SII-SWORD/CoKE huggingface dataset:
Tetrapyrrole methylase (4pyrrol_Mease)
Type: Domain

This entry represents a tetrapyrrole methylase domain, which consist of two non-similar subdomains .

Tetrapyrroles are large macrocyclic compounds derived from a common biosynthetic pathway . The end-product, uroporphyrinogen III, is used to synthesise a number of important molecules, including cobalamin (vitamin B12), haem, sirohaem, chlorophyll, coenzyme F430 and phytochromobilin .

These enzymes catalyse the methylation of their substrates using S-adenosyl-L-methionine as a methyl source. Enzymes in this family include:

Uroporphyrinogen III methyltransferase (

) (SUMT), which catalyses the conversion of uroporphyrinogen III to precorrin-2 at the first branch-point of the tetrapyrrole synthesis pathway, directing the pathway towards cobalamin or sirohaem synthesis .

Precorrin-2 C20-methyltransferase CobI/CbiL (

), which introduces a methyl group at C-20 on precorrin-2 to produce precorrin-3A during cobalamin biosynthesis. This reaction is key to the conversion of a porphyrin-type tetrapyrrole ring to a corrin ring . In some species, this enzyme is part of a bifunctional protein.

Precorrin-4 C11-methyltransferase CobM/CbiF (

), which introduces a methyl group at C-11 on precorrin-4 to produce precorrin-5 during cobalamin biosynthesis .

Sirohaem synthase CysG (

), domains 4 and 5, which synthesizes sirohaem from uroporphyrinogen III, at the first branch-point in the tetrapyrrole biosynthetic pathway, directing the pathway towards sirohaem synthesis .

Diphthine synthase (

), which carries out the methylation step during the modification of a specific histidine residue of elongation factor 2 (EF-2) during diphthine synthesis.
Guanylin (Guanylin)
Type: Family

This entry represents the guanylin family. Its members include guanylate cyclase activator 2A and 2B. They are endogenous activators of intestinal guanylate cyclases.
Myotoxin (Myotoxin)
Type: Family

Myotoxins are small basic peptides (42 to 45 residues) that can cause severe muscle necrosis by a non-enzymatic mechanism. They act extremely rapidly and serve two primary biological functions: limiting the flight of prey by causing instantaneous paralysis of the hind limbs and promoting rapid death by paralysis of the diaphragm . These myotoxins have a well-conserved structure containing six cysteines involved in three disulphide bridges.

One of the better studied myotoxins is crotamine, from South American rattlesnake Crotalus durissus terrificus. Crotamine is a multifunctional peptide with pharmacological interest; it can penetrate cells and has potential selective antitumoral activity together with its ability to inhibit the potassium current through voltage-gated potassium channels . Similar toxins have been isolated from the venom of other rattlesnake species .
Cytochrome c oxidase subunit I (Cyt_C_Oxase_1)
Type: Family

Cytochrome c oxidase (

) is a key enzyme in aerobic metabolism. Proton pumping haem-copper oxidases represent the terminal, energy-transfer enzymes of respiratory chains in prokaryotes and eukaryotes. The CuB-haem a3 (or haem o) binuclear centre, associated with the largest subunit I of cytochrome c and ubiquinol oxidases (

), is directly involved in the coupling between dioxygen reduction and proton pumping .
Some terminal oxidases generate a transmembrane proton gradient across the plasma membrane (prokaryotes) or the mitochondrial inner membrane (eukaryotes).

The enzyme complex consists of 3-4 subunits (prokaryotes) up to 13 polypeptides (mammals) of which only the catalytic subunit (equivalent to mammalian subunit I (CO I) is found in all haem-copper respiratory oxidases. The presence of a bimetallic centre (formed by a high-spin haem and copper B) as well as a low-spin haem, both ligated to six conserved histidine residues near the outer side of four transmembrane spans within CO I is common to all family members . In contrast to eukaryotes the respiratory chain of prokaryotes is branched to multiple terminal oxidases. The enzyme complexes vary in haem and copper composition, substrate type and substrate affinity. The different respiratory oxidases allow the cells to customize their respiratory systems according to a variety of environmental growth conditions .

Please note, this entry also identifies a number of proteins that are cleaved into two chains - a truncated non-functional cytochrome oxidase 1 and an intron-encoded endonuclease.
Thrombospondin type-1 (TSP1) repeat (TSP1_rpt)
Type: Repeat

This repeat was first described in 1986 by Lawler and Hynes . It was found in the thrombospondin protein where it is repeated 3 times. Now a number of proteins involved in the complement pathway (properdin, C6, C7, C8A, C8B, C9) as well as extracellular matrix protein like mindin, F-spondin , SCO-spondin and even the circumsporozoite surface protein 2 and TRAP proteins of Plasmodium contain one or more instance of this repeat. It has been involved in cell-cell interaction, inhibition of angiogenesis and apoptosis .

The intron-exon organisation of the properdin gene confirms the hypothesis that the repeat might have evolved by a process involving exon shuffling . A study of properdin structure provides some information about the structure of the thrombospondin type I repeat .

Thrombospondins are multimeric multidomain glycoproteins that function at cell surfaces and in the extracellular matrix milieu. They act as regulators of cell interactions in vertebrates. They are divided into two subfamilies, A and B, according to their overall molecular organisation. The subgroup A proteins TSP-1 and -2 contain an N-terminal domain, a VWFC domain, three TSP1 repeats, three EGF-like domains, TSP3 repeats and a C-terminal domain. They are assembled as trimer. The subgroup B thrombospondins, designated TSP-3, -4, and COMP (cartilage oligomeric matrix protein, also designated TSP-5) are distinct in that they contain unique N-terminal regions, lack the VWFC domain and TSP1 repeats, contain four copies of EGF-like domains, and are assembled as pentamers . EGF, TSP3 repeats and the C-terminal domain are thus the hallmark of a thrombospondin.
Fibrillar collagen, C-terminal (Fib_collagen_C)
Type: Domain

This entry represents the C-terminal non-collagenous domain of animal fibrillar collagens, also named C-propeptide, which is highly conserved from invertebrates to vertebrates (types I-III, V, XI, XXIV and XXVII) . This domain is involved in both intracellular molecular assembly and extracellular formation of collagen fibrils . It is found associated with triple helical repeats

.
KDPG/KHG aldolase (Aldlse_KDPG_KHG)
Type: Family

4-Hydroxy-2-oxoglutarate aldolase (

) (KHG-aldolase) catalyzes the interconversion of 4-hydroxy-2-oxoglutarate into pyruvate and glyoxylate. Phospho-2-dehydro-3-deoxygluconate aldolase (

) (KDPG-aldolase) catalyzes the interconversion of 6-phospho-2-dehydro-3-deoxy-D-gluconate into pyruvate and glyceraldehyde 3-phosphate. E. coli Eda is a KDPG-aldolase that has also been found to have a role in the degradation of 2-keto-4-hydroxyglutarate (KHG) to pyruvate and glyoxylate . In fact, KHG-aldolase and Eda are the same enzyme .

This family consists of KHG/KDPG aldolases, and also includes 2-keto-3-deoxy-6-phosphogalactonate (KDPGal) aldolase. KDPGal-aldolase catalyzes an identical reaction to KDPG, differing in substrate specificity in only the configuration of a single stereocentre .
dTDP-4-dehydrorhamnose 3,5-epimerase-like (RmlC-like)
Type: Family

Deoxythymidine diphosphate (dTDP)-4-keto-6-deoxy-d-hexulose 3, 5-epimerase (RmlC,

) is involved in the biosynthesis of dTDP-l-rhamnose, which is an essential component of the bacterial cell wall, converting dTDP-4-keto-6-deoxy-D-glucose to dTDP-4-keto-L-rhamnose.

The crystal structure of RmlC from Methanobacterium thermoautotrophicum was determined in the presence and absence of a substrate analogue. RmlC is a homodimer comprising a central jelly roll motif, which extends in two directions into longer β-sheets. Binding of dTDP is stabilised by ionic interactions to the phosphate group and by a combination of ionic and hydrophobic interactions with the base. The active site, which is located in the centre of the jelly roll, is formed by residues that are conserved in all known RmlC sequence homologues. The active site is lined with a number of charged residues and a number of residues with hydrogen-bonding potentials, which together comprise a potential network for substrate binding and catalysis. The active site is also lined with aromatic residues which provide favorable environments for the base moiety of dTDP and potentially for the sugar moiety of the substrate .

Also included in this family is the probable dTDP-4-oxo-2,6-dideoxy-D-glucose 3,5-epimerase from
Streptomyces antibioticus
which is required for the biosynthesis of the aglycone antibiotic oleandomycin .
Glutathione peroxidase (Glutathione_peroxidase)
Type: Family

Glutathione peroxidase (GSHPx) (

) is an enzyme that catalyses the reduction of hydroperoxides by glutathione . Its main function is to protect against the damaging effect of endogenously formed hydroperoxides. In higher vertebrates, several forms of GSHPx are known, including a ubiquitous cytosolic form (GSHPx-1), a gastrointestinal cytosolic form (GSHPx-GI), a plasma secreted form (GSHPx-P), and an epididymal secretory form (GSHPx-EP). In mammals there are eight GPx, divided in two clusters, the classical GPx (GPx1, GPx2, GPx3, GPx5 and GPx6) and phospholipid hydroperoxide GPx (GPx4, GPx7 and GPx8). The classical GPx is multimeric (commonly tetrameric) and soluble, while the phospholipid hydroperoxide (PHGPx) is monomeric and often membrane-associated . In addition to these characterised forms, the sequence of a protein of unknown function has been shown to be evolutionary related to those of GSHPx's.

In filarial nematode parasites, the major soluble cuticular protein (gp29) is a secreted GSHPx, which may provide a mechanism of resistance to the immune reaction of the mammalian host by neutralising the products of the oxidative burst of leukocytes . The structure of bovine seleno-glutathione peroxidase has been determined . The protein belongs to the α-β class, with a three layer(aba) sandwich architecture. The catalytic site of GSHPx contains a conserved residue which is either a cysteine or, in many eukaryotic GSHPx, a selenocysteine .
Aliphatic acid kinase, short-chain (Aliphatic_acid_kin_short-chain)
Type: Family

Acetate kinase, which is predominantly found in microorganisms, facilitates the production of acetyl-CoA by phosphorylating acetate in the presence of ATP and a divalent cation . The enzyme is important in the process of glycolysis, enzyme levels being increased in the presence of excess glucose. The growth of a bacterial mutant lacking acetate kinase has been shown to be inhibited by glucose, suggesting that the enzyme is involved in excretion of excess carbohydrate . A related enzyme, butyrate kinase, facilitates the formation of butyryl-CoA by phosphorylating butyrate in the presence of ATP to form butyryl phosphate .
Pyruvate carboxyltransferase (PYR_CT)
Type: Domain

Pyruvate carboxylase (

) (PC), a member of the biotin-dependent enzyme family, is involved in gluconeogenesis by mediating the carboxylation of pyruvate to oxaloacetate. Biotin-dependent carboxylase enzymes perform a two step reaction. Enzyme-bound biotin is first carboxylated by bicarbonate and ATP and the carboxyl group temporarily bound to biotin is subsequently transferred to an acceptor substrate such as pyruvate . PC has three functional domains: a biotin carboxylase (BC) domain, a carboxyltransferase (CT) domain which perform the second part of the reaction and a biotinyl domain . The pyruvate binding to the CT active site induces a conformational change stabilised by the interaction of conserved Asp and Tyr residues in this domain which leads to the formation of the biotin binding pocket and ensures the efficient coupling of BC and CT domain reactions . The mechanism by which the carboxyl group is transferred from the carboxybiotin to the pyruvate is not well understood.

The pyruvate carboxyltransferase domain is also found in other pyruvate binding enzymes and acetyl-CoA dependent enzymes suggesting that this domain can be associated with different enzymatic activities.

For examples, this domain is found in various synthase enzymes, including methylthioalkylmalate synthases involved in the conversion of 4-methylsulfanyl-2-oxobutanoate into 2-(2-methylsulfanyl)ethylmalate .

This domain is found towards the N-terminal region of various aldolase enzymes. This N-terminal TIM barrel domain interacts with the C-terminal domain. The C-terminal DmpG_comm domain (

) is thought to promote heterodimerization with members of

to form a bifunctional aldolase-dehydrogenase .
Small ribosomal subunit protein eS26 (Ribosomal_eS26)
Type: Family

This family represents the small ribosomal subunit protein eS26 (previously known as S26) which is found mainly in eukaryotes and includes mammalian S26 ; Octopus S26 ; Drosophila S26 (DS31) ; plant cytoplasmic S26; and fungal S26 . S26 may be involved in the attachment of eIF3 and poly (U) . Disruption of RPS26, the gene encoding a homologue of ribosomal protein small subunit S26 in yeast (S. cerevisiae), resulted in the formation of micro-colonies, suggesting that it is important for the normal cell growth of S. cerevisiae . This entry also includes uncharacterised archaeal sequences.

Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites . About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits.

Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome .
Ribulose bisphosphate carboxylase small subunit, domain (RuBisCO_ssu_dom)
Type: Domain

RuBisCO (ribulose-1,5-bisphosphate carboxylase/oxygenase) is a bifunctional enzyme that catalyses both the carboxylation and oxygenation of ribulose-1,5-bisphosphate (RuBP), thus fixing carbon dioxide as the first step of the Calvin cycle. RuBisCO is the major protein in the stroma of chloroplasts, and in higher plants exists as a complex of 8 large and 8 small subunits. The small subunits induce conformational changes in the large subunits enhancing its catalytic rate. Studies in Oryza sativa demonstrate that the availability of the small subunit upregulates the transcript levels of the large subunit . While the large subunit is coded for by a single gene, the small subunit is coded for by several different genes, which are distributed in a tissue specific manner. They are transcriptionally regulated by light receptor phytochrome , which results in RuBisCO being more abundant during the day when it is required.

The RuBisCo small subunit consists of a central four-stranded β-sheet, with two helices packed against it .
Transthyretin/hydroxyisourate hydrolase (Transthyretin/HIU_hydrolase)
Type: Family

This family includes transthyretin that is a thyroid hormone-binding protein that transports thyroxine from the bloodstream to the brain. However, most of the sequences listed in this family do not bind thyroid hormones. They are actually enzymes of the purine catabolism that catalyse the conversion of 5-hydroxyisourate (HIU) to OHCU . HIU hydrolysis is the original function of the family and is conserved from bacteria to mammals; transthyretins arose by gene duplications in the vertebrate lineage . HIUases are distinguished in the alignment from the conserved C-terminal YRGS sequence.

Transthyretin (formerly prealbumin) is one of 3 thyroid hormone-binding proteins found in the blood of vertebrates . It is produced in the liver and circulates in the bloodstream, where it binds retinol and thyroxine (T4) . It differs from the other 2 hormone-binding proteins (T4-binding globulin and albumin) in 3 distinct ways: (1) the gene is expressed at a high rate in the brain choroid plexus; (2) it is enriched in cerebrospinal fluid; and (3) no genetically caused absence has been observed, suggesting an essential role in brain function, distinct from that played in the bloodstream . The protein consists of around 130 amino acids, which assemble as a homotetramer that contains an internal channel in which T4 is bound. Within this complex, T4 appears to be transported across the blood-brain barrier, where, in the choroid plexus, the hormone stimulates further synthesis of transthyretin. The protein then diffuses back into the bloodstream, where it binds T4 for transport back to the brain .
Hemocyanin/hexamerin middle domain (Hemocyanin/hexamerin_mid_dom)
Type: Domain

This entry represents the middle domain of hemocyanin and hexamerin proteins, which is involved in copper binding in hemocyanins.

Crustacean and cheliceratan hemocyanins (oxygen-transport proteins) and insect hexamerins (storage proteins) are homologous gene products, although the latter do not bind oxygen .

Haemocyanins are found in the haemolymph of many invertebrates. They are divided into 2 main groups, arthropodan and molluscan. These have structurally similar oxygen-binding centres, which are similar to the oxygen-binding centre of tyrosinases, but their quaternary structures are arranged differently. The arthropodan proteins exist as hexamers comprising 3 heterogeneous subunits (a, b and c) and possess 1 oxygen-binding centre per subunit; and the molluscan proteins exist as cylindrical oligomers of 10 to 20 subunits and possess 7 or 8 oxygen-binding centres per subunit . Although the proteins have similar amino acid compositions, the only real similarity in their primary sequences is in the region corresponding to the second copper-binding domain, which also shows similarity to the copper-binding domain of tyrosinases.
Signal recognition particle, SRP54 subunit, GTPase domain (SRP54_GTPase_dom)
Type: Domain

The signal recognition particle (SRP) is a multimeric protein, which along with its conjugate receptor (SR), is involved in targeting secretory proteins to the rough endoplasmic reticulum (RER) membrane in eukaryotes, or to the plasma membrane in prokaryotes . SRP recognises the signal sequence of the nascent polypeptide on the ribosome. In eukaryotes this retards its elongation until SRP docks the ribosome-polypeptide complex to the RER membrane via the SR receptor . Eukaryotic SRP consists of six polypeptides (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) and a single 300 nucleotide 7S RNA molecule. The RNA component catalyses the interaction of SRP with its SR receptor . In higher eukaryotes, the SRP complex consists of the Alu domain and the S domain linked by the SRP RNA. The Alu domain consists of a heterodimer of SRP9 and SRP14 bound to the 5' and 3' terminal sequences of SRP RNA. This domain is necessary for retarding the elongation of the nascent polypeptide chain, which gives SRP time to dock the ribosome-polypeptide complex to the RER membrane. In archaea, the SRP complex contains 7S RNA like its eukaryotic counterpart, yet only includes two of the six protein subunits found in the eukaryotic complex: SRP19 and SRP54 .

This entry represents the GTPase domain of the 54kDa SRP54 component, a GTP-binding protein that interacts with the signal sequence when it emerges from the ribosome. SRP54 of the signal recognition particle has a three-domain structure: an N-terminal helical bundle domain, a GTPase domain, and the M-domain that binds the 7s RNA and also binds the signal sequence. The extreme C-terminal region is glycine-rich and lower in complexity and poorly conserved between species. The GTPase domain is evolutionary related to P-loop NTPase domains found in a variety of other proteins .

This group of proteins include Escherichia coli and Bacillus subtilis Ffh protein (P48), which seems to be the prokaryotic counterpart of SRP54 ; signal recognition particle receptor alpha subunit (docking protein), an integral membrane GTP-binding protein which ensures, in conjunction with SRP, the correct targeting of nascent secretory proteins to the endoplasmic reticulum membrane ; bacterial FtsY protein, which acts as a receptor for the complex formed by the signal recognition particle and the ribosome-nascent chain ; the PilA protein from Neisseria gonorrhoeae, the homologue of FtsY ; bacterial flagellar biosynthesis protein FlhF and archaeal SRP54.