SII-SWORD/CoKE huggingface dataset:
Phycobilisome, alpha/beta subunit (Phycobilisome_asu/bsu)
Type: Family

Cyanobacteria and red algae harvest light through water-soluble complexes, called phycobilisomes, which are attached to the outer face of the thylakoid membrane . These complexes are capable of transferring the absorbed energy to the photosynthetic reaction centre with greater than 95% efficiency. Phycobilisomes contain various photosynthetic light harvesting proteins known as biliproteins, and linker proteins which help assemble the structure. The two main structural elements of the complex are a core located near the photosynthetic reaction centre, and rods attached to this core. Allophycocyanin is the major component of the core, while the rods contain phycocyanins, phycoerythrins and linker proteins. The rod biliproteins harvest photons, with the excitation energy being passed through the rods into the allophycocyanin in the core. Other core biliproteins subsequently pass this energy to chlorophyll within the thylakoid membrane.

This entry represents the alpha and beta subunits found in biliproteins from cyanobacteria and red algae. Structural studies indicate that the basic structural unit of most biliproteins is a heterodimer composed of these alpha and beta subunits . The full protein is a ring-like trimer assembly of these heterodimers. Each subunit of the heterodimer has eight helices and binds chromophores through thioester bonds formed at particular cysteine residues. These chromophores, also known as bilins, are open-chain tetrapyrroles whose number and type vary with the particular biliprotein eg R-phyocerythrin binds five phycoerythrobilins per heterodimer, while allophycocyanin binds two phycocyanobilins per heterodimer.
Phytochrome A/B/C/D/E (Phytochrome_A-E)
Type: Family

This group represent phytochrome A to E.
Photoactive yellow-protein (PYP)
Type: Family

Members of this family are photoactive yellow protein, a cytosolic, 14kDa light-sensing protein which has a 4-hydroxycinnamyl (p-coumaric acid) chromophore covalently linked to a Cys residue. The enzyme 4-coumarate--CoA ligase as described by

is required for its biosynthesis. The modified Cys is in a PAS domain, frequently found in signal transducing proteins. Members are known in alpha and gammaproteobacteria that include Rhodobacter capsulatus (Rhodopseudomonas capsulata), Halorhodospira halophila (Ectothiorhodospira halophila), Rhodospirillum centenum (Rhodocista centenaria), etc.
Histidinol dehydrogenase (Hstdl_DH)
Type: Family

Histidinol dehydrogenase (HDH) catalyses the terminal step in the biosynthesis of histidine in bacteria, fungi, and plants, the four-electron oxidation of L-histidinol to histidine.

In 4-electron dehydrogenases, a single active site catalyses 2 separate oxidation steps: oxidation of the substrate alcohol to an intermediate aldehyde; and oxidation of the aldehyde to the product acid, in this case His . The reaction proceeds via a tightly- or covalently-bound inter-mediate, and requires the presence of 2 NAD molecules . By contrast with most dehydrogenases, the substrate is bound before the NAD coenzyme . A Cys residue has been implicated in the catalytic mechanism of the second oxidative step .

In bacteria HDH is a single chain polypeptide; in fungi it is the C-terminal domain of a multifunctional enzyme which catalyses three different steps of histidine biosynthesis; and in plants it is expressed as nuclear encoded protein precursor which is exported to the chloroplast .
Glucose-methanol-choline oxidoreductase (GMC_OxRdtase)
Type: Family

Proteins in this entry are members of the glucose-methanol-choline oxidoreductase family of flavoenzymes . These enzymes catalyse diverse reaction and include glucose dehydrogenase (

), alcohol oxidase (

), glucose oxidase (

), choline dehydrogenase (

), and cyclase atC from Aspergillus terreus which oxidizes terremutin to terreic acid, a quinone epoxide inhibitor of a tyrosine kinase .

Structural studies indicate that these proteins are composed of an N-terminal FAD-binding domain, and a C-terminal substrate-binding domain . The FAD-binding domain forms the α-β fold typical of dinucleotide binding proteins, while the substrate-binding domain consists of a β-sheet surrounded by α-helices. The general topology of these proteins is conserved, though inserted structural elements occur in both choline dehydrogenase and alcohol dehydrogenase .
Alpha-hydroxy acid dehydrogenase, FMN-dependent (Alpha-hydoxy_acid_DH_FMN)
Type: Family

This group represents alpha-hydroxy acid FMN-dependent dehydrogenases, including human glycolate oxidase (GO), L-lactate oxidase (LOX) and bacterial L-lactate dehydrogenase. GO catalyses the FMN-dependent oxidation of glycolate to glyoxylate and glyoxylate to oxalate. The latter is a key metabolite in kidney stone formation. 4-carboxy-5-dodecylsulphanyl-1,2,3-triazole (CDST) is an inhibitor of this enzyme. In contrast to most alpha-hydroxy acid oxidases, including spinach glycolate oxidase, a loop region, known as loop 4, is completely visible when the GO active site contains a small ligand. Since this is an unique structural feature, it has the potential to be a target for drugs to decrease glycolate and glyoxylate levels in primary hyperoxaluria type 1 patients who have the inability to convert peroxisomal glyoxylate to glycine .

This entry also includes the fungal protein FUB9 by virtue of sequence similarity to the FMN-dependent alpha-hydroxy acid dehydrogenase family. FUB9 is an oxidase that is part of the gene cluster that mediates the biosynthesis of fusaric acid .
Glutamate-5-semialdehyde dehydrogenase (Glu-5-SA_DH)
Type: Family

Gamma-glutamyl phosphate reductase (GPR), also known as glutamate-5-semialdehyde dehydrogenase, catalyses the second step of proline biosynthesis, the NADPH-dependent reversible reduction of gamma-glutamyl phosphate to glutamate-5-semialdehyde as shown below.

L-glutamyl 5-phosphate + NADPH + H(+) = L-glutamate 5-semialdehyde + phosphate + NADP(+)

In bacteria and yeast, GPR is a monofunctional protein, while in plants and mammals, it is part of a bifunctional enzyme that consists of two domains, an N-terminal glutamate 5-kinase domain (

) and a C-terminal GPR domain .

This entry represents the monofunctional gamma-glutamyl phosphate reductase found in bacteria and yeasts. Structural studies indicate that this protein is composed of three domains and belongs to the aldehyde dehydrogenase structural family . The first two domains, the catalytic and cofactor binding domains respectively, both form a similar three layered α-β-α fold, and are thought to close around the NADPH and gamma-glutamyl-phosphate ligands upon binding in order to orient a conserved cysteine residue for catalysis. The third domain is the oligomerisation domain which forms an antiparallel β sheet. The biological oligomerisation state of the protein is not currently known, but like most members of the aldehyde dehydrogenase family it is expected to be either a dimer or a tetramer.
Dihydroorotate dehydrogenase, class 1/ 2 (Dihydroorotate_DH_1_2)
Type: Family

Dihydroorotate dehydrogenase (DHOD), also known as dihydroorotate oxidase, catalyses the fourth step in de novo pyrimidine biosynthesis, the stereospecific oxidation of (S)-dihydroorotate to orotate, which is the only redox reaction in this pathway. DHODs can be divided into two mains classes: class 1 cytosolic enzymes found primarily in Gram-positive bacteria, and class 2 membrane-associated enzymes found primarily in eukaryotic mitochondria and Gram-negative bacteria .

The class 1 DHODs can be further divided into subclasses 1A and 1B, which differ in their structural organisation and use of electron acceptors. The 1A enzyme is a homodimer of two PyrD subunits where each subunit forms a TIM barrel fold with a bound FMN cofactor located near the top of the barrel . Fumarate is the natural electron acceptor for this enzyme. The 1B enzyme, in contrast is a heterotetramer composed of a central, FMN-containing, PyrD homodimer resembling the 1A homodimer, and two additional PyrK subunits which contain FAD and a 2Fe-2S cluster . These additional groups allow the enzyme to use NAD(+) as its natural electron acceptor.

The class 2 membrane-associated enzymes are monomers which have the FMN-containing TIM barrel domain found in the class 1 PyrD subunit, and an additional N-terminal α helical domain . These enzymes use respiratory quinones as the physiological electron acceptor.
NADP transhydrogenase, beta subunit (NADH_DH_b)
Type: Family

NAD(P) transhydrogenase catalyses the transfer of reducing equivalents between NAD(H) and NADP(H), coupled to the translocation of protons across a membrane . It is an integral membrane protein found in the inner membrane of animal mitochondria and in bacterial cytoplasmic membrane. Under most physiological conditions this enzyme synthesises NADPH, driven by consumption of the proton electrochemical gradient. The resulting NADPH is subsequently used for biosynthetic reactions or the reduction of glutathione.

The global structure of this enzyme is similar in all organisms, consisting of three distinct domains, though the polypeptide composition can vary. Domain I binds NAD(+)/NADH, domain II is a hydrophobic membrane-spanning domain, and domain III binds NADP(+)/NADPH. Domain I is composed of two subdomains, both of which form a Rossman fold, while domain III consists of a single Rossman fold where the NADP(+) is flipped relative to the normal orientation of bound nucleotides within the Rossman fold . Several residues within these domains are thought to make functionally important interdomain contacts for hydride transfer between these domains . Proton translocation occurs through domain II and is thought to induce conformational changes which are transmitted across domain III to the site of hydride transfer between domains I and III.

NAD(P) transhydrogenase from Escherichia coli contains an alpha subunit with the NAD(H)-binding domain I and a beta subunit with the NADP(H)-binding domain III. The membrane domain (domain II) harbors the proton channel and is made up of the hydrophobic parts of the alpha and beta subunits . This entry represents the beta subunit found in bacterial two-subunit NADP(H) transhydrogenases.
Nitrate reductase NADH dependent (Nitr_rd_NADH)
Type: Family

This entry represents the NADH dependent nitrate reductase (NR) from plants and fungi, including NIA1 and NIA2 from Arabidopsis. They contain an N-terminal oxidoreductase molybdopterin binding domain and a C-terminal FAD-binding domain. In Arabidopsis, NR-mediated nitric oxide (NO) synthesis is required for ABA-induced stomatal closure . AtNIA1 is involved in the first step of nitrate assimilation .
Hydroxylamine oxidase (HAO)
Type: Family

Autotrophic ammonia oxidising bacteria, such as Nitrosomonas europaea, acquire energy from the oxidation of ammonia to nitrite, and fix carbon dioxide to obtain biomass . The respiratory chain in these organisms consists of ammonia monooxygenase (AMO), which oxidises ammonia to hyroxylamine, hydroxylamine oxidoreductase (HAO), which oxidises hydroxylamine to nitrite, and several c-type cytochromes involved in the electron transport. HAO is a key enzyme within this chain as the electrons generated by its reaction are partitioned to AMO, which needs them to generate hydroxylamine, and to the electron transport chain for energy generation.

The HAO enzyme from N. europaea (

) is a homotrimer which binds a remarkable total of 24 haem groups, aligned to form a ring that has inlet and outlet sites . Each monomer binds eight haems; seven c-type haems, and a novel haem designated P460 which has a tyrosine residue attached to the tetrapyrrole ring. The c-type haem irons are all coordinated by two histidine residues, while that of P460 is coordinated by one, with the extra site on the iron being available for substrate binding. The oxidation of hydroxylamine is thought to occur in two, two-electron steps, with the tyrosine attached to P460 allowing it to transiently accept two electrons. Trimerisation is necessary for catalysis, allowing a tyrosine residue from one subunit to cross-link to P460 from a neighbouring subunit, and providing a hydrophobic environment for the haem groups where stable electron transfer can occur.
Tryptophan 2-monooxygenase (Trp_2-mOase)
Type: Family

The FAD-containing tryptophan 2-monooxygenase enzyme catalyses the oxidation of tryptophan to indoleacetamide, carbon dioxide, and water .The enzyme belongs to a group of flavoenzymes that catalyse the oxidative decarboxylation of amino acids.
Nitric-oxide synthase, eukaryote (NOS_euk)
Type: Family

Nitric oxide synthase (

) (NOS) enzymes produce nitric oxide (NO) by catalyzing a five-electron oxidation of a guanidino nitrogen of L-arginine (L-Arg). Oxidation of L-Arg to L-citrulline occurs via two successive monooxygenation reactions producing N(omega)-hydroxy-L-arginine as an intermediate. 2 mol of O(2) and 1.5 mol of NADPH are consumed per mole of NO formed .

Arginine-derived NO synthesis has been identified in mammals, fish, birds, invertebrates, plants, and bacteria . Best studied are mammals, where three distinct genes encode NOS isozymes: neuronal (nNOS or NOS-1), cytokine-inducible (iNOS or NOS-2) and endothelial (eNOS or NOS-3) . iNOS and nNOS are soluble and found predominantly in the cytosol, while eNOS is membrane associated. The enzymes exist as homodimers, each monomer consisting of two major domains: an N-terminal oxygenase domain, which belongs to the class of haem-thiolate proteins, and a C-terminal reductase domain, which is homologous to NADPH:P450 reductase (

). The interdomain linker between the oxygenase and reductase domains contains a calmodulin (CaM)-binding sequence. NOSs are the only enzymes known to simultaneously require five bound cofactors animal NOS isozymes are catalytically self-sufficient. The electron flow in the NO synthase reaction is: NADPH -->FAD -->FMN -->haem -->O(2).

eNOS localisation to endothelial membranes is mediated by cotranslational N-terminal myristoylation and post-translational palmitoylation . The subcellular localisation of nNOS in skeletal muscle is mediated by anchoring of nNOS to dystrophin. nNOS contains an additional N-terminal domain, the PDZ domain .

This entry represents all forms of NOS from eukaryotes. For further information see .
Phosphate acetyl/butyryltransferase (P_Ac_Bu_trans)
Type: Family

This group represents phosphate acetyltransferase and phosphate butyryltransferase.
Aromatic prenyltransferase DMATS-type, fungi (ABBA_DMATS-like)
Type: Family

This family of fungal proteins includes tryptophan dimethylallyltransferase, cyclic dipeptide N-prenyltransferase (CdpNPT), fumigaclavine C synthase (FgaPT1), dimethylallyltryptophan synthase (DMATS), indole diterpene prenyltransferase anaPT and related proteins. CdpNPT accepts a variety of tryptophan-containing cyclic dipeptides, including L-tryptophan itself, and prenylates these substrates inverse at the N-1 position of the indole group . FgaPT1 catalyses the prenylation of fumigaclavine A . Dimethylallyltryptophan synthases (DMATS) catalyzes the prenylation of L-tryptophan at C-4 of the indole ring during the biosynthesis of ergot alkaloids . AnaPT is required for the biosynthesis of the prenylated pyrroloindoline diketopiperazine acetylaszonalenin .
Protein-tyrosine phosphatase, non-receptor type-3, -4 (Tyr_Pase_non-rcpt_typ-3/4)
Type: Family

Protein tyrosine (pTyr) phosphorylation is a common post-translational modification which can create novel recognition motifs for protein interactions and cellular localisation, affect protein stability, and regulate enzyme activity. Consequently, maintaining an appropriate level of protein tyrosine phosphorylation is essential for many cellular functions. Tyrosine-specific protein phosphatases (PTPase;

) catalyse the removal of a phosphate group attached to a tyrosine residue, using a cysteinyl-phosphate enzyme intermediate. These enzymes are key regulatory components in signal transduction pathways (such as the MAP kinase pathway) and cell cycle control, and are important in the control of cell growth, proliferation, differentiation and transformation . The PTP superfamily can be divided into four subfamilies :

(1) pTyr-specific phosphatases

(2) dual specificity phosphatases (dTyr and dSer/dThr)

(3) Cdc25 phosphatases (dTyr and/or dThr)

(4) LMW (low molecular weight) phosphatases

Based on their cellular localisation, PTPases are also classified as:

Receptor-like, which are transmembrane receptors that contain PTPase domains

Non-receptor (intracellular) PTPases

All PTPases carry the highly conserved active site motif C(X)5R (PTP signature motif), employ a common catalytic mechanism, and share a similar core structure made of a central parallel β-sheet with flanking α-helices containing a β-loop-α-loop that encompasses the PTP signature motif . Functional diversity between PTPases is endowed by regulatory domains and subunits.

This entry represents a protein-tyrosine phosphatase, non-receptor types 3 and 4.
Protein-tyrosine phosphatase, non-receptor type-6, -11 (Tyr_Pase_non-rcpt_typ-6/11)
Type: Family

Protein tyrosine (pTyr) phosphorylation is a common post-translational modification which can create novel recognition motifs for protein interactions and cellular localisation, affect protein stability, and regulate enzyme activity. Consequently, maintaining an appropriate level of protein tyrosine phosphorylation is essential for many cellular functions. Tyrosine-specific protein phosphatases (PTPase;

) catalyse the removal of a phosphate group attached to a tyrosine residue, using a cysteinyl-phosphate enzyme intermediate. These enzymes are key regulatory components in signal transduction pathways (such as the MAP kinase pathway) and cell cycle control, and are important in the control of cell growth, proliferation, differentiation and transformation . The PTP superfamily can be divided into four subfamilies :

(1) pTyr-specific phosphatases

(2) dual specificity phosphatases (dTyr and dSer/dThr)

(3) Cdc25 phosphatases (dTyr and/or dThr)

(4) LMW (low molecular weight) phosphatases

Based on their cellular localisation, PTPases are also classified as:

Receptor-like, which are transmembrane receptors that contain PTPase domains

Non-receptor (intracellular) PTPases

All PTPases carry the highly conserved active site motif C(X)5R (PTP signature motif), employ a common catalytic mechanism, and share a similar core structure made of a central parallel β-sheet with flanking α-helices containing a β-loop-α-loop that encompasses the PTP signature motif . Functional diversity between PTPases is endowed by regulatory domains and subunits.

This entry represents non-receptor PTPase types 6 and 11, also known as SHP-1 and SHP-2 respectively. SHP-1 is expressed predominantly in haematopoietic and epithelial cells, playing an important role in haematopoiesis and functioning as a terminator of signalling transduction, predominantly by dephosphorylation of appropriate substrate proteins . SHP-2 is expressed in most cell types and is involved in signal transduction stimulated by epidermal growth factor, platelet-derived growth factor, and insulin, acting as a positive regulator of cell proliferation . The structure of human SHP-2 (

) shows that its catalytic activity is regulated by its two SH2 domains . In the absence of protein, the N-terminal SH2 domain binds the phosphatase domain, inhibiting its activity, while the binding of a tyrosine-phosphorylated substrate to this domain causes a conformational change which activates the enzyme. The C-terminal SH2 domain does not play a direct role in activation, but contributes to substrate specificity and binding energy.
Tyrosine-protein phosphatase non-receptor type 13 (PTPN13)
Type: Family

This entry represents non-receptor PTPase type 13 (also known as PTPL1, FAP-1 and PTP-BL). Studies indicate that this PTPase is involved in multiple regulatory functions including: negative regulation of FAS-induced apoptosis and NGFR-mediated pro-apoptotic signalling, regulation of the phophorylation status of ephrinB receptors in neurons, regulation of cytokinesis in epithelial cells, and the regulation of negative proliferation signals in breast cancer cells . This protein has been shown to interact with a wide variety of partners, an ability conferred by the presence of five distinct PDZ domains, and is thus suggested to function as an integrator between different signalling pathways. Multiple isoforms of this protein are formed by alternative splicing, which can dramatically affect its protein binding characteristics .
Cold shock, CspA (Cold_shock_CspA)
Type: Family

Temperature downshift produces a number of changes in cellular physiology including decreased membrane fluidity, reduced mRNA transcription and translation due to the stabilisation of secondary structures, inefficient folding of some proteins, and reduced enzyme activity . In response to this, bacteria produce a set of proteins, known as the cold-shock proteins (CSPs), to counteract these harmful effects.

This entry represents a family of small CSPs consisting of CspA, one of the first cold-shock proteins identified, and its homologues. Note that while some members of this family are induced during cold-shock, some are either constitutively expressed or induced by other stresses such as nutrient starvation. While information about the physiological functions of the CSPs is limited, their structural properties have been well studied . These proteins have a five-stranded β-barrel structural fold and are part of the wider oligonucleotide/oligosaccharide-binding (OB family). They preferentially bind pyrimidine-rich regions of single-stranded RNA and DNA with high affinity, but not double-stranded RNA or DNA. Thus it is postulated that CSPs may act as RNA chaperones by destabilising RNA secondary structures. Experimental evidence suggests that they bind mRNA and regulate ribosomal translation, rate of mRNA dergadation and termination of transcription; functions that are important during normal growth as well as cold shock.
Uncharacterised conserved protein, CBS/CP12 (UCP_CBS_CP12)
Type: Family

This protein family represents a group of predicted uncharacterised proteins from cyanobacteria with a CBS pair (also known as Bateman domain,

) and a CP12 domain (

).
Inner membrane protein YejM-like (YejM-like)
Type: Family

This entry represents the inner membrane protein YejMfrom Escherichia coli. YejM (also known as LapC, PbgA) belongs to a regulatory system that controls the activity of LpxC, the enzyme that catalyses the first committed step in the LPS synthesis .
Lipoteichoic acid synthase-like (LtaS-like)
Type: Family

This entry includes lipoteichoic acid synthase LtaS from Bacillus subtilis and some uncharacterised proteins, such as HI_1246 from Haemophilus influenzae.