SII-SWORD/CoKE huggingface dataset:
GDP-mannose 4,6-dehydratase (GDP_Man_deHydtase)
Type: Family

This family represent GDP-mannose 4,6-dehydratase, also known as GDP-D-mannose dehydratase. This enzyme converts GDP-mannose to GDP-4-dehydro-6-deoxy-D-mannose, the first of three steps for the conversion of GDP-mannose to GDP-fucose in animals, plants, and bacteria. In bacteria, GDP-L-fucose acts as a precursor of surface antigens such as the extracellular polysaccharide colanic acid of Escherichia coli. Excluded from this family are members of the clade that are poorly related because of highly dervied (phylogenetically long-branch) sequences, e.g. Aneurinibacillus thermoaerophilus Gmd, described as a bifunctional GDP-mannose 4,6-dehydratase/GDP-6-deoxy-D-lyxo-4-hexulose reductase .
Protohaem IX farnesyltransferase (Protohaem_IX_farnesylTrfase)
Type: Family

This entry represents protoheme IX farnesyltransferase, also known as haem O synthase, an enzyme that creates an intermediate in the biosynthesis of haem A . This enzyme converts heme B (protoheme IX) to heme O by substitution of the vinyl group on carbon 2 of heme B porphyrin ring with a hydroxyethyl farnesyl side group. Prior to the description of its enzymatic function, this protein was often called a cytochrome o ubiquinol oxidase assembly factor.
4-hydroxybenzoate polyprenyltransferase-like (HB_polyprenyltransferase-like)
Type: Family

Members of this family show a broad specificity for prenyl diphosphates, accepting substrates of different chain lengths. Genes coding for these enzymes have been identified in many organisms, and are mostly responsible for ubiquinone (UQ) biosynthesis . 4-hydroxybenzoate solanesyltransferase from cyanobacteria displays a broad specificity with regard to the prenyl donor substrate and uses not only solanesyl diphosphate, but also a number of shorter-chain prenyl diphosphates . One exception is LePGT1 (Lithospermum erythrorhizon 4-hydroxybenzoic acid geranyltransferase), which only accepts GPP (geranyl diphosphate) and is involved in the biosynthesis of a red naphthoquinone, shikonin, a plant secondary metabolite . LePGT1 was reported to be the key regulatory enzyme of shikonin biosynthesis and is not relevant to the formation of UQ .
Polyprenyltransferase UbiA-like (Polyprenyltransferase_UbiA-li)
Type: Family

A fairly deep split separates this polyprenyltransferase subfamily from the set of mitochondrial and proteobacterial 4-hydroxybenzoate polyprenyltransferases, described in

. Protoheme IX farnesyltransferase (heme O synthase) (

) is more distantly related. Because no species appears to have both this protein and a member of

, it is likely that this family of sequences represent 4-hydroxybenzoate polyprenyltransferase, a critical enzyme of ubiquinone biosynthesis, in the Archaea, Gram-positive bacteria, Aquifex aeolicus, and the Chlamydias. Overlap is also strong with species that synthesize menaquinone by the (alternate) futalosine pathway, suggesting MqnP activity .
Bacteriochlorophyll/chlorophyll synthetase (Chl_synth)
Type: Family

These are a subfamily of a large family of polyprenyltransferases that also includes 4-hydroxybenzoate octaprenyltransferase and protoheme IX farnesyltransferase (heme O synthase). Members of this family are found exclusively in photosynthetic organisms, including a single copy in Arabidopsis thaliana(Mouse-ear cress).
Variant surface antigen Rifin (VSA_Rifin)
Type: Family

Malaria is still a major cause of mortality in many areas of the world. Plasmodium falciparum causes the most severe human form of the disease and is responsible for most fatalities. Severe cases of malaria can occur when the parasite invades and then proliferates within red blood cell erythrocytes. The parasite produces many variant antigenic proteins, encoded by multigene families, which are present on the surface of the infected erythrocyte and play important roles in virulence. A crucial survival mechanism for the malaria parasite is its ability to evade the immune response by switching these variant surface antigens. The high virulence of P. falciparum relative to other malarial parasites is in large part due to the fact that in this organism many of these surface antigens mediate the binding of infected erythrocytes to the vascular endothelium (cytoadherence) and non-infected erythrocytes (rosetting). This can lead to the accumulation of infected cells in the vasculature of a variety of organs, blocking the blood flow and reducing the oxygen supply. Clinical symptoms of severe infection can include fever, progressive anaemia, multi-organ dysfunction and coma. For more information see .

This entry represents the rifin family of variant surface antigens, encoded by the
rif
(short for "repetetive interspersed family") genes. This is the largest variant surface antigen family in Plasmodium falciparum, with roughly 150 genes present in the genome of this parasite . Rifins have a fundamental role in the development of severe malaria . They are strongly immunogenic and high levels of anti-rifin antibodies are correlated with rapid parasite clearance and asymptomatic infections .

All RIFIN sequences contain the PEXEL motif (a pentameric sequence RxLxE/Q/D, known as the Plasmodium export element) required for correct export and surface expression or host-targeting (HT) signal which plays a central role in the export of proteins into the host cell . It has been reported that PEXEL is preferably located 15-20 amino acids downstream of an N-terminal hydrophobic signal sequence . The RIFIN protein family can be divided into A and B types based on the presence or absence of a 25 amino acid motif located approximately 66 amino acids downstream of the PEXEL motif , with A- and B-types serving different roles in distinct parasite stages . The specific type B RIFIN variant (PF13_0006) is expressed on the surface of free merozoites, internally in developing gametocytes and on the surface of gametes at the point of emerging from activated, mature stage V gametocytes. While type A RIFIN are expressed on the infected erythrocyte surface, potentially contributing to the antigenic variation capacity of the parasite .
Variant surface antigen Stevor (VSA_Stevor)
Type: Family

Malaria is still a major cause of mortality in many areas of the world. Plasmodium falciparum causes the most severe human form of the disease and is responsible for most fatalities. Severe cases of malaria can occur when the parasite invades and then proliferates within red blood cell erythrocytes. The parasite produces many variant antigenic proteins, encoded by multigene families, which are present on the surface of the infected erythrocyte and play important roles in virulence. A crucial survival mechanism for the malaria parasite is its ability to evade the immune response by switching these variant surface antigens. The high virulence of P. falciparum relative to other malarial parasites is in large part due to the fact that in this organism many of these surface antigens mediate the binding of infected erythrocytes to the vascular endothelium (cytoadherence) and non-infected erythrocytes (rosetting). This can lead to the accumulation of infected cells in the vasculature of a variety of organs, blocking the blood flow and reducing the oxygen supply. Clinical symptoms of severe infection can include fever, progressive anaemia, multi-organ dysfunction and coma. For more information see .

This entry represents the stevor (short for "subtelomeric variable open reading frame") family of predicted variant surface antigens. This is the third largest variant surface antigen family in Plasmodium falciparum, with 33 genes identified in the genome of this parasite . The function of these proteins is not known, but they are expressed during several stages of the parasite life-cycle and may play a variety of roles in parasite survival and infection .
Mannose-1-phosphate guanylyltransferase/mannose-6-phosphate isomerase (Man1P_GuaTrfase/Man6P_Isoase)
Type: Family

This enzyme is known to be bifunctional, as both mannose-6-phosphate isomerase (

) (PMI) and mannose-1-phosphate guanylyltransferase (

) in Pseudomonas aeruginosa , Xanthomonas campestris , and Acetobacter xylinus. The literature on the enzyme from Escherichia coli attributes mannose-6-phosphate isomerase activity to an adjacent gene, but the present sequence has not been shown to lack the activity. The PMI domain lies at the C-terminal.
Copper-resistance protein CopA (Cu-R_CopA)
Type: Family

These sequences represent the CopA copper resistance protein family. CopA is related to laccase (benzenediol:oxygen oxidoreductase) and L-ascorbate oxidase, both copper-containing enzymes. Most members have a typical TAT (twin-arginine translocation) signal sequence with an Arg-Arg pair. Twin-arginine translocation is observed for a large number of periplasmic proteins that cross the inner membrane with metal-containing cofactors already bound. The combination of copper-binding sites and TAT translocation motif suggests a mechanism of resistance by packaging and export.
Catabolite control protein A (CcpA)
Type: Family

Catabolite control protein A is a LacI family global transcriptional regulator found in Gram-positive bacteria. CcpA is involved in repressing carbohydrate utilization genes (e.g. alpha-amylase [amyE], acetyl-coenzyme A synthase [acsA]) and in activating genes involved in transporting excess carbon from the cell (e.g. acetate kinase [ackA], alpha-acetolactate synthase [alsS]). Additionally, disruption of CcpA in Bacillus megaterium, Staphylococcus xylosus, Lactobacillus casei and Lactobacillus pentosus also decreases growth rate, which suggests CcpA is involved in the regulation of other metabolic pathways . Its structure has been solved .
HAD-superfamily hydrolase, subfamily IIB (HAD-SF_hydro_IIB)
Type: Family

This subfamily falls within the Haloacid Dehalogenase (HAD) superfamily of aspartate-nucleophile hydrolases. The Class II subfamilies are characterised by a domain that is located between the second and third conserved catalytic motifs of the superfamily domain. The IIB subfamily is distinguished from the IIA subfamily (

) by homology and the predicted secondary structure of this domain by PSI-PRED. The IIB subfamilys Class II domain has the following predicted structure: Helix-Sheet-Sheet-(Helix or Sheet)-Helix-Sheet-(variable)-Helix-Sheet-Sheet. The IIB subfamily consists of trehalose-6-phosphatase, plant and cyanobacterial sucrose-phosphatase and a closely related group of bacterial and archaeal sequences, eukaryotic phosphomannomutase, a large subfamily of Cof-like hydrolases, containing many closely related bacterial sequences, a hypothetical equivalog containing the Escherichia coli YedP protein, as well as two other small clusters whose relationship to the other groups is unclear.
Sucrose phosphatase-like domain (SPP-like_dom)
Type: Domain

This entry represents a conserved region of the sucrose phosphate phosphohydrolase (SPP) from plants . SPP is a member of the Class IIB subfamily of the haloacid dehalogenase (HAD) superfamily of aspartate-nucleophile hydrolases. SPP catalyses the final step in the biosynthesis of sucrose, a critically important molecule for plants. Sucrose phosphate synthase (SPS), the prior step in the biosynthesis of sucrose contains a domain which exhibits considerable similarity to SPP albeit without conservation of the catalytic residues. The catalytic machinery of the synthase resides in another domain. It seems likely that the phosphatase-like domain is involved in substrate binding, possibly binding both substrates in a "product-like" orientation prior to ligation by the synthase catalytic domain. This domain is also found in bacterial proteins.
HAD-superfamily hydrolase, superfamily IIB, MPGP (HAD-SF-IIB-MPGP)
Type: Family

This group of proteins is a member of the IIB subfamily of the haloacid dehalogenase (HAD) superfamily of aspartate-nucleophile hydrolases. It consists of mannosyl-3-phosphoglycerate phosphatase from Pyrococcus horikoshii and related proteins, including GpgP from Methanococcoides burtonii and Persephonella marina, which can catalyse the dephosphorylation of both glucosyl-3-phosphoglycerate and mannosyl-3-phosphoglycerate .
Phosphoglycolate phosphatase (PGPase)
Type: Family

This group of archaeal sequences are phosphoglycolate phosphatases, which catalyse the dephosphorylation of 2-phosphoglycolate .
HAD hydrolase, subfamily IA, Pyridoxal phosphate phosphatase-like (HAD_hydro_PyrdxlP_Pase-like)
Type: Family

The Haloacid Dehalogenase (HAD) superfamily is defined by the presence of three short catalytic motifs . The subfamilies are defined based on the location and the observed or predicted fold of a so-called capping domain , or the absence of such a domain. Subfamily I consists of sequences in which the capping domain is found in between the first and second catalytic motifs. Subfamily II consists of sequences in which the capping domain is found between the second and third motifs. Subfamily III sequences have no capping domain in either of these positions.

The Subfamily IA and IB capping domains are predicted by PSI-PRED to consist of an α helical bundle. Subfamily IA and IB are separated based on an apparent phylogenetic bifurcation. This group of sequences belong to the IB subfamily of the haloacid dehalogenase (HAD) superfamily of aspartate-nucleophile hydrolases.
HAD-superfamily hydrolase, subfamily IB, SerB1-like (HAD_hydro_SerB1)
Type: Family

This group of proteins belong to the IB subfamily of the haloacid dehalogenase (HAD) superfamily of aspartate-nucleophile hydrolases. The sequences are predominantly bacterial. The IB subfamily includes the enzyme phosphoserine phosphatase SerB1 from Mycobacterium tuberculosis . This family includes Histidinol-phosphatase from Pseudomonas aeruginosa, which catalyses the dephosphorylation of histidinol-phosphate to histidinol, the direct precursor of histidine .
HAD-superfamily hydrolase, subfamily IB, PSPase-like, archaeal (HAD-SF_hydro_IB_PSP-like_arc)
Type: Family

This group of sequences belong to the IB subfamily of the haloacid dehalogenase (HAD) superfamily of aspartate-nucleophile hydrolases. The sequences are all from archaeal species. The phylogenetically closest group of sequences to these are phosphoserine phosphatases. As there are no known archaeal phosphoserine phosphatases, it seems likely that this group of sequences represent the archaeal branch of PSPase.
CPW-WPC domain (CPW_WPC_dom)
Type: Domain

This entry represents a domain of about 61 residues in length with six well-conserved cysteine residues and six well-conserved aromatic sites specific to proteins from Apicomplexa. The domain can be found in tandem repeats. It is named for motifs of CPxxW and (less well conserved) WPC. Its function is unknown.
Early transcribed membrane protein, plasmodium (Early_transc_mb_plasmodium)
Type: Family

This entry represents a family of early transcribed membrane proteins from the malaria parasite Plasmodium falciparum and related species. Members of this entry have been shown to be expressed specifically in the ring stage as well as the rodent parasite Plasmodium yoelii . A homologue from Plasmodium chabaudi was localised to the parasitophorous vacuole membrane . Members have an initial hydrophobic, Phe/Tyr-rich stretch long enough to span the membrane, a highly charged region rich in Lys, a second putative transmembrane region, and a second highly charged, low complexity sequence region. Some members have up to 100 residues of additional C-terminal sequence. These genes have been shown to be found in the sub-telomeric regions of both Plasmodium falciparum and P. yoelii chromosomes.
Dihydropteroate synthase domain (DHP_synth_dom)
Type: Domain

This domain is present in sequences representing dihydropteroate synthase, the enzyme that catalyses the second to last step in folic acid biosynthesis.

Dihydropteroate synthase (

) (DHPS), a functional homodimer, catalyses the condensation of 6-hydroxymethyl-7,8-dihydropteridine pyrophosphate to para-aminobenzoic acid to form 7,8-dihydropteroate. This is the second step in the three-step pathway leading from 6-hydroxymethyl-7,8-dihydropterin to 7,8-dihydrofolate. DHPS is the target of sulfonamides, which are substrate analogues that compete with para-aminobenzoic acid. Bacterial DHPS (gene sul or folP) is a protein of about 275 to 315 amino acid residues that is either chromosomally encoded or found on various antibiotic resistance plasmids. In the lower eukaryote Pneumocystis carinii, DHPS is the C-terminal domain of a multifunctional folate synthesis enzyme (gene fas) . Prokaryotes (and some lower eukaryotes) must synthesize folate de novo, while higher eukaryotes are able to utilize dietary folate and therefore lack DHPS.
P-type ATPase, B chain, subfamily IA (P-type_ATPase_bsu_IA)
Type: Family

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.

P-ATPases (also known as E1-E2 ATPases) (

) are found in bacteria and in a number of eukaryotic plasma membranes and organelles . P-ATPases function to transport a variety of different compounds, including ions and phospholipids, across a membrane using ATP hydrolysis for energy. There are many different classes of P-ATPases, which transport specific types of ion: H
+
, Na
+
, K
+
, Mg
2+
, Ca
2+
, Ag
+
and Ag
2+
, Zn
2+
, Co
2+
, Pb
2+
, Ni
2+
, Cd
2+
, Cu
+
and Cu
2+
. P-ATPases can be composed of one or two polypeptides, and can usually assume two main conformations called E1 and E2.

These sequences describe the P-type ATPase subunit of the complex responsible for translocating potassium ions across biological membranes in microbes. In Escherichia coli and other species, this complex consists of the proteins KdpA, KdpB, KdpC and KdpF. KdpB is the ATPase subunit, while KdpA is the potassium-ion translocating subunit . The function of KdpC is unclear, although it has been suggested to couple the ATPase subunit to the ion-translocating subunit , while KdpF serves to stabilise the complex . The potassium P-type ATPases have been characterised as Type IA based on a phylogenetic analysis which places this clade closest to the heavy-metal translocating ATPases (Type IB) . Others place this clade closer to the Na+/K+ antiporter type (Type IIC) based on physical characteristics .
Sepiapterin reductase (Sepiapterin_red)
Type: Family

This entry represents human Sepiapterin reductase (SPR) and similar sequences mainly found in animals. The enzyme catalyses the last step in the biosynthesis of tetrahydrobiopterin. Sulfamethoxazole and other sulfa drugs interfere with tetrahydrobiopterin biosynthesis through SPR inhibition , which has been shown to cause an effective reduction of pain hypersensitivity .
Glutamate mutase sigma subunit (GlmS)
Type: Family

This entry represents the sigma subunit (GlmS) of glutamate mutase, a cobalamin-dependent enzyme that catalyses the first step in a pathway of glutamate fermentation . It catalyses the carbon skeleton rearrangement of L-glutamate to L-threo-3-methylaspartate ((2S,3S)-3-methylaspartate) . The rearrangement reaction is initiated by the extraction of a hydrogen from the protein-bound substrate by a 5'-desoxyadenosyl radical, which is generated by the homolytic cleavage of the organometallic bond of the cofactor B12. The enzyme consists of an heterotetramer of 2 epsilon subunits (GlmE) and 2 sigma subunits (GlmS) .
Methylaspartate ammonia-lyase (Me_Asp_am_lyase)
Type: Family

Methylaspartate ammonia lyase (3-methylaspartase, MAL) is a homodimeric enzyme, catalyzing the magnesium-dependent reversible alpha,beta-elimination of ammonia from L-threo-(2S,3S)-3-methylaspartic acid to mesaconic acid. This reaction is part of the main catabolic pathway for glutamate. MAL belongs to the enolase superfamily of enzymes, characterised by the presence of an enolate anion intermediate which is generated by abstraction of the alpha-proton of the carboxylate substrate by an active site residue and is stabilised by coordination to the essential Mg2+ ion .
Glutamate mutase epsilon subunit (Glu_mut_E)
Type: Family

Glutamate mutase (methylaspartate mutase) catalyses the reversible interconversion of L-glutamate and L-threo-3-methylaspartate, the first step in the pathway of glutamate fermentation . Catalysis is initiated using the cobalamin cofactor. The E subunit is the catalytic subunit (MutE) . The first step in the catalysis is a homolytic cleavage of the Co-C bond of the coenzyme B12 cofactor to generate a 5'-deoxyadenosyl radical. This radical then initiates the rearrangement reaction .

This entry includes proteins similar to Clostridium cochlearium glutamate mutase (Glm) and Streptomyces tendae Tu901 NikV. Glm catalyzes a carbon-skeleton rearrangement of L-glutamate to L-threo-3-methylaspartate. C. cochlearium Glm is a sigma2epsilon2 heterotetramer. Glm plays a role in glutamate fermentation in Clostridium sp. and in members of the family Enterobacteriaceae, and in the synthesis of the lipopeptide antibiotic friulimicin in Actinoplanes friuliensis . S. tendae Tu901 glutamate mutase-like proteins NikU and NIkV participate in the synthesis of the peptidyl nucleoside antibiotic nikkomycin. NikU and NikV proteins have sequence similarity to Clostridium Glm sigma and epsilon components respectively, and may catalyze the rearrangement of 2-oxoglutaric acid to 2-keto-3-methylsuccinic acid during nikkomycin synthesis .
Glyoxylate carboligase (Glyox_carbo_lig)
Type: Family

Glyoxylate carboligase (Gcl), also called tartronate-semialdehyde synthase, releases CO2 while synthesizing a single molecule of tartronate semialdehyde from two molecules of glyoxylate. Its activity depends on the presence of thiamine diphosphate (ThDP), a derivative of vitamin B1 . In the D-glycerate pathway, part of allantoin degradation in the Enterobacteriaceae, tartronate semialdehyde is converted to D-glycerate and then 3-phosphoglycerate, a product of glycolysis and entry point in the general metabolism.
2-hydroxy-3-oxopropionate reductase (Tartro_sem_red)
Type: Family

These sequences represent 2-hydroxy-3-oxopropionate reductase (

), also called tartronate semialdehyde reductase. It follows glyoxylate carboligase and precedes glycerate kinase in D-glycerate pathway of glyoxylate degradation. The eventual product, 3-phosphoglycerate, is an intermediate of glycolysis and is readily metabolized. Tartronic semialdehyde, the substrate of this enzyme, may also come from other pathways, such as D-glucarate catabolism .
Riboflavin synthase, archaeal (Ribfl_synth_arc)
Type: Family

These archaeal proteins, like the bacterial riboflavin biosynthesis alpha chain, catalyze the final step in riboflavin biosynthesis. However, show closer similarity to 6,7-dimethyl-8-ribityllumazine synthase, which catalyzes the previous reaction and which (in bacteria) is called the riboflavin synthase beta chain .
Squalene hopene cyclase (Hopene-cyclase)
Type: Family

Hopanoids are planar, polycyclic hydrocarbons similar to eukaryotic sterols, containing five rings instead of the four rings in sterols, and they have a variety of polar and nonpolar side chains. Hopanoids and sterols share structural and functional similarities, for example, both lipid classes are able to modulate the fluidity and permeability of membranes . These lipids are found in diverse bacteria and in a handful of lichens and plants. Squalene hopene cyclase (SHC) belongs to the triterpenoid cyclase family of enzymes, involved in hopanoid (triterpenoid) biosynthesis. SHC is an integral membrane protein that directly cyclizes squalene into hopanoid products . Sequence and structure similarities of the active sites of epoxysqualene or oxidosqualene cyclases and SHCs suggest that these enzyme families are evolutionarily related . SCH are predominantly found in bacteria.