SII-SWORD/CoKE huggingface dataset:
2-methylisocitrate lyase (PrpB)
Type: Family

Propionate is the second most abundant low molecular mass carbon source found in soil, being generated by the degradation of several amino acids, fementation of crabohydrates and the oxidation of odd-chain fatty acids. Many different organisms are capable of metabolising propionate and several distinct pathways for utilising this compound exist, all of which begin with its activation to propionyl-CoA . Many bacteria metabolise propionate to pyruvate by the 2-methylcitric acid cycle. In the first step, catalysed by methycitrate synthase, oxaloacetate and propionyl-CoA are condensed to form 2-methylcitrate and CoA. The 2-methylcitrate is subsequently converted to 2-methylisocitrate by the combined actions of a dehydratase and an aconitase. In the final step, 2-methylisocitrate lyase cleaves a C-C bond within this compound to form succinate and pyruvate. The succinate is further oxidised to oxaloacetate which re-enters the cycle, while the pyruvate can be used further for either energy generation or biomass synthesis.

Proteins in this entry are mostly 2-methylisocitrate lyases. Some of them have been annotated (incorrectly it seems) as the related protein carboxyphosphoenolpyruvate phosphomutase, which is involved in synthesizing the antibiotic bialaphos in Streptomyces hygroscopicus. Structural studies indicate that these enzymes belong to the isocitrate lyase family, binding a Mg(2+) cofactor and forming a TIM barrel fold . As with other enzymes in this family, substrate-binding induces a conformational change that prevents solvent access to the active site and which is important for catalysis.
Phosphonate metabolism PhnM (PhnM)
Type: Family

This family refers to Alpha-D-ribose 1-methylphosphonate 5-triphosphate diphosphatase (also known as RPnTP diphosphatase or PhnM). PhnM is associated with phosphonate utilization in a number of bacterial species. It catalyzes the hydrolysis of alpha-D-ribose 1-methylphosphonate triphosphate (RPnTP) to form alpha-D-ribose 1-methylphosphonate phosphate (PRPn) and diphosphate . It is one of seven gene products (PhnG-PhnM) that participate in the catalysis of degradation of alkylphosphonates and are components of membrane associated C-P lyase complex .
Carboxyvinyl-carboxyphosphonate phosphorylmutase (CPEP_Pphonmut)
Type: Family

This family consists of carboxyvinyl-carboxyphosphonate phosphorylmutase (CPEP phosphonomutase), an unusual enzyme involved in the biosynthesis of the antibiotic bialaphos. So far, it is known only in that pathway and only in Streptomyces hygroscopicus. Some related proteins annotated as being functionally equivalent are likely miss-annotated examples of methylisocitrate lyase, an enzyme of propionate utilization.
Phosphoenolpyruvate phosphomutase, core (PEnolPyrv_PMutase_core)
Type: Domain

Phosphonates are a class of organophosphorus compounds, characterised by a stable C-P bond, which are found in a variety of biologically produced molecules including antiobiotics, lipids, proteins and polysaccharides . The functions of these molecules include phosphorus storage, cell communication, host recognition and chemical warfare. Phosphoenolpyruvate (PEP) phosphomutase catalyses the reversible conversion of PEP to 3-phosphonopyruvate, forming a stable C-P bond, which is the entry point to all known phosphonate biosynthetic pathways .

This entry consists of characterised and predicted PEP phosphomutases found in bacterial and eukayotic species. A closely related enzyme, phosphonopyruvate hydrolase from Variovorax sp. Pal2, is excluded from this entry, and the functional identification of some more distantly related sequences, such as from Bacteroides fragilis, Treponema denticola, and Clostridium tetani E88 is unknown.

PEP phosphomutase forms a modified TIM barrel fold where the eighth α helix adopts a different conformation than in the classical TIM barrel fold . The substrate binds in the central channel of the barrel and is anchored to the active site by the Mg(2+) cofactor . In the absence of substrate the active site is acessible to the solvent, while substrate-binding causes a conformational change where a large loop shields the site from solvent . This shielding appears to be required for catalysis to occur.
Ribose 1,5-bisphosphate phosphokinase PhnN (PhnN)
Type: Family

Many bacteria can use organophosphonates as a source of phosphate by cleaving the carbon-phosphorus bond with a multi-enzyme pathway collectively called carbon-phosphorus lyase. PhnN is part of this pathway and catalyses the phosphorylation of ribose 1,5-bisphosphate to 5-phospho-D-ribosyl alpha-1-diphosphate (PRPP) .

This family also includes some bifunctional ribose 1,5-bisphosphokinase-thymidine phosphorylases.
ATP-binding protein PhnK (PhnK)
Type: Family

This entry represents the ATP-binding protein PhnK from Escherichia coli and similar sequences mainly found in bacteria. PhnK associates with the C-P lyase core complex (PhnGHIJ), which is essential for the conversion of phosphonate into 5-phosphoribosyl-α-1-diphosphate (PRPP) in an ATP-dependent fashion under low levels of free and organic phosphate. PhnK, together with PhnL, use ATP to induce large-scale conformational changes in the enzyme . This protein, which shows an α-β structure, harbours the consensus elements of an ATP-binding cassette protein .
Phosphonate C-P lyase system, PhnL (CP_lyase_PhnL)
Type: Family

Members of this family are the PhnL protein of C-P lyase systems for utilization of phosphonates. These systems resemble phosphonatase-based systems in having a three-component ABC transporter, where

is the permease,

is the phosphonates binding protein, and

is the ATP-binding cassette (ABC) protein. They differ, however, in having, typically, ten or more additional genes, many of which are believed to form a membrane-associated C-P lyase complex. This protein (PhnL) and the adjacent-encoded PhnK (

) resemble transporter ATP-binding proteins but are suggested, based on mutagenesis studies, to be part of this C-P lyase complex rather than part of a transporter per se .
Phosphonate C-P lyase system, transcriptional regulator PhnF (CP_lyase_PhnF)
Type: Family

Members of this family are the PhnF protein associated with C-P lyase systems for utilization of phosphonates. These systems resemble phosphonatase-based systems in having a three-component ABC transporter, where

is the permease,

is the phosphonates binding protein, and

is the ATP-binding cassette (ABC) protein. They differ, however, in having, typically, ten or more additional genes, many of which are believed to form a membrane-associated C-P lyase complex. This protein (PhnF) is a predicted helix-turn-helix transcriptional regulatory protein of the broader GntR family , and is encoded in a gene cluster associated with genes for the import and degradation of phosphonates and/or related compounds (e.g. phosphonites) with a direct C-P bond. Its presence is apparently not required for phosphate utilisation to occur .
2-aminoethylphosphonate--pyruvate transaminase (NH2EtPonate_pyrv_transaminase)
Type: Family

Phosphonates are a class of organophosphorus compounds, characterised by a stable C-P bond, which are found in a variety of biologically produced molecules including antiobiotics, lipids, proteins and polysaccharides . The functions of these molecules include phosphorus storage, cell communication, host recognition and chemical warfare. 2-Aminoethylphosphonate (AEP), the most common naturally occurring phosphonate, is an important precursor used in the biosynthesis of phosphonolipids, phosphonoproteins, and phosphonoglycans.

This entry represents 2-aminoethylphosphonate-pyruvate transaminase (AEPT) (

) which catalyses the interconversion of AEP and phosphonoacetaldehyde (P-Ald), coupled with the interconversion of pryuvate and L-alanine. In some bacterial species this is the first step in an AEP degradation pathway which allows them to utilise this compound as a source of carbon, nitrogen and phosphorus. Phosphonoacetaldeyhde hydrolase, often encoded by an adjacent gene, then converts P-Ald to acetaldehyde and phosphate. Species with this pathway generally have an identified phosphonate ABC transporter but do not also have the multisubunit C-P lyase complex as found in Escherichia coli.

The crystal structure of AEPT from Salmonella typhimurium has been studied to 2.2 A resolution . The protein is a homodimer where each subunit is composed of two domains, large and small. The large domain forms an α-β complex characteristic of the aspartate transaminase family, while the small domain is composed of highly twisted β strands. The active site contains a pyridoxal 5'-phosphate cofactor and is found at the domain interface, being composed of residues from both subunits.
Signal transduction response regulator, propionate catabolism, transcriptional regulator PrpR (Sig_transdc_resp-reg_PrpR)
Type: Family

Two-component signal transduction systems enable bacteria to sense, respond, and adapt to a wide range of environments, stressors, and growth conditions . Some bacteria can contain up to as many as 200 two-component systems that need tight regulation to prevent unwanted cross-talk . These pathways have been adapted to response to a wide variety of stimuli, including nutrients, cellular redox state, changes in osmolarity, quorum signals, antibiotics, and more . Two-component systems are comprised of a sensor histidine kinase (HK) and its cognate response regulator (RR) . The HK catalyses its own auto-phosphorylation followed by the transfer of the phosphoryl group to the receiver domain on RR; phosphorylation of the RR usually activates an attached output domain, which can then effect changes in cellular physiology, often by regulating gene expression. Some HK are bifunctional, catalysing both the phosphorylation and dephosphorylation of their cognate RR. The input stimuli can regulate either the kinase or phosphatase activity of the bifunctional HK.

A variant of the two-component system is the phospho-relay system. Here a hybrid HK auto-phosphorylates and then transfers the phosphoryl group to an internal receiver domain, rather than to a separate RR protein. The phosphoryl group is then shuttled to histidine phosphotransferase (HPT) and subsequently to a terminal RR, which can evoke the desired response .

This entry represents the signal transduction response regulator PrpR. At least five distinct pathways exist for the catabolism of propionate by way of propionyl-CoA. Members of this family represent the transcriptional regulatory protein PrpR which is, in most cases, divergently transcribed from the operon that encodes the genes involved in the methylcitric acid cycle of propionate catabolism. This protein is required for the expression of the proteins involved in this pathway . 2-methylcitric acid, an intermediate in this pathway, has been proposed to be a co-activator of PrpR .
2-methylcitrate dehydratase PrpD (2Me_IsoCit_deHydtase_PrpD)
Type: Family

At least five distinct pathways exist for the catabolism of propionate by way of propionyl-CoA. Most members of this family are bacterial proteins known or predicted to act as 2-methylcitrate dehydratase; an enzyme which catalyses the third step the methylcitrate cycle of propionate catabolism . A related clade of archaeal proteins that may or may not be functionally equivalent is excluded from this family. The PrpD enzyme of Escherichia coli is responsible for the minor aconitase activity (AcnC) not accounted for by AcnA and AcnB . Some proteins in this entry are annotated as MmgE, a Bacillus subtilis protein encoded within an operon which is expressed during sporulation, subject to catabolite repression . An enzyme from Bacillus subtilis (citrate/2-methylcitrate synthase) acts as both a citrate synthase and a methylcitrate synthase .
Rib/alpha/Esp surface antigen repeat (Rib_alpha_Esp_rpt)
Type: Repeat

This entry represents a region of about 79 amino acids found tandemly repeated up to fourteen times within the proteins that contain it. The repeats lack cysteines and are highly conserved, even at the DNA level, within and between proteins . Proteins containing these repeats include the Rib and alpha surface antigens of group B Streptococcus, Esp of Enterococcus faecalis (Streptococcus faecalis), and related proteins of Lactobacillus. Most members of this protein family also have the cell wall anchor motif, LPXTG, shared by many staphyloccal and streptococcal surface antigens. These repeats are thought to define protective epitopes and may play a role in generating phenotypic and genotypic variation .
4-hydroxyphenylacetate permease (HPA_permease)
Type: Family

Among the different families of transporter only two occur ubiquitously in all classifications of organisms. These are the ATP-Binding Cassette (ABC) superfamily and the Major Facilitator Superfamily (MFS). The MFS transporters are single-polypeptide secondary carriers capable only of transporting small solutes in response to chemiosmotic ion gradients .

This entry represents a group of MFS proteins encoded in a number of proteobacterial genomes, but only in the context of having genes for 4-hydroxyphenylacetate (4-HPA) degradation. The protein is characterised as 4-HPA permease in Escherichia coli, where 3-HPA and 3,4-dihydroxyphenylacetate, but not other substrate analogues, were shown to competitively inhibit 4-HPA transport, indicating a narrow substrate specificity .
2-methylisocitrate dehydratase AcnD, Fe/S-dependent (2Me_IsoCit_deHydtase_FeS-dep)
Type: Family

This entry represents Fe/S-dependent 2-methylisocitrate dehydratase (AcnD;

), which is part of the 2-methylcitrate (2-MC) cycle that occurs in certain fungi and bacteria. The 2-MC cycle is involved in the degradation of propionyl-CoA via 2-methylcitrate, with AcnD functioning after PrpD and before PrpB. AcnD acts to catalyse the dehydration of 2-methylcitrate and citrate to 2-methyl-cis-aconitate and cis-aconitate, respectively, as well as to catalyse the hydration of cis-aconitate. However, 2-methylisocitrate and isocitrate were not substrates for AcnD, indicating that AcnD only catalyses the first half of the aconitase-like dehydration reactions . The enzyme from the fungus Yarrowia lipolytica (Candida lipolytica) does not act on isocitrate. AcnD is homologous to aconitases A and B. In Escherichia coli, which lacks a member of this family, 2-methylisocitrate dehydratase activity was traced to aconitase B (

) .
2-methyl-aconitate isomerase PrpF (PrpF)
Type: Family

PrpF is involved in the catabolism of short chain fatty acids (SCFA) via the 2-methylcitrate cycle II (propionate degradation route). PrpF catalyses the cis-trans isomerization of 2-methyl-aconitate through a base-catalyzed proton abstraction coupled with a rotation about C2-C3 bond of 2-methyl-aconitate .
Phosphonoacetate hydrolase (Phosphonoacetate_hydro)
Type: Family

This family consists of examples of phosphonoacetate hydrolase, an enzyme specific for the cleavage of the C-P bond in phosphonoacetate. Phosphonates are organic compounds with a direct C-P bond that is far less labile than the C-O-P bonds of phosphate attachment sites. Phosphonates may be degraded for phosphorus and energy by broad spectrum C-P lyase encoded by a large operon or by specific enzymes for some of the more common phosphonates in nature. This family represents an enzyme from the latter category. It may be found encoded near genes for phosphonate transport and for other specific phosphonatases .
Lacto-N-biose phosphorylase/D-galactosyl-beta-1->4-L-rhamnose phosphorylase (Lacto-N-biose_phosphorylase)
Type: Family

This entry includes a group of bacterial phosphorylases, including lacto-N-biose phosphorylase (lnpA) from Bifidobacterium and D-galactosyl-beta-1->4-L-rhamnose phosphorylase (Cphy_1920) from Lachnoclostridium phytofermentans .

LnpA can reversibly phosphorolyzes lacto-N-biose to Gal1-P and N-acetylglucosamine (GlcNAc) and galacto-N-biose to Gal1-P and N-acetylgalactosamine (GalNAc). It is involved in the lacto-N-biose I/galacto-N-biose (LNB/GNB) degradation pathway, which is important for host intestinal colonization by bifidobacteria .

Cphy_1920 can reversibly phosphorolyzes beta-D-galactosyl-(1->4)-L-rhamnose to form alpha-D-galactose 1-phosphate and L-rhamnose. But it does not phosphorolyze galacto-N-biose or lacto-N-biose .
HTH-type transcriptional regulator HpaR/FarR (HpaR/FarR)
Type: Family

This Helix-Turn-Helix transcriptional regulator is a member of the MarR family. Proteins in this family include FarR from Neisseria gonorrhoeae and HpaR from E. coli. HpaR is found in association with operons for the degradation of 4-hydroxyphenylacetic acid via homoprotocatechuate. FarR negatively controls expression of the farAB operon by binding directly to the farAB promoter region .
Prefoldin subunit beta (PfdB)
Type: Family

Chaperonins are cytosolic, ATP-dependent molecular chaperones, with a conserved toroidal architecture, that assist in the folding of nascent and/or denatured polypeptide chains. The group I chaperonin system consists of GroEL and GroES, and are found (usually) in bacteria and eukaryotic organelles. The group II chaperonin system, called the thermosome in archaea and TRiC or CCT in the Eukaryota, is structurally similar but only distantly related. Prefoldin, also called GimC, is a complex in archaea and eukaryota that works with group II chaperonins. Members of this protein family are the archaeal clade of the beta class of prefoldin subunit. Closely related, but outside the scope of this family are the eukaryotic beta-class prefoldin subunits, Gim-1,3,4 and 6. The alpha class prefoldin subunits are more distantly related .
Thermosome, archaeal (Thermosome_arc)
Type: Family

Members of this eukaryotic family are part of the group II chaperonin complex called CCT (chaperonin containing TCP-1 or Tailless Complex Polypeptide 1) or TRiC . Chaperonins are involved in productive folding of proteins . They share a common general morphology, a double toroid of 2 stacked rings. The archaeal equivalent group II chaperonin is often called the thermosome . Both the thermosome and the TCP-1 family of proteins are weakly, but significantly , related to the cpn60/groEL chaperonin family (see

).

The TCP-1 protein was first identified in mice where it is especially abundant in testis but present in all cell types. It has since been found and characterised in many other animal species, as well as in yeast, plants and protists. The TCP1 complex has a double-ring structure with central cavities where protein folding takes place . TCP-1 is a highly conserved protein of about 60kDa (556 to 560 residues) which participates in a hetero-oligomeric 900kDa double-torus shaped particle with 6 to 8 other different, but homologous, subunits . These subunits, the chaperonin containing TCP-1 (CCT) subunit beta, gamma, delta, epsilon, zeta and eta are evolutionary related to TCP-1 itself . Non-native proteins are sequestered inside the central cavity and folding is promoted by using energy derived from ATP hydrolysis . The CCT is known to act as a molecular chaperone for tubulin, actin and probably some other proteins .

Thermosome (or cpn60) is the name given to the archaeal rather than eukaryotic form of the group II chaperonin (counterpart to the group I chaperonin, GroEL/GroES, in bacteria), a toroidal, ATP-dependent molecular chaperone that assists in the folding or refolding of nascent or denatured proteins . Cpn60 consists of two stacked octameric rings, which are composed of one or two different subunits. Various homologous subunits, one to five per archaeal genome, may be designated alpha, beta, etc., but phylogenetic analysis does not show distinct alpha subunit and beta subunit lineages traceable to ancient paralogs. TF55 from thermophilic bacteria is also included in this entry.
T-complex protein 1, alpha subunit (Chap_CCT_alpha)
Type: Family

This family consists exclusively of the CCT alpha subunit (part of a paralogous family) from animals, plants, fungi, and other eukaryotes.

Members of this eukaryotic family are part of the group II chaperonin complex called CCT (chaperonin containing TCP-1 or Tailless Complex Polypeptide 1) or TRiC . Chaperonins are involved in productive folding of proteins . They share a common general morphology, a double toroid of 2 stacked rings. The archaeal equivalent group II chaperonin is often called the thermosome . Both the thermosome and the TCP-1 family of proteins are weakly, but significantly , related to the cpn60/groEL chaperonin family (see

).

The TCP-1 protein was first identified in mice where it is especially abundant in testis but present in all cell types. It has since been found and characterised in many other animal species, as well as in yeast, plants and protists. The TCP1 complex has a double-ring structure with central cavities where protein folding takes place . TCP-1 is a highly conserved protein of about 60kDa (556 to 560 residues) which participates in a hetero-oligomeric 900kDa double-torus shaped particle with 6 to 8 other different, but homologous, subunits . These subunits, the chaperonin containing TCP-1 (CCT) subunit beta, gamma, delta, epsilon, zeta and eta are evolutionary related to TCP-1 itself . Non-native proteins are sequestered inside the central cavity and folding is promoted by using energy derived from ATP hydrolysis . The CCT is known to act as a molecular chaperone for tubulin, actin and probably some other proteins .
T-complex protein 1, beta subunit (Chap_CCT_beta)
Type: Family

Members of this eukaryotic family are part of the group II chaperonin complex called CCT (chaperonin containing TCP-1 or Tailless Complex Polypeptide 1) or TRiC . Chaperonins are involved in productive folding of proteins . They share a common general morphology, a double toroid of 2 stacked rings. The archaeal equivalent group II chaperonin is often called the thermosome . Both the thermosome and the TCP-1 family of proteins are weakly, but significantly , related to the cpn60/groEL chaperonin family (see

).

The TCP-1 protein was first identified in mice where it is especially abundant in testis but present in all cell types. It has since been found and characterised in many other animal species, as well as in yeast, plants and protists. The TCP1 complex has a double-ring structure with central cavities where protein folding takes place . TCP-1 is a highly conserved protein of about 60kDa (556 to 560 residues) which participates in a hetero-oligomeric 900kDa double-torus shaped particle with 6 to 8 other different, but homologous, subunits . These subunits, the chaperonin containing TCP-1 (CCT) subunit beta, gamma, delta, epsilon, zeta and eta are evolutionary related to TCP-1 itself . Non-native proteins are sequestered inside the central cavity and folding is promoted by using energy derived from ATP hydrolysis . The CCT is known to act as a molecular chaperone for tubulin, actin and probably some other proteins .

This family consists exclusively of the CCT beta chain (part of a paralogous family) from animals, plants, fungi, and other eukaryotes.