SII-SWORD/CoKE huggingface dataset:
dTDP-glucose 4,6-dehydratase (dTDP_Gluc_deHydtase)
Type: Family

The conversion of dTDP-glucose into dTDP-4-keto-6-deoxyglucose by Escherichia coli dTDP-glucose 4,6-dehydratase takes place in the active site in three steps: dehydrogenation to dTDP-4-ketoglucose, dehydration to dTDP-4-ketoglucose-5,6-ene, and rereduction of C6 to the methyl group. The 4,6-dehydratase makes use of tightly bound NAD
+
as the coenzyme for transiently oxidizing the substrate, activating it for the dehydration step . This and other 4,6-dehydratases catalyze the first committed step in all 6-deoxysugar biosynthetic pathways described to date. Numerous 6-deoxysugars are used in bacterial lipopolysaccharide production as well as in the biosynthesis of a diverse array of secondary metabolites.
Glycine betaine/proline betaine transport system ATP-binding protein ProV-like (Gly-betaine_transp_ATP-bd)
Type: Family

This family represents the ATP binding subunit of a subfamily of ABC transporters, including ProV (for glycine betaine and proline betaine transport, ), OpuBA (choline, ), OpuCA (carnitine, ), GbuA (glycine betaine and carnitine, ) and OusV (glycine betaine and choline, ). This transport system belong to the larger ATP-Binding Cassette (ABC) transporter superfamily. The characteristic feature of these transporter is the obligatory coupling of ATP hydrolysis to substrate translocation.

The minimal configuration of bacterial ABC transport system includes an ATP binding (and hydrolysing) subunit; a hydrophilic polypeptide that forms a channel through the membrane, and a substrate binding protein; any of these subunits may be represented by two paralogs instead of just one. Substrates for many members of this transport system, such as glycine betaine (a glycine with its N trimethylated, often simply called betaine), serve as osmoprotectants , although they also may serve as nutrients. Members of the family are the ATP-binding subunit of ABC transporters for substrates such as betaine, L-proline or other amino acids, choline, carnitine, etc. The substrate specificity is best determined from the substrate-binding subunit, rather than this subunit, as it interacts with the permease subunit and not with substrate directly.
Spermidine/putrescine import ATP-binding protein PotA-like (PotA-like)
Type: Family

This entry represents the spermidine/putrescine ABC transporter ATP binding subunit in bacteria and its equivalents in archaea. This transport system belong to the larger ATP-Binding Cassette (ABC) transporter superfamily. Polyamines like spermidine and putrescine play vital role in cell proliferation, differentiation, and ion homeostasis. The concentration of polyamines within the cell are regulated by biosynthesis, degradation and transport (uptake and efflux included).
Daunorubicin resistance ABC transporter ATP-binding subunit DrrA (DrrA)
Type: Family

ABC transporters belong to the ATP-Binding Cassette (ABC) superfamily, which uses the hydrolysis of ATP to energise diverse biological systems. ABC transporters minimally consist of two conserved regions: a highly conserved ATP binding cassette (ABC) and a less conserved transmembrane domain (TMD). These can be found on the same protein or on two different ones. Most ABC transporters function as a dimer and therefore are constituted of four domains, two ABC modules and two TMDs.

This entry represents the daunorubicin resistance ABC transporter ATP binding subunit DrrA, which is found in bacteria and archaea. DrrA is part of the ABC transporter complex DrrABC (composed of two ATP-binding proteins (DrrA) and two transmembrane proteins (DrrB and DrrC)). The DrrABC complex functions as an ATP dependent antiporter and is involved in doxorubicin and daunorubicin efflux .
ABC transporter, haem export, CcmA (ABC_transptr_haem_export_CcmA)
Type: Family

This family contains the cytochrome c biogenesis protein encoded by ccmA, part Ccm-System I found in bacteria, archaea and plant mitochondria. Bacterial c-type cytochromes are located on the periplasmic side of the cytoplasmic membrane. Several gene products encoded in a locus designated as Cytochrome c maturation (Ccm)-System I are implicated in the transport and assembly of the functional cytochrome c. In some organisms this process involves up to nine (CcmABCDEFGHI) membrane proteins working together to achieve heme ligation. The post-translational pathway includes the transport of a heme b moiety, the translocation of the apocytochrome c and the covalent attachment of the heme with the apocytochrome c. CcmABCD are homologous to the ABC (ATP-binding cassette) transporters and are responsible for conveying heme b to the periplasm and loading it to the heme-chaperone CcmE .
Glucan exporter ATP-binding protein, NdvA (NdvA)
Type: Family

The ATP-Binding Cassette (ABC) superfamily forms one of the largest of all protein families with a diversity of physiological functions . Several studies have shown that there is a correlation between the functional characterisation and the phylogenetic classification of the ABC cassette . More than 50 subfamilies have been described based on a phylogenetic and functional classification ; (for further information see http://www.tcdb.org/tcdb/index.php?tc=3.A.1).

This family consists of glucan exporter ATP binding protein NdvA found in proteobacteria . It belongs to the larger ABC transporter superfamily with the characteristic ATP binding motif. In general, this protein is in some ways implicated in osmo-regulation and is suggested to participate in the export of glucan from the cytoplasm to periplasm. The cyclic beta-1,2-glucan in the bacterial periplasmic space is suggested to confer the property of high osmolority. It has also been demonstrated that mutants in this loci have lost functions of virulence and motility. It is unclear as to how virulence and osmo-adaptaion are related.
Sodium ion-translocating decarboxylase (Na_pump_deCOase)
Type: Family

This family comprises distantly related, low complexity, hydrophobic small subunits of several related sodium ion-pumping decarboxylases. These include oxaloacetate decarboxylase gamma subunit and methylmalonyl-CoA decarboxylase delta subunit .
6-phosphogluconolactonase, DevB-type (6-phosphogluconolactonase_DevB)
Type: Domain

This entry refers to the DevB type of 6-phosphogluconolactonase.

6-phosphogluconolactonases (6PGL)

are cytosolic enzymes found in all organisms that catalyse the hydrolysis of 6-phosphogluconolactone to 6-phosphogluconic acid in the oxidative phase of the pentose phosphate pathway. Trypanosoma brucei and other characterised 6PGL proteins [

] share an α/β hydrolase fold, with both parallel and anti-parallel β-sheets surrounded by eight α-helices . In Escherichia coli (strain K12), 6PGL (YbhE) is characterised by a 7-bladed β-propeller fold

(

) .
GLPGLI family protein (GLPGLI)
Type: Family

This protein family was first noted as a paralogous set in Porphyromonas gingivalis, but it is more widely distributed among the Bacteroidetes. The protein family is now renamed GLPGLI after its best-conserved motif.
Putative DNA-binding protein, HU-related (HU_DNA-bd_put)
Type: Family

This family of proteins is related to, but longer than, DNA-binding protein HU. It contains a distinctive domain architecture when compared to HU and related histone-like DNA-binding. Members include, so far, a protein from Bacteroides fragilis and ten from Porphyromonas gingivalis (Bacteroides gingivalis). Both species are oral pathogens.
2-desacetyl-2-hydroxyethyl bacteriochlorophyllide a dehydrogenase (BchC)
Type: Family

Some prokaryotes, such as the purple and green sulphur bacteria, gain energy from a mode of photosynthesis that does not generate oxygen, and is inhibited by its presence . These organisms do not include chlorophylls in their photosynthetic pigments, but instead use closely related molecules known as bacteriochlorophylls. Like chlorophylls, bacteriochlorophylls are tetrapyroles with a five-membered ring structure, differing in the side chains and hydration state of the ring structure. These alterations in structure determine what light wavelengths can be harvested by the organism .

Bacteriochlorophyll a is a photosynthetic pigment found in many of the purple bacteria. It is synthesised from protoporphyrin IX in a series of reactions including magnesium-chelation, methyl transfer, ring formation, vinyl-group reduction protochlorophyllide reduction, and finally phytol addition . This entry represents 2-desacetyl-2-hydroxyethyl bacteriochlorophyllide a dehydrogenase, the enzyme catalysing the penultimate step in light-independent bacteriochlorophyll a biosynthesis .
Hypoxanthine phosphoribosyl transferase (Hxn_phspho_trans)
Type: Family

Phosphoribosyltransferases (PRT) are enzymes that catalyze the synthesis of beta-n-5'-monophosphates from phosphoribosylpyrophosphate (PRPP) and an enzyme specific amine. A number of PRT's are involved in the biosynthesis of purine, pyrimidine, and pyridine nucleotides, or in the salvage of purines and pyrimidines. Purine nucleotides are synthesized both via the de novo pathway and via the salvage pathway and are vital for cell functions and cell proliferation through DNA and RNA syntheses and ATP energy supply.
D-alanine--D-alanine ligase (D_ala_D_ala)
Type: Family

D-alanine--D-alanine ligase (

) is a bacterial enzyme involved in cell-wall biosynthesis. It participates in forming UDP-N-acetylmuramoyl pentapeptide, the peptidoglycan precursor. These enzymes are proteins of 300 to 360 amino acids containing many conserved regions. The N-terminal Gly-rich region could be involved in ATP-binding.

This family of enzymes represent chromosomal versions of species not specifically resistant to glycopeptide antibiotics such as vancomycin. The mechanism of glycopeptide antibiotic resistance involves the production of D-alanine-D-lactate (VanA and VanB families) or D-alanine-D-serine (VanC). This model attempts to exclude the VanA/VanB and VanC subfamilies while capturing most other D-Ala-D-Ala ligases above the trusted cut-off. However, changes in small numbers of amino acids, as demonstrated crystallographically, can alter specificity. In chlamydial species, this enzyme is found as a fusion protein with UDP-N-acetylmuramate--alanine ligase.
Lysine biosynthesis protein LysW (LysW)
Type: Family

While most bacteria synthesise lysine via diaminopimelate, a few species, such as Thermus thermophilus, and some hyperthermophilic archaea, synthesise this amino acid from alpha-aminoadipate (AAA). LysW plays an essential role in this pathway by preventing unstable intermediates from undergoing intramolecular cyclisation . This is accomplished by covalent binding of the reactive amino group of AAA to a glutamate residue in LysW. The covalently attached AAA is subsequently converted to lysine and then released from LysW by the action of other proteins in this pathway.
Glucose-1-phosphate thymidylyltransferase, short form (G1P_thy_trans_s)
Type: Family

This group of proteins comprises a tightly conserved but broadly distributed subfamily (here designated as short form) of known and putative bacterial glucose-1-phosphate thymidylyltransferases (

, also known as dTDP-D-glucose synthase). It is well characterised in several species as the first of four enzymes involved in the biosynthesis of dTDP-L-rhamnose, a cell wall constituent and a feedback inhibitor of the enzyme. The enzyme is active as a homotetramer .

dTTP + alpha-D-glucose 1-phosphate = diphosphate + dTDP-glucose
.
Glucose-1-phosphate thymidylyltransferase, long form (G1P_thy_trans_l)
Type: Family

This family is the long form of Glucose-1-phosphate thymidylyltransferase. Glucose-1-phosphate thymidylyltransferase catalyses the formation of dTDP-glucose, from dTTP and glucose 1-phosphate. It is the first enzyme in the biosynthesis of dTDP-L-rhamnose, a cell wall constituent and a feedback inhibitor of the enzyme .

There are two forms of Glucose-1-phosphate thymidylyltransferase in bacteria and archeae, a short form (see

) and a long form. The homotetrameric short form is found in numerous bacterial species that incorporate dTDP-L-rhamnose, which it helps synthesize, into the cell wall. It is subject to feedback inhibition. The long form, in contrast, is found in many species for which it serves as a sugar-activating enzyme for antibiotic biosynthesis and or other, unknown pathways, and in which dTDP-L-rhamnose is not necessarily produced. The long from enzymes also have a left-handed parallel helix domain at the C terminus, whereas, the short form enzymes do not have this domain .
Archaeosine synthase subunit beta (RaSEA)
Type: Family

This is a family of archaeal radical SAM enzymes (RaSEA) which are involved in the synthesis of archaeosine, a modified nucleoside present in the dihydrouridine loop (D-loop) of archaeal tRNAs. RaSEA forms a robust complex with archaeosine synthase (ArcS) to catalyse the cleavage of the C(epsilon)-N bond of the lysine moiety of q0kN15-tRNA, leading to the formation of archaeosine. RaSEA enzymes have a conserved CX3CX2C motif, in which the three cysteine residues coordinate three of the four iron atoms of the [4Fe-4S] cluster at the active site of the enzyme. It has been demonstrated that the formation of an ArcS-RaSEA complex is crucial for archaeosine formation, following this discovery ArcS has been renamed archaeosine synthase subunit alpha (lysine transferase), and RaSEA has been renamed archaeosine synthase subunit beta (q0kN-tRNA lyase) .
Protein YhcC-like (YhcC-like)
Type: Family

This family of radical-SAM enzymes incudes Protein YhcC from Escherichia coli, which can cleave S-adenosyl-L-methionine into methionine and 5'-deoxyadenosine (AdoH) in vitro .
tRNA pseudouridine synthase, Pus10 (Pus10)
Type: Family

This entry represents the Pus 10 family of tRNA pseudouridine synthases. Family members are responsible for the synthesis of pseudouridine from uracil-54 and uracil-55 in the psi GC loop of transfer RNAs . The family appears to be distinct from the five commonly identified families of Psi synthases .
dTDP-4-dehydrorhamnose reductase family (dTDP_dehydrorham_reduct)
Type: Family

dTDP-4-dehydrorhamnose reductase (

) catalyses the reduction of dTDP-6-deoxy-L-lyxo-4-hexulose to yield dTDP-L-rhamnose, which is the final step in the conversion of dTDP-D-glucose to dTDP-L-rhamnose . dTDP-rhamnose is essential for growth of mycobacteria . dTDP-L-rhamnose is the precursor of L-Rhamnose (L-Rha), a component of the lipopolysaccharide (LPS) core and several O antigen polysaccharides of Pseudomonas .

Methionine adenosyltransferase 2 subunit beta (MAT2B) also belongs to this family. It is the regulatory subunit of MAT2A, an enzyme that catalyses the formation of S-adenosylmethionine (AdoMet) from methionine and ATP . Also in this family is the probable dTDP-4,6-dihydroxy-2-methyloxan-3-one 4-ketoreductase (oleU) from
Streptomyces antibioticus
, which is required for the biosynthesis of the aglycone antibiotic oleandomycin .
Acetoacetyl-CoA synthase (Acac_CoA_synth)
Type: Family

Isoprenoids are a large class of compounds, with more than 20,000 structures currently known, which are found in all living organisms. Some play essential physiological roles, such as sterols that stabilise cell membranes or carotenoids involved in photosynthesis, while the function of many others is not well understood. In all eukaryotes and some prokaryotes, isoprenoids are synthesised by the mevalonate pathway, while most prokaryotes use a mevalonate-independent pathway .

This entry represents acetoacetyl-CoA synthase (

), catalysing the first step of the mevalonate pathway of isoprenoid biosynthesis via isopentenyl diphosphate.

ATP + acetoacetate + CoA = AMP + diphosphate + acetoacetyl-CoA

A Sinorhizobium protein in this entry is also required for growth on polyhydroxybutyrate, a commonly used carbon storage molecule in bacteria . This entry also includes malonamoyl-CoA synthetase which in Penicillium is involved in the biosynthesis of the tetracycline-like viridicatumtoxin .
Tandem five-TM protein (Tandem_5TM)
Type: Family

Members of this family of proteins, with average length of 210, have no invariant residues but five predicted transmembrane segments. Strangely, most members occur in groups of consecutive paralogous genes. A striking example is a set of eleven encoded consecutively, head-to-tail, in Staphylococcus aureus strain COL.
Phosphomevalonate kinase, bacteria (Pmev_kinase_bact)
Type: Family

This entry represents a group of predicted phosphomevalonate kinases from bacteria.
Conantokin, conserved site (Conantokin_CS)
Type: Conserved_site

The conantokins are a family of neuroactive peptides found in the venoms of fish-hunting cone snails. They possess a relatively high number of residues (4-5) of the non-standard amino acid gamma-carboxyglutamic acid (Gla), which is generated by the post-translational modification of glutamate (Glu) residues. Conantokins are the only naturally produced peptides known to be N-methyl-D-aspartate (NMDA) receptor antagonists and show therapeutic promise in treating conditions associated with NMDA receptor dysfunction. In animal models they have exhibited anticonvulsant and anti-Parkinsonian properties and have provided neuroprotection within therapeutically acceptable times following transient focal brain ischemia .

Upon binding of Ca2+ to Gla, conantokin undergoes a conformational transition from a distorted curvilinear 3(10) helix to a linear α-helix. The binding of Ca2+ to conantokin leads to the exposure of a hydrophobic region on the opposite face of the helix . Conantokins share relatively few sequence elements, which include include sequence identity at the first four residues, homologous positioning of the two most C-terminal Gla residues, and an Arg preceding the most C-terminal Gla .

The conantokin family is currently known to include:

Conotoxin G from Conus geographus (Geography cone) (Nubecula geographus).

Conantokin-L from Conus lynceus (Lynceus cone) .

Conantokin-R from Conus radiatus (Rayed cone) .

Conantokin-T from Conus tulipa (Fish-hunting cone snail) (Tulip cone) .

Conantokin-P from Conus purpurascens (Purple cone) .

Conantokin-Pr3	from Conus parius (Cone snail) .

Conantokin-Br	Conus sulcatus (Sulcate cone) .
Higher eukaryotic phosphomevalonate kinase (Pmev_kin_anim)
Type: Family

Phosphomevalonate kinase (

) catalyses the phosphorylation of 5-phosphomevalonate into 5-diphosphomevalonate,
an essential step in isoprenoid biosynthesis via the mevalonate pathway. In an example of non orthologous gene displacement, two different types of phosphomevalonate kinase are found -the higher eukaryotic form and the ERG8 type. This model represents the form of the enzyme found in animals.
Imidazolonepropionase (HutI)
Type: Family

Imidazolonepropionase catalyzes the third step in histidine degradation. It hydrolyses the carbon-nitrogen bonds in 4-imidazolone-5-propionic acid to yield N-formimino-l-glutamic acid . The enzyme contains two domains, a TIM (triose-phosphate isomerase) barrel domain with two insertions and a small β-sandwich domain. It has been conserved from bacteria to eukaryotes . In bacteria, the enzyme is part of histidine utilization (hut) operon .
Histidine ammonia-lyase (HutH)
Type: Family

Histidine ammonia-lyase deaminates histidine to urocanic acid, the first step in histidine degradation. It is closely related to the plant enzyme phenylalanine ammonia-lyase but is absent in plants and viruses. This enzyme contains a unique cofactor called 4-methylidene-imidazole-5-one group (MIO), which is produced autocatalytically by a cyclization and dehydration of the three amino-acid residues alanine, serine and glycine, for its chain folding .
Phenylalanine ammonia-lyase (Phe_NH3-lyase)
Type: Family

This entry represents phenylalanine ammonia-lyase proteins.

The ubiquitous higher plant enzyme phenylalanine ammonia-lyase (PAL;

) is a key biosynthetic catalyst in phenylpropanoid assembly. PAL catalyses the non-oxidative deamination of L-phenylalanine to trans-cinnamic acid. PAL contains a catalytic Ala-Ser-Gly triad that is post-translationally cyclised. PAL is structurally similar to the mechanistically related histidine ammonia lyase (HAL;

), with PAL having an additional approximately 160 residues extending from the common fold . Catalysis in PAL may be governed by the dipole moments of seven α-helices associated with the PAL active site. The cofactor 3,5-dihydro-5-methylidene-4H-imidazol-4-one (MIO) resides atop the positive poles of three helices, increasing its electrophillicity. Plant and fungal PAL enzymes contain a 100-residue-long C-terminal multi-helix domain, which might play a role in the rapid response of PAL in the regulation of phenylpropanoid biosynthesis by destabilising the enzyme . This entry also includes fungal proteins such as phenolylalanine ammonia-lyase CLZ10, which mediates the biosynthesis of squalestatin S1 with potent cholesterol-lowering activity by targeting squalene synthase (SS) , and phenolylalanine ammonia-lyase hkm12, involved in the biosynthesis of hancockiamides, an unusual new family of N-cinnamoylated piperazines .
Formiminoglutamase (HutG)
Type: Family

Formiminoglutamase (

), the fourth enzyme of histidine degradation, is similar to arginases and agmatinases . It is often encoded near other enzymes of the histidine degredation pathway: histidine ammonia-lyase, urocanate hydratase, and imidazolonepropionase. It catalyses the reaction:

N-formimidoyl-L-glutamate + H2O = L-glutamate + formamide.
Agmatinase-related (Agmatinase-rel)
Type: Family

Members of this family include known and predicted examples of agmatinase (agmatine ureohydrolase,

) and members of archaea, for which no definitive agmatinase sequence has yet been made available . However, archaeal sequences are phylogenetically close to the experimentally verified Bacillus subtilis sequence. One species of Halobacterium has been demonstrated in vitro to produce agmatine from arginine, but no putrescine from ornithine, suggesting that arginine decarboxylase and agmatinase, rather than arginase and ornithine decarboxylase, lead from arginine to polyamine biosynthesis.
Tagatose-6-phosphate kinase (LacC)
Type: Family

Tagatose-6-phosphate kinase (

) is part of the tagatose-6-phosphate pathway of lactose degradation. The enzyme catalyses the following reaction:
ATP + D-tagatose 6-phosphate = ADP + D-tagatose 1,6-bisphosphate

The genes coding for the enzymes of the tagatose 6-phosphate pathway have been found to be part of the lac operon, together with the genes coding for the lactose-phosphotransferase system and the phospho-beta-galactosidase in Lactococcus lactis, Staphlococcus aureus, and Streptococcus mutans.
Tagatose 1,6-diphosphate aldolase (Tag_1.6-dipho_adolase)
Type: Family

Proteins from this entry are from Gram-positive bacteria and belong to the aldolase lacD family. Tagatose 1,6-diphosphate aldolase is a class I aldolase. It catalyses the reversible cleavage of four diastereoisomers (fructose 1,6-bisphosphate (FBP), psicose 1,6-bisphosphate, sorbose 1,6-bisphosphate, and tagatose 1,6-bisphosphate) to dihydroxyacetone phosphate (DHAP) and d-glyceraldehyde 3-phosphate with high catalytic efficiency .

Aldolases play important roles in essential metabolic pathways, such as gluconeogenesis and glycolysis. They are classified with respect to their catalytic mechanism into two classes: class I adolases are are characterised by formation of covalent Schiff base intermediates, while class II aldolases are metallodependent enzymes and use a divalent transition metal ion to polarize the substrate ketose .
6-phospho-beta-galactosidase (6P-beta-galactosidase)
Type: Family

6-phospho-beta-galactosidase (

) is part of the tagatose-6-phosphate pathway of galactose-6-phosphate degradation.
A 6-phospho-beta-D-galactoside + H2O = an alcohol + 6-phospho-D-galactose
The genes coding for the enzymes of the tagatose 6-phosphate pathway have been found to be part of the lac operon together with the genes coding for the lactose-phosphotransferase system and the phospho-beta-galactosidase in Lactococcus lactis, Staphylococcus aureus, and Streptococcus mutans.