SII-SWORD/CoKE huggingface dataset:
Heme chaperone HemW-like (HemW-like)
Type: Family

Proteins in this entry include HemW (also known as oxygen-independent coproporphyrinogen-III oxidase-like protein). HemW is a heme chaperone catalyzing the insertion of heme into hemoproteins .

Experimentally determined examples of oxygen-independent coproporphyrinogen III oxidase, an enzyme that replaces HemF function under anaerobic conditions, belong to a family of proteins called HemN (

). This family contains a closely related protein, shorter at the amino end and lacking the region containing the motif PYRT[SC]YP found in members of the hemN family. Several species, including Escherichia coli, Helicobacter pylori, Aquifex aeolicus, and Chlamydia trachomatis, have members of both this family and the Escherichia coli hemN family. The member of this family from Bacillus subtilis was shown to complement a hemF/hemN double mutant of Salmonella typhimurium and to prevent accumulation of coproporphyrinogen III under anaerobic conditions, but the exact role of this protein is still uncertain. It is found in a number of species that do not synthesize haem
de novo
.
L-ribulose-5-phosphate 3-epimerase (L-Ru-5P_3-Epase)
Type: Family

This entry represents the L-ribulose-5-phosphate 3-epimerase UlaE and SgbU from Escherichia coli and other bacterial species. L-ribulose-5-phosphate 3-epimerase (

) is involved in isomerisation of L-xylulose-5-phosphate to L-ribulose-5-phosphate. Along with UlaD and UlaF, UlaE is involved in a pathway leading to fermentation of l-ascorbate under anaerobic conditions. UlaE in E. coli adopts a TIM barrel fold with the active site located at the C-terminal ends of the parallel β-strands. UlaE forms back-to-back dimers .

The ulaABCDEF operon encodes an L-ascorbate phosphotransferase transport system (UlaABC, formerly designated SgaTBA)responsible for the uptake and phosphorylation of L-ascorbate. The ulaDEF genes encode three enzymes that catalyze the anaerobic conversion of the phosphorylated, hydrolytic product of L-ascorbate, 3-keto-L-gulonate-6-phosphate, to D-xylulose-5-phosphate, which is subsequently metabolized by the pentose phosphate pathway. UlaD catalyzes a β-keto acid decarboxylation reaction to produce L-xylulose-5-phosphate, which undergoes successive epimerization reactions with UlaE (L-xylulose-5-phosphate 3-epimerase) and UlaF (L-ribulose-5-phosphate 4-epimerase), yielding D-xylulose-5-phosphate, an intermediate in the pentose phosphate pathway.
Isochorismate synthase (IsoChor_synthase)
Type: Family

Isochorismate synthase (

) catalyses the conversion of chorismate to isochorismate, the first step in the biosynthesis of both the respiratory chain component menaquinone (MK, vitamin K2) and phylloquinone (vitamin K1). In bacteria, isochorismate is a precursor of siderophores enterobactin (via the 2,3-dihydroxybenzoate (DHB) precursor) , amonabactins and salicylic acid . Most aerobic bacteria secrete siderophores to facilitate iron acquisition . Siderophores are iron-chelating agents which are low molecular weight compounds that specifically bind ferric iron and mediate iron uptake into the cell by recognition of specific membrane receptor proteins and transport systems. In plants, isochorismate synthase is required for defence against pathogens. Salicylic acid synthesised via the pathway using isochorismate synthase is responsible for both local and systemic acquired resistance in plants .

In Escherichia coli and Bacillus subtilis, two distinct isochorismate synthase isoenzymes, MenF and EntC /DhbC , are known to be involved in MK and siderophore biosynthesis pathways, respectively . MenF and EntC are differentially regulated and isochorismate synthesised by EntC is mainly channelled into enterobactin synthesis, whereas isochorismate synthesised by MenF is mainly channelled into menaquinone synthesis .

The catalytic/chorismate binding domain characteristic of members of this group is related to other chorismate binding enzymes : component I of anthranilate synthase, para-aminobenzoate synthase, and aminodeoxychorismate synthase (please see

).

There is a significant heterogeneity in the length and sequence of the N-terminal region of members of this group. Partially on the basis of the N-terminal region, the group can be divided into subfamilies, with the enzymes involved in DHB (enterobactin precursor) biosynthesis (EntC/DhbC/VibC) forming a distinct subfamily, and the enzymes involved in MK biosynthesis (MenF) forming two groups (E. coli and B. subtilis types).
Lipoyltransferase/lipoate-protein ligase (LipoylTrfase_LipoateP_Ligase)
Type: Family

Lipoic acid is an essential cofactor of the alpha-ketoacid dehydrogenase complexes and the glycine cleavage system. It is covalently attached to a specific lysine residue of the subunit of the complexes.

In mammals, covalent attachment of lipoic acid to the proteins occurs in two successive reactions. First, lipoic acid is activated to lipoyl-AMP by lipoate-activating enzyme, and then the lipoyl moiety is transferred to apoproteins by the action of lipoyltransferase . In contrast, in Escherichia coli, lipoate-protein ligase A catalyses both the activation and the transfer of lipoate . This entry includes lipoyltransferases and lipoate-protein ligases.

This entry contains Lipoyl amidotransferase LIPT1, which is found in mitochondria .
Apolipoprotein N-acyltransferase (Apolipo_AcylTrfase)
Type: Family

Apolipoprotein N-acyltransferase (Lnt) transfers the acyl group to lipoproteins and is involved in lipoprotein biosynthesis in Gram-negative bacteria. It is an integral membrane protein . In the last step of lipoprotein maturation, N-acylation by apolipoprotein N-acyltransferase of the plasma membrane is required for recognition of the outer membrane lipoproteins by the Lol system, which transports the lipoproteins from the plasma to the outer membrane . This is a reverse amidase (i.e. condensation) reaction.
Outer membrane lipoprotein carrier protein LolA-like (OM_lipoprot_carrier_LolA-like)
Type: Family

In Escherichia coli, lipoproteins are anchored to the periplasmic side of either the inner or outer membrane through N-terminal lipids, depending on the lipoprotein-sorting signal present at position 2 . Five Lol proteins are involved in the sorting and outer membrane localization of lipoproteins. LolCDE, an ATP binding cassette (ABC) transporter, in the inner membrane releases outer membrane-directed lipoproteins from the inner membrane in an ATP-dependent manner, leading to the formation of a water-soluble complex between the lipoprotein and the molecular chaperone, LolA. The LolA-lipoprotein complex crosses the periplasm and then interacts with outer membrane receptor LolB, which is essential for the anchoring of lipoproteins to the outer membrane .

E. coli lipoproteins are anchored to the inner or outer membrane depending on the residue at position 2. Aspartate at this position makes lipoproteins specific to the inner membrane, whereas other residues cause the release of lipoproteins from the inner membrane .
Outer membrane lipoprotein LolB (OM_lipoprot_LolB)
Type: Family

This protein, LolB, is known so far only in the gamma subdivision of the Proteobacteria. It is a processed, lipid-modified outer membrane protein. In Escherichia coli, lipoproteins are anchored to the periplasmic side of either the inner or outer membrane through N-terminal lipids, depending on the lipoprotein-sorting signal present at position 2 . Five Lol proteins are involved in the sorting and outer membrane localization of lipoproteins. LolCDE, an ATP binding cassette (ABC) transporter, in the inner membrane releases outer membrane-directed lipoproteins from the inner membrane in an ATP-dependent manner, leading to the formation of a water-soluble complex between the lipoprotein and LolA. The LolA-lipoprotein complex crosses the periplasm and then interacts with outer membrane receptor LolB, which is essential for the anchoring of lipoproteins to the outer membrane.
Pantothenate kinase (PanK)
Type: Family

Pantothenate kinase (

) catalyses the rate-limiting step in the biosynthesis of coenzyme A, the conversion of pantothenate to D-4'-phosphopantothenate in the presence of ATP. It is very well conserved from Escherichia coli to Bacillus subtilis, but differs considerably from known eukaryotic forms, described in a separate family. It has been shown to be a homodimer in E. coli and is regulated by feedback inhibition by CoA and its thioesters .
Type II pantothenate kinase (Type_II_PanK)
Type: Family

This family describes the type II form of pantothenate kinase PanK, characterised from the fungus Emericella nidulans and with similar forms known in several other eukaryotes. It also includes forms from several Gram-positive bacteria suggested to have originated from the eukaryotic form by lateral transfer. It differs in a number of biochemical properties (such as inhibition by acetyl-CoA) from type I PanK enzymes and shows little sequence similarity .

Pantothenate kinase (PanK or CoaA) catalyses the first step of the universal five step coenzyme A (CoA) biosynthesis pathway. CoA is a ubiquitous and essential cofactor in all living organsims. Pantothenate kinase catalyses the first and rate limiting step in the CoA biosynthetic pathway, which involves transferring a phosphoryl group from ATP to pantothenate, also known as vitamin B5. Three distinct types of pantothenate kinase enzymes have been identified: type I PanK enzymes are typified by the E. coli CoaA protein, type II enzymes are primarily found in eukaryotic organisms whilst type III enzymes have a wider phylogenic distribution and are not feedback inhibited by CoA .
Phosphopantetheine-protein transferase domain (Ppantetheine-prot_Trfase_dom)
Type: Domain

This domain is active in transferring the phophopantetheine prosthetic group to its attachment site on enzymes and carrier proteins. Many members of the family containing this domain are small proteins that act on the acyl carrier protein involved in fatty acid biosynthesis . Some members are domains of larger proteins involved in specialised pathways for the synthesis of unusual molecules including polyketides, atypical fatty acids, and antibiotics.
Pyridoxal phosphate (active vitamin B6) biosynthesis PdxJ (PyrdxlP_synth_PdxJ)
Type: Family

Pyridoxal phosphate is the active form of vitamin B6 (pyridoxine or pyridoxal). Pyridoxal 5'-phosphate (PLP) is a versatile catalyst, acting as a coenzyme in a multitude of reactions, including decarboxylation, deamination and transamination . PLP-dependent enzymes are primarily involved in the biosynthesis of amino acids and amino acid-derived metabolites, but they are also found in the biosynthetic pathways of amino sugars and in the synthesis or catabolism of neurotransmitters; pyridoxal phosphate can also inhibit DNA polymerases and several steroid receptors . Inadequate levels of pyridoxal phosphate in the brain can cause neurological dysfunction, particularly epilepsy .

PLP enzymes exist in their resting state as a Schiff base, the aldehyde group of PLP forming a linkage with the ε-amino group of an active site lysine residue on the enzyme. The α-amino group of the substrate displaces the lysine ε-amino group, in the process forming a new aldimine with the substrate. This aldimine is the common central intermediate for all PLP-catalysed reactions, enzymatic and non-enzymatic .

In Escherichia coli, the pdx genes involved in vitamin B6 have been characterised . This entry represents PdxJ (also called PNP synthase), which catalyses the condensation of 4-hydroxy-L-threonine and 1-deoxy-D-xylulose-5-phosphate to form pyridoxine-5'-phosphate (PNP) . The product of the PdxJ reaction is then oxidized by PdxH to form pyridoxal 5'-phosphate (PLP).

PNP synthase (PdxJ) adopts a TIM barrel topology. Intersubunit contacts are mediated by three ''extra'' helices, generating a tetramer of symmetric dimers with shared active sites. The open state has been proposed to accept substrates and to release products, while most of the catalytic events are likely to occur in the closed state. A hydrophilic channel running through the centre of the barrel was identified as the essential structural feature that enables PNP synthase to release water molecules produced during the reaction from the closed, solvent-shielded active site .
CDP-diacylglycerol--glycerol-3-phosphate 3-phosphatidyltransferase (Phosphatidylglycerol_P_synth)
Type: Family

CDP-diacylglycerol--glycerol-3-phosphate 3-phosphatidyltransferase (

), also known as phosphatidylglycerophosphate synthase, glycerophosphate phosphatidyltransferase and PGP synthase, catalyses the conversion of CDP-diacylglycerol and glycerol-3-phosphate to CMP and 3-(3-phosphatidyl)-glycerol 1-phosphate in the committed step to the synthesis of acidic phospholipids. It is an integral membrane protein. A number of related enzymes are quite similar in both sequence and catalytic activity, including Saccharomyces cerevisiae (Baker's yeast) YDL142c, now known to be a cardiolipin synthase. There may be problems with incorrect transitive annotation of near homologues as authentic CDP-diacylglycerol--glycerol-3-phosphate 3-phosphatidyltransferase.
Protoporphyrinogen oxidase (Protoporphyrinogen_oxidase)
Type: Family

Protoporphyrinogen oxidase (

) oxidises protoporphyrinogen IX to protoporphyrin IX, a precursor of haem and chlorophyll, in the penultimate step in haem and porphyrin biosynthesis. Bacillus subtilis HemY also has coproporphyrinogen III to coproporphyrin III oxidase activity in a heterologous expression system, although the role for this activity
in vivo
is unclear. This protein is a flavoprotein and has a β-α-β dinucleotide binding motif near the amino end.
rRNA small subunit methyltransferase B (rRNA_ssu_MeTfrase_B)
Type: Family

RNA (C5-cytosine) methyltransferases (RCMTs) catalyse the transfer of a methyl group to the 5th carbon of a cytosine base in RNA sequences to produce C5-methylcytosine. RCMTs use the cofactor S-adenosyl-L-methionine (SAM) as a methyl donor . The catalytic mechanism of RCMTs involves an attack by the thiolate of a Cys residue on position 6 of the target cytosine base to form a covalent link, thereby activating C5 for methyl-group transfer. Following the addition of the methyl group, a second Cys residue acts as a general base in the beta-elimination of the proton from the methylated cytosine ring. The free enzyme is restored and the methylated product is released .

Numerous putative RCMTs have been identified in archaea, bacteria and eukaryota ; most are predicted to be nuclear or nucleolar proteins . The Escherichia coli Ribosomal RNA Small-subunit Methyltransferase Beta (RSMB) FMU (FirMicUtes) represents the first protein identified and characterised as a cytosine-specific RNA methyltransferase. RSMB was reported to catalyse the formation of C5-methylcytosine at position 967 of 16S rRNA .

A classification of RCMTs has been proposed on the basis of sequence similarity . According to this classification, RCMTs are divided into 8 distinct subfamilies . Recently, a new RCMT subfamily, termed RCMT9, was identified . Members of the RCMT contain a core domain, responsible for the cytosine-specific RNA methyltransferase activity. This 'catalytic' domain adopts the Rossman fold for the accommodation of the cofactor SAM . The RCMT subfamilies are also distinguished by N-terminal and C-terminal extensions, variable both in size and sequence .

The rRNA small subunit methyltransferase B (RsmB) protein, often referred to as Fmu, has been demonstrated to methylate only C967 of the 16S ribosomal RNA and to produce only m5C at that position . The structure of the E. coli protein has been determined . It contains three subdomains which share structural homology to DNA m5C methyltransferases and two RNA binding protein families. The N-terminal sequence shares homology to another (noncatalytic) RNA binding protein, e.g. the ribosomal RNA antiterminator protein NusB (

). The catalytic lobe of the N1 domain, comprises the conserved core identified in all of the putative RNA m5C MTase sequences. Although the N1 domain is structurally homologous to known RNA binding proteins, there is no clear sequence motif that defines its role in RNA binding and recognition. At the functional centre of the catalytic lobe is the MTase domain of Fmu (residues 232-429), which adopts a fold typical of known AdoMet-dependent methyltransferases. In spite of the lack of a conserved RNA binding motif in the N1 domain, the close association of the N1 and MTase domains suggest that any RNA bound in the active site of the MTase domain is likely to interact with the N1 domain.
Alkylated DNA repair protein AlkB (Alkb)
Type: Family

AlkB proteins are dioxygenases that repair alkylation damage to DNA and RNA . The Escherichia coli alkB gene product protects against cell killing by S(N)2-alkylating agents through DNA repair by a novel direct reversal DNA repair mechanism: the oxidative demethylation of N1-methyladenine or N3-methylcytosine DNA lesions. This reaction occurs on both single- and double-stranded DNA, and requires AlkB-bound non-heme Fe(2+), O(2) and alpha-ketogluterate to oxidize the offending methyl group. This is followed by the release of succinate, CO(2) and formaldehyde, and the restoration of undamaged A or C in DNA .

Nine mammalian AlkB homologues exist (ALKBH1-8, FTO), but only a subset functions as DNA/RNA repair enzymes , and only ALKBH1 is included in this entry. In humans, ALKBH1 (ABH1) is responsible for the conversion of 5-methylcytosine to 5-formylcytosine (f5C) in position 34 in mitochondrial tRNAMet .
Cdk-activating kinase assembly factor MAT1/Tfb3 (MAT1/Tfb3)
Type: Family

MAT1/Tfb3 acts as component of the general transcription and DNA repair factor IIH (TFIIH), which is essential for both basal and activated transcription, and is involved in nucleotide excision repair (NER) of damaged DNA .

It is a RING finger protein with a characteristic C3HC4 motif located in the N-terminal domain. MAT1/Tfb3 stabilises the cyclin H-CDK7 complex to form a functional CDK-activating kinase (CAK) enzymatic complex which then goes on to activate many of the CDK enzymes intimately involved in the cell cycle . CDK7 forms a stable complex with cyclin H and MAT1/Tfb3 in vivo only when phosphorylated on either one of two residues (Ser164 or Thr170) in its T-loop. The requirement for MAT1/Tfb3 for the activation of CAK can be by-passed by the phosphorylation of CDK7 on the T-loop. The two mechanisms for CDK7 complex stabilisation and activation (MAT1 addition and T-loop phosphorylation), which can operate independently in vitro, actually cooperate under physiological conditions to maintain complex integrity. With prolonged exposure to elevated temperature, dissociation to monomeric subunits occurs in vivo when CDK7 is dephosphorylated, even in the presence of MAT1/Tfb3 .
Transcription-repair coupling factor (Mfd)
Type: Family

The bacterial transcription-repair coupling factor (Mfd) binds to stalled transcription elongation complexes in vitro and catalyses their dissociation from template DNA in an ATP-dependent manner . A lesion in the template strand blocks the RNA polymerase complex (RNAP). The RNAP-DNA-RNA complex is specifically recognised by Mdf, which releases RNAP and the truncated transcript. Mfd displaces RNAP at the lesion site by pushing the polymerase forward , allowing the lesion to be accessed by repair proteins . Mfd contains superfamily II helicase motifs which are essential for the RNAP displacement activity of Mfd , but does not possess conventional strand-separating helicase activity .
8-oxoguanine DNA-glycosylase (Ogg1)
Type: Family

One of the major base lesions induced by oxidative stress is 8-oxoguanine (8-oxoG), one of the oxidised forms of guanine. 8-oxoguanine DNA glycosylase (also known as N-glycosylase/DNA lyase) functions in base excision repair and is responsible for the excision of 8-oxoguanine. It has beta-lyase activity that nicks DNA 3' to the lesion .
ERCC1/RAD10/SWI10 family (ERCC1/RAD10/SWI10)
Type: Family

This group of proteins includes Rad10 from budding yeasts, Swi10 from fission yeasts and ERCC-1 from animals and plants. All proteins in this family for which functions are known are components in a multiprotein endonuclease complex (usually made up of Rad1 and Rad10 homologues). This complex is used primarily for nucleotide excision repair but also for some aspects of recombination repair.

In budding yeast, Rad10 works as a heterodimer with Rad1, and is involved in nucleotide excision repair of DNA damaged with UV light, bulky adducts or cross-linking agents. The complex forms an endonuclease which specifically degrades single-stranded DNA .

ERCC1 and XPF (xeroderma pigmentosum group F-complementing protein) are two structure-specific endonucleases of a class of seven containing an ERCC4 domain. Together they form an obligate complex that functions primarily in nucleotide excision repair (NER), a versatile pathway able to detect and remove a variety of DNA lesions induced by UV light and environmental carcinogens, and secondarily in DNA inter-strand cross-link repair and telomere maintenance. This domain in fact binds simultaneously to both XPF and single-stranded DNA; this ternary complex explains the important role of Ercc1 in targeting its catalytic XPF partner to the NER pre-incision complex .
DNA repair protein Rad18, fungi (Rad18_fungi)
Type: Family

During DNA replication, lesion bypass is an important cellular response to unrepaired damage in the genome. In the yeast Saccharomyces cerevisiae (Baker's yeast), Rad6 and Rad18 are required for both the error-free and error-prone lesion bypass mechanisms. The Rad18 gene encodes a RING-finger protein with single-stranded DNA binding activity that interacts with the ubiquitin-conjugating enzyme Rad6.
Checkpoint protein Rad17/Rad24 (Checkpoint_prot_Rad17_Rad24)
Type: Family

This entry represents checkpoint protein Rad24 from budding yeasts and its homologue, Rad17 from other organisms.

In Saccharomyces cerevisiae, Rad24 forms a complex with replication factor C (RFC) proteins, including Rfc2, Rfc3, Rfc4, and Rfc5. When DNA damage is detected, the Rad24-RFC complex loads Rad17-Mec3-Ddc1 complex onto chromatin and activates DNA damage checkpoint, which then leads to cell cycle arrest and DNA repair . The Rad24-RFC complex is involved in both the mitotic and meiotic checkpoints . Besides checkpoint activation, Rad24 is also involved in double-strand break ends processing, DNA repair and telomere maintenance .
DNA repair protein Rad4 (DNA_repair_Rad4)
Type: Family

Mutations in the nucleotide excision repair (NER) pathway can cause the xeroderma pigmentosum skin cancer predisposition syndrome. NER lesions are limited to one DNA strand, but otherwise they are chemically and structurally diverse, being caused by a wide variety of genotoxic chemicals and ultraviolet radiation. The xeroderma pigmentosum C (XPC) protein has a central role in initiating global-genome NER by recognising the lesion and recruiting downstream factors.
DNA repair protein Rad50, eukaryotes (Rad50_eukaryotes)
Type: Family

RAD50 is involved in DNA double-strand break repair (DSBR), telomere maintenance and meiotic recombination . The RAD50/MRE11 complex possesses single-strand endonuclease activity and ATP-dependent double-strand-specific exonuclease activity . RAD50 provides ATP-dependent control of Mre11 by unwinding and/or repositioning DNA ends into the MRE11 active site . This entry represents the eukaryotic Rad50 that is distantly related to the SbcC family of bacterial proteins.

In Saccharomyces cerevisiae, Rad50 forms the MRX complex with Mre11 and Xrs2.