SII-SWORD/CoKE huggingface dataset:
RecBCD enzyme subunit RecD (RecD)
Type: Family

Exodeoxyribonuclease V or RecBCD is an heterotrimeric enzyme comprised of the proteins RecB, RecC and RecD. RecBCD is a helicase/nuclease that prepares dsDNA breaks (DSB) for recombinational DNA repair . Subunit RecD is a DNA helicase with 5' --> 3' polarity, whereas the RecB subunit possesses a 3' --> 5' DNA helicase activity. This points to a bipolar translocation model for RecBCD in which the two DNA helicases are travelling with opposite polarities, but in the same direction, on each strand of the antiparallel DNA duplex .
ATP-dependent RecD2 DNA helicase (RecD2)
Type: Family

These sequences represent a family similar to RecD from the RecBCD enzyme

. Members of this family, however, are not found in a context of RecB and RecC and are longer by about 200 amino acids at the amino end. In Deinococcus radiodurans RecD2 is a DNA helicase with 5'-3' polarity and low processivity . Chlamydia muridarum has both a member of this family and a RecD.
2-phosphoglycolate phosphatase, eukaryotic (PGP_euk)
Type: Family

This family of sequences represent 2-phosphoglycolate phosphatase which is limited to the eukaryotic lineage. PGP is an essential enzyme in the glycolate salvage pathway in higher organisms (photorespiration in plants). Phosphoglycolate results from the oxidase activity of RubisCO in the Calvin cycle when concentrations of carbon dioxide are low relative to oxygen. In mammals, PGP (also known as Glycerol-3-phosphate phosphatase) is found in many tissues, notably in red blood cells where P-glycolate is and important activator of the hydrolysis of 2,3-bisphosphoglycerate, a major modifier of the oxygen affinity of hemoglobin. The PGPase enzyme described here is a member of the Haloacid dehalogenase superfamily of hydrolase enzymes. Unlike the bacterial PGP equivalog, which is a member of class (subfamily) I, this enzyme is a member of class (subfamily) II . These two enzymes have almost certainly arisen from convergent evolution (although these two ancestors may themselves have diverged from a more distant HAD superfamily progenitor). One of the sequences in the group comes from Chlamydomonas reinhardtii, a photosynthetic alga. The enzyme has been purified and characterised and these data are fully consistent with the assignment of function as a PGPase involved in photorespiration . Another, from Homo sapiens (Human), is supported as a member of the family indirectly. Biochemical characterisation of partially purified PGP's from various tissues including red blood cells have been performed while one gene for PGP has been localized to chromosome 16p13.3 . The Homo sapiens (Human) sequence maps to chromosome 22. There is indeed a related gene on chromosome 16 (and it is expressed, since EST's are found) which shows 46% identity and 59% positives by BLAST2 (E=1e-66). Presumably, these two genes are isoforms and have the same catalytic function while being expressed in different tissues and may be differently regulated. The sequence from Caenorhabditis elegans, is only supported by sequence similarity. This family is closely related to a family of bacterial sequences including the Escherichia coli NagD and Bacillus subtilis AraL genes which are characterised by the ability to hydrolyze para-nitrophenylphosphate (pNPPases or NPPases). The Chlamydomonas reinhardtii PGPase does not catalyze this reaction and so presumably these two groups have different functions and substrate specificities. Many of the genes in this family have been annotated as pNPPases due to this association.
Intron endonuclease, group I (Intron_endoG1)
Type: Family

This entry represents a subfamily of endonucleases containing the N-terminal endo/excinuclease amino terminal domain,

. Sequences containing this domain are often termed often termed GIY-YIG endonucleases after a conserved sequence motif. The sequences are encoded by open reading frames found in group I introns in both phage and mitochondria. The closely related endonucleases of Bacteriophage T4: segA, segB, segC, segD and segE, are not included in this family.

I-TevI (

) from Bacteriophage T4 consists of an N-terminal catalytic GIY-YIG domain, a flexible linker region and a C-terminal DNA-binding domain . The GIY-YIG domain forms a novel α/β fold, with the putative catalytic residues and a putative metal-binding site located on a concave surface. The C-terminal DNA-binding region forms three subdomains - a zinc-finger, a DNA minor-groove binding α helix and a helix-turn helix region. Multiple DNA-protein contacts over an extended region of the DNA substrate molecule are thought to contribute to the high site specificity of this protein.
3-amino-5-hydroxybenzoic acid synthesis-related (AHBA_synth-like)
Type: Family

The enzymes in this family are all located in the operons for the biosynthesis of 3-amino-5-hydroxybenzoic acid (AHBA), which is a precursor of several antibiotics including ansatrienin , naphthomycin , rifamycin and mitomycin . The role that this enzyme plays in this biosynthesis has not been elucidated. It is a member of the haloacid dehalogenase superfamily of aspartate-nucleophile hydrolases. This enzyme is closely related to phosphoglycolate phosphatase, but it is unclear what purpose a PGPase or PGPase-like activity would serve in these biosyntheses. The family is restricted to the Gram-positive actinobacteria.
Phosphoglucosamine mutase, bacterial type (GlmM_bact)
Type: Family

The alpha-D-phosphohexomutase superfamily is composed of four related enzymes, each of which catalyses a phosphoryl transfer on their sugar substrates: phosphoglucomutase (PGM), phosphoglucomutase/phosphomannomutase (PGM/PMM), phosphoglucosamine mutase (PNGM), and phosphoacetylglucosamine mutase (PAGM) . PGM (

) converts D-glucose 1-phosphate into D-glucose 6-phosphate, and participates in both the breakdown and synthesis of glucose . PGM/PMM (

;

) are primarily bacterial enzymes that use either glucose or mannose as substrate, participating in the biosynthesis of a variety of carbohydrates such as lipopolysaccharides and alginate . Both PNGM (

) and PAGM (

) are involved in the biosynthesis of UDP-N-acetylglucosamine .

This family describes GlmM, phosphoglucosamine mutase, also designated MrsA and YhbF in Escherichia coli , UreC in Helicobacter pylori, and femR315 or FemD in Staphylococcus aureus. It converts glucosamine-6-phosphate to glucosamine-1-phosphate as part of the pathway toward UDP-N-acetylglucosamine for peptidoglycan and lipopolysaccharides.

In order to be active, GlmM must be phosphorylated, which can occur via autophosphorylation or by the Ser/Thr kinase StkP. GlmM functions in a classical ping-pong bi-bi mechanism with glucosamine-1,6-diphosphate as an intermediate. .
HAD-superfamily hydrolase, subfamily IIA, CECR5 (HAD-SF_hydro_IIA_CECR5)
Type: Family

This family is a member of the Class IIA subfamily of the haloacid dehalogenase superfamily of aspartate-nucleophile hydrolases. Sequences in this family are all from eukaryotes. The human sequence is called "Cat Eye Syndrome critical region protein 5" (CECR5) , also known as Haloacid dehalogenase-like hydrolase domain-containing 5 (HDHD5). The gene codifying for this protein has been cloned from a pericentromere region of human chromosome 22 believed to be the location of the gene or genes responsible for Cat Eye Syndrome. This is one of a number of candidate genes.

The Schizosaccharomyces pombe (Fission yeast) sequence used to be annotated as "phosphatidyl synthase" due to a C-terminal region of the protein (outside the region of similarity covered by this entry) which is highly homologous to a family of CDP-alcohol phosphatidyltransferases. It is currently known as Cardiolipin synthase (CMP-forming) / mitochondrial hydrolase fusion protein as it is cleaved into two chains, one of which catalyses the synthesis of cardiolipin (CL) (diphosphatidylglycerol) by specifically transferring a phosphatidyl group from CDP-diacylglycerol to phosphatidylglycerol (PG) .

This family also includes Mitochondrial hydrolase YKR070W from Saccharomyces cerevisiae .
HAD-superfamily hydrolase, subfamily IIA, hypothetical 1 (HAD-SF_hydro_IIA_hyp1)
Type: Family

These sequences are all members of the Class IIA subfamily of the haloacid dehalogenase superfamily of aspartate-nucleophile hydrolases. The sequences are all from the Gram-positive (low-GC) bacteria. Some proteins in this entry are annotated as acid sugar phosphatases, which catalyse the dephosphorylation of 2-6 carbon acid sugars.
HAD hydrolase, LHPP/HDHD2 (LHPP/HDHD2)
Type: Family

Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) hydrolyzes nitrogen-phosphorus bonds in phospholysine, phosphohistidine and imidodiphosphate as well as oxygen-phosphorus bonds in inorganic pyrophosphate in vitro . This family also includes human haloacid dehalogenase like hydrolase domain containing 2 protine (HDHD2) a phosphatase which may be involved in polygenic hypertension . Members of this family belong to the haloacid dehalogenase-like (HAD) hydrolases, diverse enzymes that catalyze carbon or phosphoryl group transfer reactions on a range of substrates, using an active site aspartate in nucleophilic catalysis.
HAD-superfamily hydrolase, subfamily IIA, hypothetical 3 (HAD-SF_hydro_IIA_hyp3)
Type: Family

These sequences are all members of the Class IIA subfamily of the haloacid dehalogenase superfamily of aspartate-nucleophile hydrolases. The sequences are restricted to the Gram-negative and primarily alpha proteobacteria. Only one sequence has been annotated as other than "hypothetical." That one, from Brucella, is annotated as related to NagD, but only by sequence similarity and should be treated with some scepticism.
HAD-superfamily hydrolase, subfamily IIA (HAD-SF_hydro_IIA)
Type: Family

These sequences form one of the structural subclasses of the Haloacid Dehalogenase (HAD) superfamily of aspartate-nucleophile hydrolases. The superfamily is defined by the presence of three short catalytic motifs . The classes 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. Class I consists of sequences in which the capping domain is found in between the first and second catalytic motifs. Class II consists of sequences in which the capping domain is found between the second and third motifs. Class III sequences have no capping domain in either of these positions. The Class IIA capping domain is predicted to consist of a mixed α-β fold with the basic pattern: Helix-Helix-Helix-Sheet-Helix-Loop-Sheet-Helix-Sheet-Helix. Presently, this subfamily covers the eukaryotic phosphoglycolate phosphatase, as well as four further subfamilies covering closely related sequences in eukaryotes, in Gram-positive bacteria and in Gram-negative bacteria. The Escherichia coli NagD gene and the Bacillus subtilis AraL gene are members of this subfamily but are not members of the any of the presently defined equivalogs within it. NagD is part of the NAG operon responsible for N-acetylglucosamine metabolism . Genes from several organisms have been annotated as NagD, or NagD-like. However, without data on the presence of other members of this pathway, (such as in the case of Yersinia pestis) these assignments should not be given great weight. The AraL gene is similar and is part of the L-arabinose operon . A gene from
Halobacterium
has been annotated as AraL, but no other Ara operon genes have been annotated. Many of the genes in this subfamily have been annotated as "pNPPase" "4-nitrophenyl phosphatase" or "NPPase". These all refer to the same activity versus a common lab test compound used to determine phosphatase activity. There is no evidence that this activity is physiologically relevant. Dihydroxyacetone phosphatase from
Corynebacterium glutamicum
is also a member of this superfamily, and catalyses the dephosphorylation of dihydroxyacetone phosphate to produce 1,3-dihydroxyacetone .

The structure of NagD from Escherichia coli (strain K12) has been reported and its activity against various substrates determined. It has high specificity for nucleotide monophosphates, and in particular UMP and GMP. In the context of its occurrence in the NAG operon, it may well be involved in the recycling of cell wall metabolites .
Transcription elongation factor GreB (Tscrpt_elong_fac_GreB)
Type: Family

Bacterial GreA

and GreB promote transcription elongation by stimulating an endogenous, endonucleolytic transcript cleavage activity of the RNA polymerase, allowing RNA transcription to continue past template-encoded arresting sites. GreA and GreB are sequence homologues and have homologues in every known bacterial genome. GreA and GreB stimulate transcript cleavage in different ways; GreA induces cleavage of 3'-RNA fragments 2-3 nt in length and can only prevent the formation of arrested complexes, whereas GreB induces cleavage of fragments up to 18 nt in length and can rescue preexisting arrested complexes .

A 15 Angstrom resolution helical reconstruction of the Escherichia coli core RNA polymerase (RNAP)/GreB complex that allows fitting of high-resolution RNAP and GreB structures. The model of the complex reveals a remarkable binding mode for GreB; the globular C-terminal domain binds RNAP at the edge of the active site channel, while the N-terminal coiled-coil domain extends 45 Angstrom into a channel directly to the RNAP active site. The results point to a key role for conserved acidic residues at the tip of the Gre factor coiled coil in modifying the RNAP active site to catalyse the transcript cleavage reaction, and mutational studies confirm that these positions are critical for Gre factor function. Functional differences between GreA and GreB correlate with the distribution of positively charged residues on one face of the N-terminal coiled coil.
Transcription elongation factor GreA (Tscrpt_elong_fac_GreA)
Type: Family

Bacterial GreA and GreB

promote transcription elongation by stimulating an endogenous, endonucleolytic transcript cleavage activity of the RNA polymerase (RNAP) , allowing RNA transcription to continue past template-encoded arresting sites. GreA and GreB are sequence homologues and have homologues in every known bacterial genome. GreA and GreB stimulate transcript cleavage in different ways; GreA induces cleavage of 3'-RNA fragments 2-3 nt in length and can only prevent the formation of arrested complexes, whereas GreB induces cleavage of fragments up to 18 nt in length and can rescue pre-existing arrested complexes.

The 2.2 Angstrom resolution crystal structure of Escherichia coli GreA comprises an N-terminal antiparallel α-helical coiled coil, and a C-terminal globular domain. While the C-terminal domain binds RNAP, the N-terminal coiled coil interacts with the transcript 3' end and is responsible for stimulating the transcript cleavage reaction . Functional differences between GreA and GreB correlate with the distribution of positively charged residues on one face of the N-terminal coiled coil.

Because members of the family outside the Proteobacteria resemble GreA more closely than GreB, the GreB clade (

) forms a plausible outgroup and the remainder of the GreA/B family, included in this family, is designated GreA. In the Chlamydias and some spirochetes, the conserved region of these proteins is found as the C-terminal region of a much larger protein.
Methyltransferase MtaA/CmuA (Mtase_MtaA_CmuA)
Type: Domain

This entry represents a methyltransferase domain found in proteins which are involved in C1 metabolism in methanogenic archaea and methylotrophic bacteria. It is closely related to, yet is distinct from, uroporphyrinogen decarboxylase (

).

In methanogens, this domain is found in single-domain proteins catalysing the transfer of the methyl group of methylcobalamin to coenzymeM . In Methanosarcina barkeri these proteins have been shown to be involved in methanogenesis from C1 compounds such as methylamine and dimethylsulphide .

CH3-cob(III)alamin + coenzymeM -->cob(I)alamin + CH3-coenzymeM

In methylotrophic bacteria, this domain is found at the N terminus of the bifunctional corrinoid-binding CmuA protein, which is involved in chloromethane utilisation. The pathway of chloromethane utilisation allows the microorganisms that possess it to grow with chloromethane as the sole carbon and energy source. It is initiated by a corrinoid-dependent methyltransferase system involving methyltransferase I (CmuA) and methyltransferase II (CmuB), which transfer the methyl group of chloromethane onto tetrahydrofolate . The methyl group of chloromethane is first transferred by the protein CmuA to its corrinoid moiety, from where it is transferred to tetrahydrofolate by CmuB, thereby yielding methyltetrahydrofolate .

CH3Cl + cob(I)alamin --->CH3-cob(III)alamin + Cl-
Uroporphyrinogen decarboxylase HemE (Uroporphyrinogen_deCO2ase_HemE)
Type: Family

This entry represents uroporphyrinogen decarboxylase (URO-D or HemE), which catalyzes the fifth step in the haem biosynthetic pathway, converting uroporphyrinogen III to coproporphyrinogen III by decarboxylating the four acetate side chains of the substrate . This step takes the pathway toward protoporphyrin IX, a common precursor of both haem and chlorophyll, rather than toward precorrin 2 and its products.

This activity is essential in all organisms, and subnormal activity of URO-D leads to the most common form of porphyria in humans, porphyria cutanea tarda (PCT) as well as hepatoerythropoietic porphyria (HEP) .
Cobalamin (vitamin B12) biosynthesis CobM/CbiF, precorrin-4 C11-methyltransferase (Cbl_synth_CobM/CibF)
Type: Domain

Cobalamin (vitamin B12) is a structurally complex cofactor, consisting of a modified tetrapyrrole with a centrally chelated cobalt. Cobalamin is usually found in one of two biologically active forms: methylcobalamin and adocobalamin. Most prokaryotes, as well as animals, have cobalamin-dependent enzymes, whereas plants and fungi do not appear to use it. In bacteria and archaea, these include methionine synthase, ribonucleotide reductase, glutamate and methylmalonyl-CoA mutases, ethanolamine ammonia lyase, and diol dehydratase . In mammals, cobalamin is obtained through the diet, and is required for methionine synthase and methylmalonyl-CoA mutase .

This entry represents CobM and CibF precorrin-4 C11-methyltransferase (

), both as stand-alone enzymes and when CobJ forms part of a bifunctional enzyme. In the aerobic pathway, CobM catalyses the methylation of precorrin-4 at C-11 to yield precorrin-5. The extruded acyl group is then removed in the subsequent step catalysed by CobF. In the anaerobic pathway, CibF catalyses the methylation of cobalt-precorrin-4 to cobalt-precoriin-5 .
Precorrin-3B C17-methyltransferase domain (Cbl_synth_CobJ/CibH_dom)
Type: Domain

This entry represents a domain found in CobJ and CbiH precorrin-3B C(17)-methyltransferase (

). In the aerobic pathway, once CobG has generated precorrin-3b, CobJ catalyses the methylation of precorrin-3b at C-17 to form precorrin-4 (the extruded methylated C-20 fragment is left attached as an acyl group at C-1) . In the corresponding anaerobic pathway, CbiH carries out this ring contraction, using cobalt-precorrin-3b as a substrate to generate a tetramethylated delta-lactone . In Mycobacterium this domain fuses with the P
precorrin-2 C(20)-methyltransferase domain (

) into a bifunctional enzyme known as cobIJ.

Cobalamin (vitamin B12) is a structurally complex cofactor, consisting of a modified tetrapyrrole with a centrally chelated cobalt. Cobalamin is usually found in one of two biologically active forms: methylcobalamin and adocobalamin. Most prokaryotes, as well as animals, have cobalamin-dependent enzymes, whereas plants and fungi do not appear to use it. In bacteria and archaea, these include methionine synthase, ribonucleotide reductase, glutamate and methylmalonyl-CoA mutases, ethanolamine ammonia lyase, and diol dehydratase . In mammals, cobalamin is obtained through the diet, and is required for methionine synthase and methylmalonyl-CoA mutase .
Precorrin-2 C(20)-methyltransferase domain (CobI/CbiL/CobIJ_dom)
Type: Domain

This entry represents a domain found in precorrin-2 C(20)-methyltransferase, one of several closely related S-adenosylmethionine-dependent methyltransferases, which introduces a methyl group at C-20 on precorrin-2 to produce precorrin-3A during cobalamin (vitamin B12) biosynthesis. This reaction is key to the conversion of a porphyrin-type tetrapyrrole ring to a corrin ring . This domain covers full length of cobI, cbiL. In Mycobacterium this domain fuses with the precorrin-3B C17-methyltransferase domain (

) into a bifunctional enzyme known as cobIJ.
Cobalamin (vitamin B12) biosynthesis CobL/Precorrin-6Y C(5,15)-methyltransferase (Cbl_synth_CobL)
Type: Family

Cobalamin (vitamin B12) is a structurally complex cofactor, consisting of a modified tetrapyrrole with a centrally chelated cobalt. Cobalamin is usually found in one of two biologically active forms: methylcobalamin and adocobalamin. Most prokaryotes, as well as animals, have cobalamin-dependent enzymes, whereas plants and fungi do not appear to use it. In bacteria and archaea, these include methionine synthase, ribonucleotide reductase, glutamate and methylmalonyl-CoA mutases, ethanolamine ammonia lyase, and diol dehydratase . In mammals, cobalamin is obtained through the diet, and is required for methionine synthase and methylmalonyl-CoA mutase .

This entry represents CobL precorrin-6Y C5,15-methyltransferase (

) from the aerobic pathway. CobL is a bifunctional enzyme that catalyses two methylations (at C-5 and C-15) in precorrin-6Y, as well as the decarboxylation of the acetate side chain located in ring C, in order to generate precorrin-8X. . In the anaerobic pathway, two enzymes are required to produce precorrin-8X: CbiE and CbiT, which can be fused as CbiET (sometimes also called CobL) .
Uroporphyrin-III C-methyltransferase (CobA/CysG_C)
Type: Domain

SUMT, an enzyme of the cobalamin and siroheme biosynthetic pathway, catalyses the transformation of uroporphyrinogen III into precorrin-2. It transfers two methyl groups from S-adenosyl-L-methionine to the C-2 and C-7 atoms of uroporphyrinogen III to yield precorrin-2 via the intermediate formation of precorrin-1. SUMT is the first enzyme committed to the biosynthesis of siroheme or cobalamin (vitamin B12), and precorrin-2 is a common intermediate in the biosynthesis of corrinoids such as vitamin B12, siroheme and coenzyme F430 .
Sirohaem synthase, N-terminal (Sirohaem_synthase_N)
Type: Domain

Bacterial sulphur metabolism depends on the iron-containing porphinoid sirohaem. CysG is a multi-functional enzyme with S-adenosyl-L-methionine (SAM)-dependent bismethyltransferase, dehydrogenase and ferrochelatase activities. CysG synthesizes sirohaem from uroporphyrinogen III via reactions which encompass two branchpoint intermediates in tetrapyrrole biosynthesis, diverting flux first from protoporphyrin IX biosynthesis and then from cobalamin (vitamin B12) biosynthesis. CysG is a dimer. Its dimerisation region is 74 residues long, and acts to hold the two structurally similar protomers held together asymmetrically through a number of salt-bridges across complementary residues within the dimerisation region . CysG dimerisation produces a series of active sites, accounting for CysG's multi-functionality, catalysing four diverse reactions:

Two SAM-dependent methylations

NAD+-dependent tetrapyrrole dehydrogenation

Metal chelation

This group represent a subfamily of CysG N-terminal region-related sequences. All sequences in the seed alignment for this model are N-terminal regions of known or predicted sirohaem synthases. The C-terminal region of each is uroporphyrin-III C-methyltransferase (

), which catalyses the first step committed to the biosynthesis of either sirohaem or cobalamin (vitamin B12) rather than protohaem (haem). Functionally these sequences complete the process of oxidation and iron insertion to yield sirohaem. Sirohaem is a cofactor for nitrite and sulphite reductases, so sirohaem synthase is CysG of cysteine biosynthesis in some organisms.