SII-SWORD/CoKE huggingface dataset:
ATP synthase, F0 complex, subunit C, DCCD-binding site (ATP_synth_F0_csu_DDCD_BS)
Type: Binding_site

Transmembrane ATPases are membrane-bound enzyme complexes/ion transporters that use ATP hydrolysis to drive the transport of protons across a membrane. Some transmembrane ATPases also work in reverse, harnessing the energy from a proton gradient, using the flux of ions across the membrane via the ATPase proton channel to drive the synthesis of ATP.

F-ATPases (also known as ATP synthases, F1F0-ATPase, or H(+)-transporting two-sector ATPase) (

) are composed of two linked complexes: the F1 ATPase complex is the catalytic core and is composed of 5 subunits (alpha, beta, gamma, delta, epsilon), while the F0 ATPase complex is the membrane-embedded proton channel that is composed of at least 3 subunits (A-C), with additional subunits in mitochondria. Both the F1 and F0 complexes are rotary motors that are coupled back-to-back. In the F1 complex, the central gamma subunit forms the rotor inside the cylinder made of the α(3)β(3) subunits, while in the F0 complex, the ring-shaped C subunits forms the rotor. The two rotors rotate in opposite directions, but the F0 rotor is usually stronger, using the force from the proton gradient to push the F1 rotor in reverse in order to drive ATP synthesis . These ATPases can also work in reverse in bacteria, hydrolysing ATP to create a proton gradient.

Subunit C (also called subunit 9, or proteolipid) is found in the F0 complex of F-ATPases. Ten C subunits form an oligomeric ring that makes up the F0 rotor. The flux of protons through the ATPase channel drives the rotation of the C subunit ring, which in turn is coupled to the rotation of the F1 complex gamma subunit rotor due to the permanent binding between the gamma and epsilon subunits of F1 and the C subunit ring of F0. The sequential protonation and deprotonation of Asp61 of subunit C is coupled to the stepwise movement of the rotor .
Hydrogenase nickel incorporation protein HypA/HybF, conserved site (Hydgase_Ni_incorp_HypA/HybF_CS)
Type: Conserved_site

Bacterial membrane-bound nickel-dependent hydrogenases require a number of accessory proteins which are involved in their maturation . One of these proteins is generally known as HypA. HypA is a metallochaperone that binds nickel to bring it safely to its target. The nickel coordinates with four nitrogens within the protein. Four conserved cysteines towards the C terminus bind one zinc moiety, probably to stabilise the protein fold . In Helicobacter pylori, HypA is involved in the maturation of both hydrogenase and urease . Escherichia coli has two proteins that belong to this family, HypA and HybF . A homologue, MJ0214, has also been found in a number of archaeal species, including the genome of Methanocaldococcus jannaschii (Methanococcus jannaschii). Guanidine hydrolase-activating protein A (GhaA) from Synechocystis sp. is also included in this entry, as it shows similarity to HypA. GhaA is involved in the maturation of the nickel-dependent guanidine hydrolase GdmH .

This entry represents a region from these proteins that contains two of the conserved cysteines.
Ribonuclease P, conserved site (RNase_P_CS)
Type: Conserved_site

Ribonuclease P (

) (RNase P) is a site specific endonuclease that generates mature tRNAs by catalysing the removal of the 5'-leader sequence from pre-tRNA to produce the mature 5'-terminus. It can also cleave other RNA substrates such as 4.5S RNA. In bacteria RNase P is known to be composed of two components: a large RNA (about 400 base pairs) encoded by rnpB, and a small protein (119 to 133 amino acids) encoded by rnpA. The RNA moiety of RNase P carries the catalytic activity; the protein component plays an auxiliary, but essential, role in vivo by binding to the 5'-leader sequence and broadening the substrate specificity of the ribozyme. The sequence of rnpA is not highly conserved, however there is, in the central part of the protein, a conserved basic region.

This entry represents a conserved basic region found towards the centre of ribonuclease P.
Chorismate synthase, conserved site (Chorismate_synthase_CS)
Type: Conserved_site

Chorismate synthase (CS; 5-enolpyruvylshikimate-3-phosphate phospholyase; 1-carboxyvinyl-3-phosphoshikimate phosphate-lyase; E.C. 4.2.3.5) catalyzes the seventh and final step in the shikimate pathway which is used in prokaryotes, fungi and plants for the biosynthesis of aromatic amino acids. It catalyzes the 1,4-trans elimination of the phosphate group from 5-enolpyruvylshikimate-3-phosphate (EPSP) to form chorismate which can then be used in phenylalanine, tyrosine or tryptophan biosynthesis. Chorismate synthase requires the presence of a reduced flavin mononucleotide (FMNH2 or FADH2) for its activity. Chorismate synthase from various sources shows a high degree of sequence conservation . It is a protein of about 360 to 400 amino-acid residues.

Depending on the capacity of these enzymes to regenerate the reduced form of FMN, chorismate synthases are divided into two groups: enzymes, mostly from plants and eubacteria, that sequester CS from the cellular environment, are monofunctional, while those that can generate reduced FMN at the expense of NADPH, such as found in fungi and the ciliated protozoan Euglena gracilis, are bifunctional, having an additional NADPH:FMN oxidoreductase activity. Recently, bifunctionality of the Mycobacterium tuberculosis enzyme (MtCS) was determined by measurements of both chorismate synthase and NADH:FMN oxidoreductase activities. Since shikimate pathway enzymes are present in bacteria, fungi and apicomplexan parasites (such as Toxoplasma gondii, Plasmodium falciparum, and Cryptosporidium parvum) but absent in mammals, they are potentially attractive targets for the development of new therapy against infectious diseases such as tuberculosis (TB) .

This entry represents conserved regions from chorismate synthase that are rich in basic residues.
Aspartate carbamoyltransferase regulatory subunit, C-terminal (Asp_carbamoyltrfase_reg_C)
Type: Domain

This entry represents the C-terminal domain in ATCase and related proteins.

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.
Aspartate carbamoyltransferase regulatory subunit, N-terminal (Asp_carbamoyltransf_reg_N)
Type: Domain

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.
ATP synthase, F1 complex, delta/epsilon subunit, N-terminal (ATP_synth_F1_dsu/esu_N)
Type: Domain

This family represents subunits called delta (in mitochondrial ATPase) or epsilon (in bacteria or chloroplast ATPase). The interaction site of subunit C of the F0 complex with the delta or epsilon subunit of the F1 complex may be important for connecting the rotor of F1 (gamma subunit) to the rotor of F0 (C subunit) . In bacterial species, the delta subunit is the equivalent of the Oligomycin sensitive subunit (OSCP,

) in metazoans. The C-terminal domain of the epsilon subunit appears to act as an inhibitor of ATPase activity .

Transmembrane ATPases are membrane-bound enzyme complexes/ion transporters that use ATP hydrolysis to drive the transport of protons across a membrane. Some transmembrane ATPases also work in reverse, harnessing the energy from a proton gradient, using the flux of ions across the membrane via the ATPase proton channel to drive the synthesis of ATP.

F-ATPases (also known as ATP synthases, F1F0-ATPase, or H(+)-transporting two-sector ATPase) (

) are composed of two linked complexes: the F1 ATPase complex is the catalytic core and is composed of 5 subunits (alpha, beta, gamma, delta, epsilon), while the F0 ATPase complex is the membrane-embedded proton channel that is composed of at least 3 subunits (A-C), with additional subunits in mitochondria. Both the F1 and F0 complexes are rotary motors that are coupled back-to-back. In the F1 complex, the central gamma subunit forms the rotor inside the cylinder made of the α(3)β(3) subunits, while in the F0 complex, the ring-shaped C subunits forms the rotor. The two rotors rotate in opposite directions, but the F0 rotor is usually stronger, using the force from the proton gradient to push the F1 rotor in reverse in order to drive ATP synthesis . These ATPases can also work in reverse in bacteria, hydrolysing ATP to create a proton gradient.
ATP synthase epsilon subunit, C-terminal domain (ATP_synth_F1_esu_C)
Type: Domain

This entry represents the C-terminal long α-helix domain of ATPase subunit epsilon (in bacteria or chloroplast ATPase) from bacteria and plants .

The interaction site of subunit C of the F0 complex with the delta or epsilon subunit of the F1 complex may be important for connecting the rotor of F1 (gamma subunit) to the rotor of F0 (C subunit) . In bacterial species, the delta subunit is the equivalent of the Oligomycin sensitive subunit (OSCP,

) in metazoans. The C-terminal domain of the epsilon subunit appears to act as an inhibitor of ATPase activity .
Fructose-1,6-bisphosphatase, active site (Fructose_bisphosphatase_AS)
Type: Active_site

This entry represents fructose-1,6-bisphosphatase (FBPase), a critical regulatory enzyme in gluconeogenesis that catalyses the removal of 1-phosphate from fructose 1,6-bis-phosphate to form fructose 6-phosphate . It is involved in many different metabolic pathways and found in most organisms. FBPase requires metal ions for catalysis (Mg
2+
and Mn
2+
being preferred) and the enzyme is potently inhibited by Li
+
. The fold of fructose-1,6-bisphosphatase was noted to be identical to that of inositol-1-phosphatase (IMPase) . Inositol polyphosphate 1-phosphatase (IPPase), IMPase and FBPase share a sequence motif (Asp-Pro-Ile/Leu-Asp-Gly/Ser-Thr/Ser) which has been shown to bind metal ions and participate in catalysis. This motif is also found in the distantly-related fungal, bacterial and yeast IMPase homologues. It has been suggested that these proteins define an ancient structurally conserved family involved in diverse metabolic pathways, including inositol signalling, gluconeogenesis, sulphate assimilation and possibly quinone metabolism .

In mammalian FBPase, a lysine residue has been shown to be involved in the catalytic mechanism . The region around this residue is highly conserved and can be used as a signature pattern for FBPase and sedoheptulose-1,7-bisphosphatase (SBPase) an enzyme found plant chloroplasts and in photosynthetic bacteria that is functionally and structurally related to FBPase . SBPase catalyses the hydrolysis of sedoheptulose 1,7-bisphosphate to sedoheptulose 7-phosphate, a step in the Calvin's reductive pentose phosphate cycle. This signature contains the active site lysine, however, it must be noted that, in some bacterial FBPase sequences, the active site lysine is replaced by an arginine.
Endoribonuclease YbeY, conserved site (YbeY_CS)
Type: Conserved_site

YbeY is a single strand-specific metallo-endoribonuclease involved in late-stage 70S ribosome quality control and in maturation of the 3' terminus of the 16S rRNA. It acts together with the RNase R to eliminate defective 70S ribosomes, but not properly matured 70S ribosomes or individual subunits, by a process mediated specifically by the 30S ribosomal subunit. It is involved in the processing of 16S, 23S and 5S rRNAs, with a particularly strong effect on maturation at both the 5'-and 3'-ends of 16S rRNA as well as maturation of the 5'-end of 23S and 5S rRNAs .

YbeY contains a conserved region with three histidines at the C terminus. This entry represents this region.
Inositol monophosphatase, conserved site (Inositol_monophosphatase_CS)
Type: Conserved_site

This entry represents a conserved signature pattern found within the inositol monophosphatase family of proteins. It is suggested that these proteins may act by enhancing the synthesis or degradation of phosphorylated messenger molecules.

It has been shown that several proteins share two sequence motifs . Two of these proteins, vertebrate and plant inositol monophosphatase (

), and vertebrate inositol polyphosphate 1-phosphatase (

), are enzymes of the inositol phosphate second messenger signalling pathway, and share similar enzyme activity. Both enzymes exhibit an absolute requirement for metal ions (Mg2 is preferred), and their amino acid sequences contain a number of conserved motifs, which are also shared by several other proteins related to MPTASE (including products of fungal QaX and qutG, bacterial suhB and cysQ, and yeast hal2) . The function of the other proteins is not yet clear, but it is suggested that they may act by enhancing the synthesis or degradation of phosphorylated messenger molecules .

Structural analysis of these proteins has revealed a common core of 155 residues, which includes residues essential for metal binding and catalysis. An interesting property of the enzymes of this family is their sensitivity to Li+. The targets and mechanism of action of Li+ are unknown, but overactive inositol phosphate signalling may account for symptoms of manic depression .
Inositol monophosphatase, lithium-sensitive (Inositol_monoPase_Li-sen)
Type: Family

It has been shown that several proteins share two sequence motifs . Two of these proteins, vertebrate and plant inositol monophosphatase (

), and vertebrate inositol polyphosphate 1-phosphatase (

), are enzymes of the inositol phosphate second messenger signalling pathway, and share similar enzyme activity. Both enzymes exhibit an absolute requirement for metal ions (Mg2 is preferred), and their amino acid sequences contain a number of conserved motifs, which are also shared by several other proteins related to MPTASE (including products of fungal QaX and qutG, bacterial suhB and cysQ, and yeast hal2) . The function of the other proteins is not yet clear, but it is suggested that they may act by enhancing the synthesis or degradation of phosphorylated messenger molecules .

Structural analysis of these proteins has revealed a common core of 155 residues, which includes residues essential for metal binding and catalysis. An interesting property of the enzymes of this family is their sensitivity to Li+. The targets and mechanism of action of Li+ are unknown, but overactive inositol phosphate signalling may account for symptoms of manic depression .

An interesting property of the enzymes of this family is their sensitivity to Li+ at levels achieved in patients undergoing therapy for manic depression. The targets and mechanism of action of Li+ are unknown, but overactive inositol phosphate signalling may account for symptoms of the disease . It has been proposed that these Li+-sensitive proteins could represent targets for Li+ in manic depressive disease .
Uncharacterised protein family UPF0021, conserved site (UPF0021_CS)
Type: Conserved_site

The following uncharacterised proteins have been shown to share regions of similarities, yeast chromosome VII hypothetical protein YGL211w; Dictyostelium discoideum (Slime mold) protein veg136; and Methanocaldococcus jannaschii (Methanococcus jannaschii) hypothetical proteins MJ1157 and MJ1478.

The signature in this entry recognises a conserved pattern in the N-terminal domain of the proteins.
2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase, conserved site (MECDP_synthase_CS)
Type: Conserved_site

IspF is a MECDP (2-C-methyl-D-erythritol 2,4-cyclodiphosphate) synthetase, also known as YgbB. It is an enzyme in the non-mevalonate pathway of isoprenoid synthesis. Isoprenoids are essential in all organisms, and can also be synthesized through the mevalonate pathway. The non-mevolante route is used by many bacteria and human pathogens, including Mycobacterium tuberculosis and Plasmodium falciparum. This route appears to involve seven enzymes. MECDP synthetase catalyses the intramolecular attack by a phosphate group on a diphosphate, with cytidine monophosphate (CMP) acting as the leaving group to give the cyclic diphosphate product MEDCP. The enzyme is a trimer with three active sites shared between adjacent copies of the protein. The enzyme also has two metal binding sites, the metals playing key roles in catalysis.

A number of proteins from eukaryotes and prokaryotes are bifunctional proteins with an N-terminal IspD domain and a C-terminal IspF domain .

This entry represents a MECDP (2-C-methyl-D-erythritol 2,4-cyclodiphosphate) synthetase conserved site.
Amidase, conserved site (Amidase_CS)
Type: Conserved_site

Amidase signature (AS) enzymes are a large group of hydrolytic enzymes that contain a conserved stretch of approximately 130 amino acids known as the AS sequence. They are widespread, being found in both prokaryotes and eukaryotes. AS enzymes catalyse the hydrolysis of amide bonds (CO-NH2), although the family has diverged widely with regard to substrate specificity and function. Nonetheless, these enzymes maintain a core α/β/α structure, where the topologies of the N-and C-terminal halves are similar. AS enzymes characteristically have a highly conserved C-terminal region rich in serine and glycine residues, but devoid of aspartic acid and histidine residues, therefore they differ from classical serine hydrolases. These enzymes posses a unique, highly conserved Ser-Ser-Lys catalytic triad used for amide hydrolysis, although the catalytic mechanism for acyl-enzyme intermediate formation can differ between enzymes .

Examples of AS enzymes include:

Peptide amidase (Pam) , which catalyses the hydrolysis of the C-terminal amide bond of peptides.

Fatty acid amide hydrolases , which hydrolyse fatty acid amid substrates (e.g. cannabinoid anandamide and sleep-inducing oleamide), thereby controlling the level and duration of signalling induced by this diverse class of lipid transmitters.

Malonamidase E2 , which catalyses the hydrolysis of malonamate into malonate and ammonia, and which is involved in the transport of fixed nitrogen from bacteroids to plant cells in symbiotic nitrogen metabolism.

Subunit A of Glu-tRNA(Gln) amidotransferase ,a heterotrimeric enzyme that catalyses the formation of Gln-tRNA(Gln) by the transamidation of misacylated Glu-tRNA(Gln) via amidolysis of glutamine.
Fumarate lyase, conserved site (Fumarate_lyase_CS)
Type: Conserved_site

A number of enzymes, belonging to the lyase class, for which fumarate is a substrate, have been shown to share a short conserved sequence around a methionine which is probably involved in the catalytic activity of this type of enzymes . The following are examples of members of this family:

: 3-carboxymuconate lactonizing enzyme,

(3-carboxy-cis,cis-muconate cycloisomerase), an enzyme involved in aromatic acids catabolism .

: Delta-crystallin shares around 90% sequence identity with arginosuccinate lyase, showing that it is an example of a 'hijacked' enzyme -accumulated mutations have, however, rendered the protein enzymatically inactive.

: Class I Fumarase enzyme,

(fumarate hydratase), which catalyses the reversible hydration of fumarate to L-malate. Class I enzymes are thermolabile dimeric enzymes (as for example: Escherichia coli fumC).

: Arginosuccinase,

(argininosuccinate lyase), which catalyses the formation of arginine and fumarate from argininosuccinate, the last step in the biosynthesis of arginine.

: Aspartate ammonia-lyase,

(aspartase), which catalyses the reversible conversion of aspartate to fumarate and ammonia. This reaction is analogous to that catalyzed by fumarase, except that ammonia rather than water is involved in the trans-elimination reaction.

: class II Fumarase enzyme,

, are thermostable and tetrameric and are found in prokaryotes (as for example: E. coli fumA and fumB) as well as in eukaryotes. The sequence of the two classes of fumarases are not closely related.

: Adenylosuccinase,

(adenylosuccinate lyase) , which catalyses the eighth step in the de novo biosynthesis of purines, the formation of 5'-phosphoribosyl-5-amino-4-imidazolecarboxamide and fumarate from 1-(5-phosphoribosyl)-4-(N-succino-carboxamide). That enzyme can also catalyse the formation of fumarate and AMP from adenylosuccinate.

: Trans-aconitate decarboxylase 1, which decarboxylates trans-aconitate, an intermediate in the biosynthesis of itaconic acid and 2-hydroxyparaconate .

This signature contains the conserved methionine which is probably involved in the catalytic activity.