SII-SWORD/CoKE huggingface dataset:
Acetylglutamate kinase ArgB, GNAT domain-containing (ArgB_GNAT)
Type: Family

N -Acetylglutamate (NAG) fulfils distinct biological roles in lower and higher organisms. In prokaryotes, lower eukaryotes and plants it is the first intermediate in the biosynthesis of arginine, whereas in ureotelic (excreting nitrogen mostly in the form of urea) vertebrates, it is an essential allosteric cofactor for carbamyl phosphate synthetase I (CPSI), the first enzyme of the urea cycle. The pathway that leads from glutamate to arginine in lower organisms employs eight steps, starting with the acetylation of glutamate to form NAG. In these species, NAG can be produced by two enzymatic reactions: one catalysed by NAG synthase (NAGS) and the other by ornithine acetyltransferase (OAT). In ureotelic species, NAG is produced exclusively by NAGS. In lower organisms, NAGS is feedback-inhibited by L-arginine, whereas mammalian NAGS activity is significantly enhanced by this amino acid. The NAGS genes of bacteria, fungi and mammals are more diverse than other arginine-biosynthesis and urea-cycle genes. The evolutionary relationship between the distinctly different roles of NAG and its metabolism in lower and higher organisms remains to be determined .

The pathway from glutamate to arginine is:

NAGS; N-acetylglutamate synthase (

) (glutamate to N-acetylglutamate)

NAGK; N-acetylglutamate kinase (

) (N-acetylglutamate to N-acetylglutamate-5P)

N-acetyl-gamma-glutamyl-phosphate reductase (

) (N-acetylglutamate-5P to N-acetylglumate semialdehyde)

Acetylornithine aminotransferase (

) (N-acetylglumate semialdehyde to N-acetylornithine)

Acetylornithine deacetylase (

) (N-acetylornithine to ornithine)

Arginase (

) (ornithine to arginine)

This entry represents N-acetylglutamate kinase (NAGK) with a C-terminal GNAT domain. Majority of proteins in this entry are from bacteria, including argB from Xylella fastidiosa (UniProt:Q9PEM7).
N-acetylglutamate synthase, animal (GlcNAc_Synth_met)
Type: Family

N -Acetylglutamate (NAG) fulfils distinct biological roles in lower and higher organisms. In prokaryotes, lower eukaryotes and plants it is the first intermediate in the biosynthesis of arginine, whereas in ureotelic (excreting nitrogen mostly in the form of urea) vertebrates, it is an essential allosteric cofactor for carbamyl phosphate synthetase I (CPSI), the first enzyme of the urea cycle. The pathway that leads from glutamate to arginine in lower organisms employs eight steps, starting with the acetylation of glutamate to form NAG. In these species, NAG can be produced by two enzymatic reactions: one catalysed by NAG synthase (NAGS) and the other by ornithine acetyltransferase (OAT). In ureotelic species, NAG is produced exclusively by NAGS. In lower organisms, NAGS is feedback-inhibited by L-arginine, whereas mammalian NAGS activity is significantly enhanced by this amino acid. The NAGS genes of bacteria, fungi and mammals are more diverse than other arginine-biosynthesis and urea-cycle genes. The evolutionary relationship between the distinctly different roles of NAG and its metabolism in lower and higher organisms remains to be determined .

The pathway from glutamate to arginine is:

NAGS; N-acetylglutamate synthase (

) (glutamate to N-acetylglutamate)

NAGK; N-acetylglutamate kinase (

) (N-acetylglutamate to N-acetylglutamate-5P)

N-acetyl-gamma-glutamyl-phosphate reductase (

) (N-acetylglutamate-5P to N-acetylglumate semialdehyde)

Acetylornithine aminotransferase (

) (N-acetylglumate semialdehyde to N-acetylornithine)

Acetylornithine deacetylase (

) (N-acetylornithine to ornithine)

Arginase (

) (ornithine to arginine)

This group represents a N-acetylglutamate synthase, animal type .
Bifunctional argininosuccinate lyase/acetyltransferase (ASAL_AGS_AcTrfase)
Type: Family

This group represents a predicted bifunctional argininosuccinate lyase/acetyltransferase from Gammaproteobacteria.
Butyrate kinase (Butyrate_kin)
Type: Family

Butyrate kinase is an enzyme that facilitates the formation of butyryl-CoA by phosphorylating butyrate in the presence of ATP to form butyryl phosphate . The final steps in butyrate synthesis by anaerobic bacteria can occur via butyrate kinase and phosphotransbutyrylase or via butyryl-CoA:acetate CoA-transferase, the latter providing the dominant route for butyrate formation in human colonic bacteria .
Bifunctional diaminopimelate decarboxylase/aspartate kinase (DAP_dec_asp_kin)
Type: Family

This group represents a predicted bifunctional diaminopimelate decarboxylase/aspartate kinase from the Gammaproteobacteria.

Bifunctional enzymes permit the direct channelling of intermediates between catalytic centres involved in consecutive reactions in a pathway, offering an efficient means of directing the flow of catalysis and protecting intermediates from degradation . Both diaminopimelate decarboxylase and aspartate kinase are involved in lysine biosynthesis in bacteria, which can be synthesized from aspartate via the formation of the intermediate diaminopimelate (DAP), a metabolite that is also involved in peptidoglycan formation . Aspartate kinase catalyses the transfer of a phosphate group from ATP to aspartic acid, while diaminopimelate decarboxylase catalyses the conversion of diaminopimelate to lysine.
Chemotaxis protein-glutamate methylesterase (Chemotax_prot-Glu_Me-esterase)
Type: Family

In bacterial chemotaxis, cellular movement is directed in response to chemical gradients. Transmembrane chemoreceptors that sense the stimuli are coupled (via a coupling protein, CheW) with a signal transduction histidine kinase (CheA). CheA phosphorylates response regulators CheB and CheY. Phosphorylated CheY binds to FliM, a component of the flagellar motor switch complex, and modulates the direction of flagellar rotation . Response regulator CheB (receptor modification enzyme, protein-glutamate methylesterase) modulates the signalling output of the chemotaxis receptors through control of the level of chemoreceptor methylation . Specific glutamyl residues in the transmembrane chemoreceptor cytoplasmic domain are methylated by methyltransferase CheR to form γ-carboxyl glutamyl methyl esters. These esters can be hydrolyzed by methylesterase CheB. Receptor modification resets the signalling states of receptors, allowing for responses to changes in concentration of the chemical stimuli irrespective of their absolute concentrations .

Proteins in this family contain a divergent form of the CheB-like protein-glutamate methylesterase domain in the C-terminal region. This domain is usually found fused with the CheY-like receiver (response regulator) domain, forming CheB response regulator methylesterase (

). The stand-alone form is presumed also to be involved in the process of regulating bacterial chemotaxis , but there is no experimental evidence to confirm this.
Serine/alanine racemase (Serine/alanine_racemase)
Type: Family

This family represents a serine/alanine racemase from Enterococcus spp .

Vancomycin resistance in Enterococcus gallinarum results from the production of UDP-MurNAc-pentapeptide[D-Ser]. VanT, a membrane-bound serine racemase, is one of three proteins essential for this resistance. VanT also has alanine racemase activity but it is able to racemize serine more efficiently than alanine. It requires pyridoxal phosphate for activity and there is a highly conserved pyridoxal phosphate attachment site in the C-terminal domain, typical of alanine racemases . The N-terminal domain contains 10 predicted transmembrane segments and is likely to be involved in the transport of L-Ser, and that in its absence the vancomycin resistance phenotype is compromised .
Metalloenzyme, LuxS/M16 peptidase-like (Metalloenz_LuxS/M16)
Type: Homologous_superfamily

This entry represents domains with a two-layer α/β structure found in metalloenzymes such as LuxS (S-ribosylhomocysteinase;

) and metallopeptidases belonging to MEROPS peptidase family M16. These domains share the same active site motif of HxxEH located in the first core helix, but differ in one of the metal-binding residues. LuxS, the AI-2 (autoinducer-2) producing enzyme for quorum sensing in bacteria, is a homodimeric iron-dependent metalloenzyme containing two identical tetrahedral metal-binding sites similar to those found in peptidases and amidases, although it contains an extra N-terminal strand . Some M16 family metallopeptidases, such as mitochondrial processing peptidase (MPP), share the same common fold elaborated with many extra additional structures . These peptidases usually contain a duplication of this domain, although only the N-terminal domain binds the catalytic metal.

Domains found in metallopeptidases and non-peptidase homologues belonging to MEROPS peptidase family M16 (clan ME), subfamilies M16A, M16B and M16C; include:

Insulinase, insulin-degrading enzyme (

)

Mitochondrial processing peptidase alpha subunit, (Alpha-MPP,

)

Pitrlysin, Protease III precursor (

)

Nardilysin, (

)

Ubiquinol-cytochrome C reductase complex core protein I,mitochondrial precursor (

)

Coenzyme PQQ synthesis protein F (

)
Outer membrane protein/outer membrane enzyme PagP, beta-barrel (OMP/PagP_B-barrel)
Type: Homologous_superfamily

This entry represents a transmembrane β(8,10)-barrel found in outer membrane proteins such as OmpA, OmpX and NspA, and in the outer membrane enzyme PagP .
Luciferase-like domain (Luciferase-like_dom)
Type: Domain

Bacterial luciferase is a flavin monooxygenase that catalyses the oxidation of long-chain aldehydes and releases energy in the form of visible light, and which uses flavin as a substrate rather than a cofactor . Bacterial luciferase is an alpha/beta (LuxA/LuxB) heterodimer, where each individual subunit folds into a single TIM (β/α)8-barrel domain. There are structural similarities between bacterial luciferase and nonfluorescent flavoproteins (LuxF, FP390), alkanesulphonate monooxygenase (SsuD), and coenzyme F420-dependent terahydromethanopterin reductase, which make up clearly related families with somewhat different folds .
Fibrogen-binding domain 1 (Fibrogen-bd_dom1)
Type: Homologous_superfamily

This superfamily represents fibrinogen-binding domain 1. In proteins such as fibrinogen-binding adhesion SdrG and clumping factor A, there are two fibrinogen-binding domains with similar core β-sandwich topologies, but with different modulations in their structure. This entry represents the first domain, while

represents the second domain.
Prismane-like superfamily (Prismane-like_sf)
Type: Homologous_superfamily

Prismane (hybrid-cluster) proteins are present in a wide range of bacteria and archaea, and are characterised by their two Fe/S centres: a [4Fe-4S] cubane cluster, and a hybrid [4Fe-2S-2O] cluster . Prismane proteins contain four domains: two spectrin repeat-like 3-helical bundle domains, and two α/β domains with Rossmann-fold topology. Several proteins are structurally related to Prismane, including Ni-containing carbon monoxide dehydrogenase (CODH) (lack one of the N-terminal 3-helical bundle domains), the alpha and beta subunits of bifunctional CODH, and the alpha and beta subunits of acetyl-CoA synthetase.

This superfamily represents the spectrin repeat-like 3-helical bundle domains, as well as the two α/β domains with Rossmann-fold topology.
Regulatory factor, effector binding domain superfamily (Reg_factor_effector_dom_sf)
Type: Homologous_superfamily

The effector domain is found in bacterial transcription factors and other regulatory proteins. The effector domain consists of a duplicated β/α/β motif, where the antiparallel β sheets form a barrel structure. Several proteins contain this domain. For example, the multidrug-binding domain of the transcription factor BmrR, which transcriptionally regulates multidrug transporters . This domain is also present at the C-terminal domain of the Rob transcription factor, which regulates genes involved in resistance to antibiotics, organic solvents, and heavy metals . Additionally, the effector domain can be found in the gyrase inhibitory protein GyrI (SbmC, TeeB) that suppresses cell proliferation by inhibiting bacterial gyrase activity .

This domain is also found in heme-binding proteins 1-2 (HEBP1-2) and testis-expressed 264 proteins found in eukaryotes.

HEBP1-2 are part of the heme-binding protein HBP/SOUL family, which represents a group of evolutionary conserved putative heme-binding proteins. In humans, HEBP1 binds metalloporphyrins, free porphyrins and N-methylprotoporphyrins with similar affinities . HEBP2, in humans, can promote mitochondrial permeability transition and facilitate necrotic cell death under different types of stress conditions .
DNA glycosylase (DNA_glycosylase)
Type: Homologous_superfamily

DNA glycosylases act to repair oxidative damage in DNA. These proteins are redundant as there are several different types of DNA glycosylases that are able to compensate for one another. Examples include the endonuclease III subfamily, the mismatch glycosylases subfamily, the 3-methyladenine DNA glycosylases I subfamily, and the DNA repair glycosylases subfamily .
BPG-independent PGAM, N-terminal (BPG-indep_PGM_N)
Type: Domain

This family represents the N-terminal region of the 2,3-bisphosphoglycerate-independent phosphoglycerate mutase (or phosphoglyceromutase or BPG-independent PGAM) protein (

). The family is found in conjunction with Metalloenzyme (located in the C-terminal region of the protein).
Ezrin/radixin/moesin, C-terminal (ERM_C_dom)
Type: Domain

This entry represents the C-terminal domain of ERM family of proteins which corresponds to the actin-binding tail domain .

The ERM family consists of three closely-related proteins, ezrin, radixin and moesin . Ezrin was first identified as a constituent of microvilli , radixin as a barbed, end-capping actin-modulating protein from isolated junctional fractions , and moesin as a heparin binding protein , which is particularly important in immunity acting on both T and B-cells homeostasis and self-tolerance . Members of this family have been associated with axon-associated Schwann cell (SC) motility and the maintenance of the polarity of these cells . A tumour suppressor molecule responsible for neurofibromatosis type 2 (NF2) is highly similar to ERM proteins and has been designated merlin (moesin-ezrin-radixin-like protein) . ERM molecules contain 3 domains, an N-terminal globular domain, an extended α-helical domain and a charged C-terminal domain . Ezrin, radixin and merlin also contain a polyproline region between the helical and C-terminal domains. The N-terminal domain is highly conserved, and is also found in merlin, band 4.1 proteins and members of the band 4.1 superfamily, designated the FERM domain . ERM proteins crosslink actin filaments with plasma membranes. They co-localise with CD44 at actin filament plasma membrane interaction sites, associating with CD44 via their N-terminal domains and with actin filaments via their C-terminal domains . The α-helical region is involved in intramolecular masking of protein-protein interaction sites which regulates the activity of this proteins .
RNA polymerase, alpha subunit, C-terminal (RNAP_asu_C)
Type: Domain

The core of the bacterial RNA polymerase (RNAP) consists of four subunits, two alpha, a beta and a beta', which are conserved from bacteria to mammals. The alpha subunit (RpoA) initiates RNAP assembly by dimerising to form a platform on which the beta subunits can interact. The alpha subunit consists of a N-terminal domain (NTD) and a C-terminal domain (CTD), connected by a short linker. The NTD is essential for RNAP assembly, while the CTD is necessary for transcription regulation, interacting with transcription factors and promoter upstream elements. In Escherichia coli, the catabolite activator protein (CAP or CRP) was shown to exert its effect through its interactions with the CTD, where CAP binding to CTD promotes RNAP binding to promoter DNA, thereby stimulating transcription initiation at class I CAP-dependent promoters. At class II CAP-dependent promoters, the interaction of CAP with CTD is one of multiple interactions involved in activation .

The CTD has a compact structure of four helices and two long arms enclosing its hydrophobic core, making its folding topology distinct from most other binding proteins. The upstream promoter element-binding site is formed from helices 1 and 4 .
DNA-directed RNA polymerase, insert domain (DNA-dir_RNA_pol_insert)
Type: Domain

DNA-directed RNA polymerases

(also known as DNA-dependent RNA polymerases) are responsible for the polymerisation of ribonucleotides into a sequence complementary to the template DNA. In eukaryotes, there are three different forms of DNA-directed RNA polymerases transcribing different sets of genes. Most RNA polymerases are multimeric enzymes and are composed of a variable number of subunits. The core RNA polymerase complex consists of five subunits (two alpha, one beta, one beta-prime and one omega) and is sufficient for transcription elongation and termination but is unable to initiate transcription. Transcription initiation from promoter elements requires a sixth, dissociable subunit called a sigma factor, which reversibly associates with the core RNA polymerase complex to form a holoenzyme . The core RNA polymerase complex forms a "crab claw"-like structure with an internal channel running along the full length . The key functional sites of the enzyme, as defined by mutational and cross-linking analysis, are located on the inner wall of this channel.

RNA synthesis follows after the attachment of RNA polymerase to a specific site, the promoter, on the template DNA strand. The RNA synthesis process continues until a termination sequence is reached. The RNA product, which is synthesised in the 5' to 3' direction, is known as the primary transcript.

Eukaryotic nuclei contain three distinct types of RNA polymerases that differ in the RNA they synthesise:

RNA polymerase I: located in the nucleoli, synthesises precursors of most ribosomal RNAs.

RNA polymerase II: occurs in the nucleoplasm, synthesises mRNA precursors.

RNA polymerase III: also occurs in the nucleoplasm, synthesises the precursors of 5S ribosomal RNA, the tRNAs, and a variety of other small nuclear and cytosolic RNAs.

Eukaryotic cells are also known to contain separate mitochondrial and chloroplast RNA polymerases. Eukaryotic RNA polymerases, whose molecular masses vary in size from 500 to 700kDa, contain two non-identical large (>100kDa) subunits and an array of up to 12 different small (less than 50kDa) subunits.

RNA polymerase (RNAP) II, which is responsible for all mRNA synthesis in eukaryotes, consists of 12 subunits. Subunits Rpb3 and Rpb11 form a heterodimer that is functionally analogous to the archaeal RNAP D/L heterodimer, and to the prokaryotic RNAP alpha (RpoA) subunit homodimer. In each case, they play a key role in RNAP assembly by forming a platform on which the catalytic subunits (eukaryotic Rpb1/Rpb2, and prokaryotic beta/beta') can interact .

The dimerisation domains differ between the different subunit families. In eukaryotic Rpb3, archaeal D and bacterial RpoA subunits (

), the dimerisation domain is comprised of a central insert domain, which interrupts an Rpb11-like domain (

), dividing it into two halves . In eukaryotic Rpb11 and archaeal L subunits, the insert domain is lacking, leaving the Rpb11-like domain intact and contiguous.
DNA-directed RNA polymerase, RpoA/D/Rpb3-type (DNA-dir_RNA_pol_RpoA/D/Rpb3)
Type: Domain

The core of the bacterial RNA polymerase (RNAP) consists of four subunits, two alpha, a beta and a beta', which are conserved from bacteria to mammals. The alpha subunit (RpoA) initiates RNAP assembly by dimerising to form a platform on which the beta subunits can interact, and plays a direct role in promoter recognition . In eukaryotes, RNA polymerase (RNAP) II is responsible for all mRNA synthesis. RNAP-II consists of 12 subunits, where subunits Rpb3 and Rpb11 form a heterodimer that is functionally analogous to the bacterial RpoA homodimer . Archaeal RNAP closely resembles eukaryotic RNAP-II, and is composed of 12 subunits, of which D and L form a heterodimer resembling the Rpb3/Rpb11 and RpoA/RpoA dimers .

The bacterial RpoA, eukaryotic Rpb3 and archaeal D subunits share sequence and structural motifs, and can be placed into a single family. These subunits also have unique sequence motifs, especially at their C-terminal ends, which are involved in promoter specificity, for example the CTD of the bacterial RNAP alpha subunit (

).
Betaine aldehyde dehydrogenase (BADH)
Type: Family

Under osmotic stress, betaine aldehyde dehydrogenase oxidises glycine betaine aldehyde into the osmoprotectant glycine betaine, via the second of two oxidation steps from exogenously supplied choline or betaine aldehyde. This choline-glycine betaine synthesis pathway can be found in Gram-positive and Gram-negative bacteria. In Escherichia coli, betaine aldehyde dehydrogenase (betB) is osmotically co-induced with choline dehydrogenase (betA) in the presence of choline. These dehydrogenases are located in a betaine gene cluster with the upstream choline transporter (betT) and transcriptional regulator (betI) .

Similar to E. coli, betaine synthesis in Staphylococcus xylosus is also influenced by osmotic stress and the presence of choline with genes localised in a functionally equivalent gene cluster . Organisation of the betaine gene cluster in Rhizobium meliloti (Sinorhizobium meliloti) and Bacillus subtilis differs from that of E. coli by the absence of upstream choline transporter and transcriptional regulator homologues . Additionally, B. subtilis co-expresses a type II alcohol dehydrogenase with betaine aldehyde dehydrogenase instead of choline dehydrogenase as in E. coli, S. xylosus, and S. meliloti . Betaine aldehyde dehydrogenase is a member of the aldehyde dehydrogenase family. BetB from P. aeruginosa catalyses the irreversible oxidation of betaine aldehyde to the corresponding acid, a compulsory step in the assimilation of carbon and nitrogen when bacteria are growing in choline or choline precursors and it can use NADP+ with similar efficiency to NAD+, a property that can be used by the bacterium to produce the NADPH needed to combat the oxidative stress imposed by the host defenses .
GABA permease (GABA_permease)
Type: Family

GABA permease (gabP) catalyses the translocation of 4-aminobutyrate (GABA) across the plasma membrane, with homologues expressed in Gram-negative and Gram-positive organisms. This permease is a highly hydrophobic transmembrane protein consisting of 12 transmembrane domains with hydrophilic N- and C-terminal ends . Induced by nitrogen-limited culture conditions in both Escherichia coli and Bacillus subtilis, gabP is an energy dependent transport system stimulated by membrane potential and has been observed adjacent and distant from other GABA degradation proteins .
Fibrinogen-binding domain 2 (Adhesin_Fg-bd_dom_2)
Type: Domain

This entry represents the fibrinogen-binding domain from bacterial proteins such as fibrinogen-binding adhesion SdrG and clumping factor A. In both SdrG and clumping factor A, there are two fibrinogen-binding domains with similar core β-sandwich topologies, but with different modulations in their structure. This entry represents the second domain, while

represents the first domain.
Vegetative storage protein (Veg_Stor_Prot)
Type: Family

These vegatative storage proteins are close relatives of the plant acid phosphatases (

) and are limited to members of the Phaseoleae including Glycine max (Soybean) and Phaseolus vulgaris (Kidney bean). These proteins are highly expressed in the leaves of repeatedly depodded plants . Vegetative storage protein (VSP) differs most strikingly from the acid phosphatases in the lack of the conserved nucleophilic aspartate residue in the N terminus, thus, they should be inactive as phosphatases. This issue was confused by the publication in 1992 of an article claiming activity for the G. max VSP. In 1994 this assertion was refuted by the separation of the activity from the VSP .