcium load-activated calcium channel . TMCO1 is required for the normal development of corpus callosum as it plays a role in Ca2 homeostasis . Archaeal members may function as insertases of the archaeal plasma membrane .
NfeD-like, C-terminal domain (NfeD-like_C)
Type: Domain

NfeD-like proteins are widely distributed throughout prokaryotes and are frequently associated with genes encoding stomatin-like proteins (slipins) . The homologue from hyperthermophilic archaebacterium Pyrococcus horikoshii is thought to be a serine protease involved in ion channel opening through the cleavage of a stomatin-homologue .

There appear to be three major groups of NfeD-like proteins: an ancestral group with only an N-terminal serine protease domain and this C-terminal β- sheet-rich domain which is structurally very similar to the OB-fold domain , associated with its neighbouring slipin cluster; a second major group with an additional middle, membrane-spanning domain, associated in some species with eoslipin and in others with yqfA; a final 'artificial' group which unites truncated forms lacking the protease region and associated with their ancestral gene partner, either yqfA or eoslipin.

This NefD, C-terminal domain appears to be the major one for relating to the associated protein. NfeD homologues are clearly reliant on their conserved gene neighbour which is assumed to be necessary for function, either through direct physical interaction or by functioning in the same pathway, possibly involve with lipid-rafts .
Aspartate dehydrogenase (Asp_DH)
Type: Domain

This group contains aspartate dehydrogenases that belong to a unique class of amino acid dehydrogenases.

The structure of Thermotoga maritima TM1643 has been found to contain an N-terminal Rossmann fold domain (which binds the NAD(P)
+
cofactor) and a C-terminal α/β domain . This suggested that TM1643 may be a dehydrogenase with the active
site located at the interface between the two domains. Enzymatic characterisation of TM1643 revealed that it possesses NAD or NADP-dependent dehydrogenase activity toward L-aspartate but no aspartate oxidase activity . The product of the aspartate dehydrogenase activity is also iminoaspartate. It has been suggested that two different enzymes, an oxidase and a dehydrogenase, may have evolved to catalyse the
first step of NAD biosynthesis . Members of this group share some structural similarity to several other NAD(P)
+
-dependent oxidoreductases, including inositol 1-phosphate synthase, dihydrodipicolinate reductase, and ASA-DH .

It has been proposed that in Thermotoga maritima, TM1643 catalyses the first reaction of de novo biosynthesis of NAD from aspartate, and it produces iminoaspartate required for this pathway. The formation of an enzyme complex between TM1643 and NadA, the next enzyme of the pathway, may allow the channeling of this unstable product directly to the NadA active site .
3-dehydroquinate synthase (DHQ_synth)
Type: Family

3-Dehydroquinate synthase (

) is an enzyme in the common pathway of aromatic amino acid biosynthesis that catalyses the conversion of 3-deoxy-D-arabino-heptulosonic acid 7-phosphate (DAHP) into 3-dehydroquinic acid . This synthesis of aromatic amino acids is an essential metabolic function for most prokaryotic as well as lower eukaryotic cells, including plants. The pathway is absent in humans; therefore, DHQS represents a potential target for the development of novel and selective antimicrobial agents. Owing to the threat posed by the spread of pathogenic bacteria resistant to many currently used antimicrobial drugs, there is clearly a need to develop new anti-infective drugs acting at novel targets. A further potential use for DHQS inhibitors is as herbicides .
Arginine biosynthesis protein ArgJ (Arg_biosynth_ArgJ)
Type: Family

ArgJ (also known as Ornithine acetyltransferase/OAT) is a bifunctional protein that catalyses the first

and fifth steps

in arginine biosynthesis , coupling acetylation of glutamate with deacetylation of N-acetylornithine, which allows recycling of the acetyl group in the arginine biosynthetic pathway. The structure has been determined for glutamate N-acetyltransferase 2 (ornithine acetyltransferase;

), an ArgJ-like protein from Streptomyces clavuligerus .

Members of this family may experience feedback inhibition by L-arginine. The active enzyme is a heterotetramer of two alpha and two beta chains, where the alpha and beta chains are the result of autocatalytic cleavage. OATs found in the clavulanic acid biosynthesis gene cluster catalyze the fifth step only, and may utilize acetyl acceptors other than glutamate .
Spo11/DNA topoisomerase VI subunit A (Spo11/TopoVI_A)
Type: Family

This entry represents Spo11, a meiotic recombination protein found in eukaryotes, and subunit A of topoisomerase VI, a type IIB topoisomerase found predominantly in archaea . These two types of proteins share structural homology.

DNA topoisomerases regulate the number of topological links between two DNA strands (i.e. change the number of superhelical turns) by catalysing transient single- or double-strand breaks, crossing the strands through one another, then resealing the breaks. They can be divided into two classes: type I enzymes (

, topoisomerases I, III and V) break single-strand DNA, and type II enzymes (

, topoisomerases II, IV and VI) break double-strand DNA . Topoisomerase VI is a type IIB enzymes that assembles as a heterotetramer, consisting of two A subunits required for DNA cleavage and two B subunits required for ATP hydrolysis. The B subunit is structurally similar to the ATPase domain of type IIA topoisomerases, but the A subunit is distinct, and instead shares homology with the Spo11 protein.
TraB/PrgY/GumN family (TraB/PrgY/GumN_fam)
Type: Family

This entry includes Tiki1/2 from humans, TraB/PrgY from the gut flora Enterococcus faecalis and gumN from the plant pathogen Xanthomonas. Tiki1 is homologous to TraB/PrgY. They have a pair of widely spaced GX2H motifs and a conserved glutamate. From the structural study, this group of proteins have been identified as an ancient metalloprotease clan with a common protein architecture -cobbled from the folds of the EreA/ChaN/PMT group- that mediates proteolytic activities .

Tiki1 is a membrane-associated protease that inhibits Wnt via the cleavage of its amino terminus, diminishing Wnt's binding to receptors .

TraB/PrgY is an inhibitor peptide that may act as a protease to inactivate the mating pheromone .
Phosphomethylpyrimidine synthase ThiC/5-hydroxybenzimidazole synthase BzaA/B (ThiC/BzaA/B)
Type: Family

This entry includes phosphomethylpyrimidine synthases, including thiC from prokaryotes and AtTHIC from Arabidopsis. thiC is found within the thiamin biosynthesis operon and is involved in thiamin biosynthesis . ThiC catalyzes the synthesis of the hydroxymethylpyrimidine phosphate (HMP-P) moiety of thiamine from aminoimidazole ribotide (AIR) in a radical S-adenosyl-L-methionine (SAM)-dependent reaction .

AtTHIC is involved in pyrimidine synthesis in the thiamine biosynthesis pathway of Arabidopsis. Heterologous expression of AtTHIC could functionally complement the thiC knock-out mutant of E. coli .

This entry also includes 5-hydroxybenzimidazole synthase BzaA and BzaB. They are part of the bzaABCDE genes that are necessary and sufficient for the anaerobic biosynthesis of DMB (5,6-dimethylbenzimidazole), the "lower ligand" of vitamin B12 .
DJ-1/PfpI (DJ-1/PfpI)
Type: Domain

The domain is found in intracellular cysteine peptidase PfpI and other members of the DJ-1/ThiJ/PfpI superfamily . Some of these have been characterised:

Pyrococcus horikoshii PH1704, which has both aminopeptidase and endopeptidase activity .

Arabidopsis thaliana DJ1D, which has glyoxalase I activity .

Candida albicans glyoxalase 3 .

It is also found in transcriptional regulators in combination with a HTH (araC) domain, such as in Pseudomonas aeruginosa cdhR .
Molybdopterin cofactor biosynthesis C (MoaC) domain (Mopterin_CF_biosynth-C_dom)
Type: Domain

The majority of molybdenum-containing enzymes utilise a molybdenum cofactor (MoCF or Moco) consisting of a Mo atom coordinated via a cis-dithiolene moiety to molybdopterin (MPT). MoCF is ubiquitous in nature, and the pathway for MoCF biosynthesis is conserved in all three domains of life. MoCF-containing enzymes function as oxidoreductases in carbon, nitrogen, and sulphur metabolism .

This entry represents the molybdenum cofactor biosynthesis protein MoaC from prokaryotes and eukaryotes, also known as cyclic pyranopterin monophosphate synthase.
Hydantoinase A/oxoprolinase (Hydantoinase_A)
Type: Domain

This domain is found in the enzymes hydantoinase A (HyuA) and oxoprolinase (

). Both enzymes catalyse reactions involving the hydrolysis of 5-membered rings via hydrolysis of their internal imide bonds . This domain is also found in (4-{4-[2-(gamma-L-glutamylamino)ethyl]phenoxymethyl}furan-2-yl)methanamine synthase from
Methanocaldococcus jannaschii
, which is involved in methanofuran biosynthesis, catalysing the condensation between 5-(aminomethyl)-3-furanmethanol diphosphate and gamma-glutamyltyramine to produce 4-[N-(gamma-L-glutamyl)-p-(beta-aminoethyl)phenoxymethyl]-(aminomethyl)furan (APMF-Glu) . D-5-(2-methylthioethyl)hydantoin amidohydrolase (HyuA) from
Pseudomonas
is a component of the hydantoinase process, an enzymatic cascade converting D-5-(2-methylthioethyl)hydantoin to N-carbamoyl-D-methionine .
Nickel insertion protein (Ni_insertion)
Type: Family

Members of this family may be involved in the activation of nickel-pincer cofactor-dependent enzymes. LarC from Lactobacillus plantarum is involved, together with LarB and LarE, in the synthesis of the enzyme-bound cofactor of lactate racemase (LarA). Larc C binds Ni2+, and functions in nickel delivery to pyridinium-3,5-bisthiocarboxylic acid mononucleotide (P2TMN), to form the mature cofactor .
Protein of unknown function DUF112, transmembrane (DUF112_TM)
Type: Domain

This entry represents a domain found in a group of uncharacterised prokaryotic sequences, including 52.8 kDa protein in TAR-I ttuC' 3'region from the common pathogen of grapevine Agrobacterium vitis . In most members of this group, predicted to be integral membrane proteins, this domain covers the whole length of the protein, and many of them are annotated as the TctA subunit of the tripartite tricarboxylate transport (TTT) family.

A member of this group from M. maripaludis (MMJJ_13030,

) was shown to be essential for natural transformation .
Peptidase S49, serine-peptidase prokaryotes (Pept_S49_ser-pept_pro)
Type: Family

This family of archaebacterial proteins, formerly known as DUF114, has been found to be a serine proteinase, distantly related to ClpP proteinases that belong to the serine proteinase superfamily. The family belong to MEROPS peptidase family S49; they are mostly uncharacterised peptidases.

Members of this family contain a catalytic triad of Ser, Asp, His residues in a linear sequential arrangement (SDH), which shows an altered residue ordering compared with the classical ClpP proteinases (SHD) but similar to that of the carboxypeptidase clan.

Proteolytic enzymes that exploit serine in their catalytic activity are ubiquitous, being found in viruses, bacteria and eukaryotes . They include a wide range of peptidase activity, including exopeptidase, endopeptidase, oligopeptidase and omega-peptidase activity. Many families of serine protease have been identified, these being grouped into clans on the basis of structural similarity and other functional evidence . Structures are known for members of the clans and the structures indicate that some appear to be totally unrelated, suggesting different evolutionary origins for the serine peptidases .

Not withstanding their different evolutionary origins, there are similarities in the reaction mechanisms of several peptidases. Chymotrypsin, subtilisin and carboxypeptidase C have a catalytic triad of serine, aspartate and histidine in common: serine acts as a nucleophile, aspartate as an electrophile, and histidine as a base . The geometric orientations of the catalytic residues are similar between families, despite different protein folds . The linear arrangements of the catalytic residues commonly reflect clan relationships. For example the catalytic triad in the chymotrypsin clan (PA) is ordered HDS, but is ordered DHS in the subtilisin clan (SB) and SDH in the carboxypeptidase clan (SC) .
6-hydroxymethylpterin diphosphokinase MptE-like (MptE-like)
Type: Domain

This domain can be found in a group of proteins, including archaeal 6-hydroxymethylpterin diphosphokinase (6-HMDPK), known as MptE, which catalyses the formation of 6-hydroxymethyl-7,8-dihydropterin diphosphate (6-HMDP) from 6-HMD and ATP . 6-HMDP is the precursor of the pterin containing moiety of the essential C1-carriers tetrahydrofolate and tetrahydromethanopterin. This entry also includes a number of uncharacterised proteins from bacteria.