SII-SWORD/CoKE huggingface dataset:
Formylmethanofuran dehydrogenase, fused subunit C/D (Formylmethanofuran_DH_csu/dsu)
Type: Family

Formylmethanofuran dehydrogenase (

) is found in methanogenic and sulphate-reducing archaea. The enzyme contains molybdenum or tungsten, a molybdopterin guanine dinuceotide cofactor (MGD) and iron-sulphur clusters . It catalyses the reversible reduction of CO
2
and methanofuran via N-carboxymethanofuran (carbamate) to N-formylmethanofuran, the first and second steps in methanogenesis from CO
2
. This reaction is important for the reduction of CO
2
to methane, in autotrophic CO
2
fixation, and in CO
2
formation from reduced C
1
units . The synthesis of formylmethanofuran is crucial for the energy metabolism of archaea. Methanogenic archaea derives the energy for autrophic growth from the reduction of CO
2
with molecular hydrogen as the electron donor . The process of methanogenesis consists of a series of reduction reactions at which the one-carbon unit derived from CO
2
is bound to C
1
carriers.

There are two isoenzymes of formylmethanofuran dehydrogenase: a tungsten-containing isoenzyme (Fwd) and a molybdenum-containing isoenzyme (Fmd). The tungsten isoenzyme is constitutively transcribed, whereas transcription of the molybdenum operon is induced by molybdate . The archaean Methanobacterium thermoautotrophicum contains a 4-subunit (FwdA, FwdB, FwdC, FwdD) tungsten formylmethanofuran dehydrogenase and a 3-subunit (FmdA, FmdB, FmdC) molybdenum formylmethanofuran dehydrogenase .

This entry represents a fusion of subunits C (FmdC) and D (FmdD) of molybdenum-containing formylmethanofuran dehydrogenase. These enzymes consist of five subunits: FmdA (

), FmdB (

), FmdC, FmdD and FmdE (

).
Menaquinone:cytochrome c reductase, cytochrome b/c subunit (MenaQ_cyt_c_Rdtase_cyt_b/c-su)
Type: Family

The qcr operon in Bacillus subtilis encodes the menaquinone:cytochrome c reductase complex, which is closely related to but distinct from mitochondrial cytochrome bc1 and chloroplast b6f complexes. QcrA is similar to Rieske-type iron-sulphur proteins; QcrB is similar in size and sequence to b-type cytochromes from b6f complexes; and QcrC has a novel structure that resembles a fusion between subunit IV of b6f complexes and cytochrome c. The amino (subunit IV) region of QcrC appears to have three transmembrane domains. The carboxyl (cytochrome c) region most closely resembles the small cytochromes c-550 (

) found in Bacillus species .
Sporulation transcription factor Spo0A (Spore_0_A)
Type: Family

Members of this group are response regulators/transcription factors that contain CheY-like receiver (phosphoacceptor) domain and a unique DNA-binding domain. Spo0A controls the entry of Bacillus subtilis into the developmental process of sporulation . Activation of the Spo0A transcription factor by phosphorylation serves as a developmental checkpoint and to integrate several physiological signals that control entry into the sporulation pathway. The signals are generated by conditions of nutrient deprivation, high cell density, the Krebs cycle, DNA replication, DNA damage, and some aspect of the chromosome partitioning machinery .

Activated Spo0A has multiple functions . It represses promoters (such as the abrB promoter) by binding to sites (0A boxes) downstream from the transcription start site. Spo0A also activates transcription from promoters used by two forms of RNA polymerase that differ by containing either the major sigma factor, sigma A (e.g. the spoIIE and spoIIG promoters) or the alternate sigma factor, sigma H (e.g. the spoIIA promoter). At promoters activated by Spo0A, the 0A boxes lie upstream of the transcription-initiation site.
[NiFe]-hydrogenase-3-type complex Eha, subunit EhaM (NiFe-hyd_3_EhaM)
Type: Family

[NiFe] hydrogenases function in H2 metabolism in a variety of microorganisms, enabling them to use H2 as a source of reducing equivalent under aerobic and anaerobic conditions [NiFe] hydrogenases consist of two subunits, hydrogenase large and hydrogenase small. The large subunit contains the binuclear [NiFe] active site, while the small subunit binds at least one [4Fe-4S] cluster .

Energy-converting [NiFe] hydrogenases (or [NiFe]-hydrogenase-3-type) form a distinct group within the [NiFe] hydrogenase family . Members of this subgroup include:

Hydrogenase 3 and 4 (Hyc and Hyf) from Escherichia coli

CO-induced hydrogenase (Coo) from Rhodospirillum rubrum

Mbh hydrogenase from Pyrococcus furiosus

Eha and Ehb hydrogenases from Methanothermobacter species

Ech hydrogenase from Methanosarcina barkeri

Energy-converting [NiFe] hydrogenases are membrane-bound enzymes with a six-subunit core: the large and small hydrogenase subunits, plus two hydrophilic proteins and two integral membrane proteins. Their large and small subunits show little sequence similarity to other [NiFe] hydrogenases, except for key conserved residues coordinating the active site and [FeS] cluster. However, they show considerable sequence similarity to the six-subunit, energy-conserving NADH:quinone oxidoreductases (complex I), which are present in cytoplasmic membranes of many bacteria and in inner mitochondrial membranes. However, the reactions they catalyse differ significantly from complex I. Energy-converting [NiFe] hydrogenases function as ion pumps.

Eha and Ehb hydrogenases contain extra subunits in addition to those shared by other energy-converting [NiFe] hydrogenases (or [NiFe]-hydrogenase-3-type). Eha contains a 6[4Fe-4S] polyferredoxin, a 10[4F-4S] polyferredoxin, ten other predicted integral membrane proteins (EhaA

, EhaB

, EhaC

, EhaD

, EhaE

, EhaF

, EhaG

, EhaI

, EhaK

, EhaL

and

) and four hydrophilic subunits (EhaM, EhaR, EhS, EhT) . The ten predicted integral membrane proteins are absent from Ech, Coo, Hyc and Hyf complexes, which may have simpler membrane components than Eha. Eha and Ehb catalyse the reduction of low-potential redox carriers (e.g. ferredoxins or polyferredoxins), which then might function as electron donors to oxidoreductases.

This entry represents proteins that are predicted to be the hydrophilic EhaM subunits of Eha-type energy-converting [NiFe] hydrogenase complexes.
Glutamate synthase, large subunit domain 3 stand-alone protein (Glu_synth_lsu_3)
Type: Family

The large (alpha, GltB) subunit of bacterial glutamate synthase (GOGAT) consists of three domains: N-terminal domain (amidotransferase domain) or related (in archaeal GOGAT), central domain and the FMN-binding domain, and C-terminal domain. This family represents a stand-alone form of the C-terminal domain. The stand-alone form occurs in the archaeal type of GOGAT, where the large subunit is represented by three separate proteins, corresponding to the three domains of the "standard" bacterial enzyme . Similar organisation of GOGAT with stand-alone domains has been found in some bacteria (e.g., members from Sinorhizobium meliloti, Thermotoga maritima), but its function is not clear in those organisms where the "standard" bacterial form is also present (e.g., Sinorhizobium meliloti).

This domain is also called the GXGXG structural domain, containing repeated sequence motif G-XX-G-XXX-G). It has a right-handed β-helix topology composing seven β-helical turns. It does not have a direct function in glutamate synthase activity but rather a structural function through extensive interactions with the amidotransferase and FMN-binding domains .

Originally, only the ORF encoding the central domain of GOGAT has been recognised and annotated as GltB in archaea, and the rest of the large subunit was thought to be missing, which may lead to some miss-annotations . This has led to speculations that the archaeal form of the GOGAT large subunit is the ancestral minimum form of the enzyme. Later analysis showed, however, that in all archaea where the large subunit has been found, its entire sequence is represented by three separate ORFs .

Glutamate synthase (GOGAT, GltS) is a complex iron-sulphur flavoprotein that catalyses the reductive synthesis of L-glutamate from 2-oxoglutarate and L-glutamine via intramolecular channelling of ammonia, a reaction in the bacterial, yeast and plant pathways for ammonia assimilation . GOGAT is a multifunctional enzyme that performs L-glutamine hydrolysis, conversion of 2-oxoglutarate into L-glutamate, and electron uptake from an electron donor .

There are four classes of GOGAT :

1. Bacterial NADPH-dependent GOGAT (NADPH-GOGAT,

). This standard bacterial NADPH-GOGAT is composed of a large (alpha, GltB) subunit and a small (beta, GltD) subunit.

2. Ferredoxin-dependent form in cyanobacteria and plants (Fd-GOGAT,

) displays a single-subunit structure corresponding to the large bacterial subunit.

3. Pyridine-linked form in both photosynthetic and nonphotosynthetic eukaryotes (eukaryotic GOGAT or NADH-GOGAT,

) displays a single-subunit structure corresponding to the fusion of the small and the large bacterial subunits (

).

4. The archaeal type with stand-alone proteins corresponding to the N-terminal, FMN-binding, and the C-terminal domains of the large subunit (

,

,

), and to the small subunit.
D-tagatose-1,6-bisphosphate aldolase subunit GatZ/KbaZ-like (GatZ/KbaZ-like)
Type: Family

Escherichia coli and other enteric bacteria contain two closely related D-tagatose 1,6-bisphosphate (TagBP)-specific aldolases involved in catabolism of galactitol (genes gatY gatZ) and of N-acetyl-galactosamine and D-galactosamine (genes kbaY, kbaZ, also called agaY, agaZ). The catalytic subunits GatY/KbaY alone are sufficient to show aldolase activity and contain most or all of the residues that have been identified as essential in substrate/product recognition and catalysis for class II aldolases . However, these aldolases differ from other Class II aldolases (which are homodimeric enzymes) in that they require subunits GatZ/KbaZ for full activity and for good in vivo and in vitro stability. The Z subunits alone do not show any aldolase activity . It should be noted that the previous suggestion of a tagatose 6P-kinase function for AgaZ and other members of this family have been debated .

Interestingly, this entry also includes the D-tagatose 6-phosphate 4-epimerase Atu3167 from Agrobacterium fabrum and SMb21373 from Sinorhizobium meliloti. Atu3167 catalyzes the epimerization of D-tagatose 6-phosphate to D-fructose 6-phosphate . SMb21373 is a epimerase .
Uroporphyrin-III C-methyltransferase, fungi (Met1_fungi)
Type: Family

This entry represents Met1, an uroporphyrinogen-III C-methyltransferase that is involved in the biosynthesis of siroheme and is required for sulfate assimilation and methionine biosynthesis .
Uncharacterised protein family, CYTH/CHAD/HD-like domain-containing (UPF_CYTH/CHAD/HD-like)
Type: Family

This group includes uncharacterised proteins from Methanosarcina spp. with CYTH and CHAD domains, and a central HD-like domain.

CYTH domain proteins may play a central role in the interface between nucleotide and polyphosphate metabolism . Based on the conservation of catalytic residues, CYTH domains are likely to chelate two divalent cations and exhibit a reaction mechanism that is dependent on two metal ions, analogous to nucleotide cyclases, polymerases, and certain phosphoesterases . It has also been suggested that the experimentally characterised members of the CYTH domain superfamily, namely, adenylyl cyclase and thiamine triphosphatase, are secondary derivatives of proteins that performed an ancient role in polyphosphate and nucleotide metabolism .

The C-terminal CHAD domain (

) is an α-helical domain that is found fused to the CYTH domain or is encoded by genes occurring in the same operon as those encoding CYTH domains. Therefore, it is predicted to be functionally associated with CYTH adenylate cyclases . While there is no experimental evidence as to the function of the CHAD domain, and no clear functional prediction can be made for it, the conserved histidines and other charged residues could form a strongly polar surface that could either participate in metal chelation, or act as phosphoacceptors .

Apart from these two domains, members of this group have a unique central domain. It is distantly related to the HD-type metal dependent phosphohydrolase domain (

), but there is no indication as to its function.
Arogenate dehydrogenase 2 (Arogenate_DH_2)
Type: Family

Proteins in this entry belong to the prephenate dehydrogenase (PDH) domain superfamily (

). Members of this group catalyse a step in tyrosine biosynthesis in the shikimate pathway, which is present only in bacteria, archaea, fungi, and plants . Many of the PDH enzymes are able to use the alternative intermediates of tyrosine biosynthesis, prephenate or L-arogenate, as substrates, having both prephenate dehydrogenase and arogenate dehydrogenase activities, and are sometimes collectively called cyclohexadienyl dehydrogenases . Arogenate dehydrogenase 2 has a weak prephenate dehydrogenase activity .

Arabidopsis thaliana has two arogenate dehydrogenase isoforms, tyrAAT1 and tyrAAT2. TyrAAT1 is unusual in that it contains a duplication of the PDH domain. Both copies of the PDH domain have arogenate dehydrogenase activity with similar biochemical characteristics . The experimentally studied plant enzymes are NADP-dependent arogenate dehydrogenases that are very sensitive toward feedback inhibition by the product of the reaction (tyrosine); in fact, they exhibit a higher affinity for tyrosine than for their arogenate substrate . Interestingly, these proteins do not seem to have any additional domain that can be suggested to be responsible for this regulation.
Chemotaxis glutamate methyltransferase (Chemotax_glutamate_MeTrfase)
Type: Family

Members of this group contain a divergent form of CheB-like protein-glutamate methylesterase domain in the C-terminal region. This domain is usually found fused with CheY-like receiver (response regulator) domain, forming CheB response regulator methylesterase (

). The stand-alone form is presumed to be involved in the same process of regulating bacterial chemotaxis , but there is no experimental evidence to confirm this. Members of this family have an N-terminal domain which has some amino acid residues in common with the CheY-like receiver domain but it is not clear whether it is evolutionarily or functionally related to CheY.

In bacterial chemotaxis, cellular movement is directed in response to chemical gradients. Transmembrane chemoreceptors that sense the stimuli are coupled (via a coupling protein, CheW) with a signal transduction histidine kinase (CheA). CheA phosphorylates response regulators CheB and CheY. Phosphorylated CheY binds to FliM, a component of the flagellar motor switch complex, and modulates the direction of flagellar rotation . Response regulator CheB (receptor modification enzyme, protein-glutamate methylesterase) modulates the signalling output of the chemotaxis receptors through control of the level of chemoreceptor methylation . Specific glutamyl residues in the transmembrane chemoreceptor cytoplasmic domain are methylated by methyltransferase CheR to form γ-carboxyl glutamyl methyl esters. These esters can be hydrolysed by methylesterase CheB. Receptor modification resets the signalling states of receptors, allowing for responses to changes in concentration of the chemical stimuli irrespective of their absolute concentrations .
LytTR signal transduction protein, putative (Sigtransdc_LytTR)
Type: Family

Members of this group contain a C-terminal LytTR DNA-binding transcriptional regulator domain and an N-terminal domain that is also present in a distinct group of methyl-accepting chemotaxis proteins typified by Bacillus subtilis YfmS). Therefore, these proteins are predicted to be involved in transcriptional regulation and signal transduction, but their exact regulatory role or the mode of signal transduction as well as the type of signal they transmit are unknown.
LytTR MHYT transcriptional regulator (LytTR_MHYT)
Type: Family

This entry includes the CoxC protein from the CO-metabolizing bacterium Oligotropha carboxidovorans . In the CoxC and CoxH proteins, the LytTR DNA-binding transcriptional regulator domain is found in association with MHYT, a recently described sensor domain, which contains six transmembrane segments carrying conserved His and Met residues . The
coxC
and
coxH
genes flank the operon encoding the CO dehydrogenase and are involved in transcriptional regulaton of the autotrophic metabolism in Oligotropha carboxidovorans .
GAF-ANTAR transcription anti-termination regulator, putative (GAF_ANTAR)
Type: Family

Members of this group are predicted signal transduction proteins containing cytoplasmic sensor domain GAF and an RNA-binding anti-terminator ANTAR domain.

In members of this group, regulation/signal receiving is predicted to be performed by the GAF domain. GAF is a ubiquitous signalling/sensory domain. It has been originally described as a non-catalytic cGMP-binding domain conserved in cyclic nucleotide phosphodiesterases . Subsequently, this domain was recognised in cyanobacterial adenylate cyclases, histidine kinases and certain other proteins . It has been predicted to regulate allosterically catalytic activities via binding ligands, such as nucleotides and small molecules .

ANTAR is a transcriptional anti-terminator domain and is most often found fused to the CheY-like receiver domain to form response regulator anti-terminator (

). Superficially, the coiled-coil and three-helix bundle that form this domain in AmiR (

) appear radically different from the compact HTH DNA-binding domain of the NarL protein. However, the last three helices in AmiR are very similar in length and hydropathy profiles to those of NarL and its homologues, and are arranged in a very similar topology, suggesting an evolutionary relationship . These C-terminal helices of AmiR appear to be essential for its transcription anti-termination activity . However, helix-turn-helix domains like those in NarL or OmpR are adapted to sequence-specific binding in the major groove of double-stranded B-form DNA. It is not clear how such a structure might function in a protein whose role is to prevent the formation of a termination stem-loop structure, by binding single-stranded RNA .
Glutamate synthase, large subunit domains 1/3 fusion (Glu_synth_lsu_1/3)
Type: Family

The large (alpha, GltB) subunit of bacterial glutamate synthase (GOGAT) consists of three domains: N-terminal domain (amidotransferase domain

), central (consisting of

and the FMN-binding domain

), and C-terminal domain. This family of sequences represent a fusion of the N-terminal (amidotransferase) domain and the C-terminal structural domain.

The stand-alone forms of the three domains (

and

for domains 1 and 2), as well as partial fusions, occur in the archaeal type of GOGAT, where the large subunit is represented by three separate proteins, corresponding to the three domains of the "standard" bacterial enzyme .

Originally, only the ORF encoding the central domain of GOGAT has been recognised and annotated as GltB in archaea, and the rest of the large subunit was thought to be missing, which may lead to some miss-annotations . This has led to speculations that the archaeal form of the GOGAT large subunit is the ancestral minimum form of the enzyme. Later analysis showed, however, that in all archaea where the large subunit has been found, its entire sequence is represented by three separate ORFs .

Glutamate synthase is a complex iron-sulphur flavoprotein that catalyses the reductive synthesis of L-glutamate from 2-oxoglutarate and L-glutamine via intramolecular channelling of ammonia, a reaction in the bacterial, yeast and plant pathways for ammonia assimilation . GOGAT is a multifunctional enzyme that performs L-glutamine hydrolysis, conversion of 2-oxoglutarate into L-glutamate, and electron uptake from an electron donor .

There are four classes of GOGAT :

1. Bacterial NADPH-dependent GOGAT (NADPH-GOGAT,

). This standard bacterial NADPH-GOGAT is composed of a large subunit and a small subunit.

2. Ferredoxin-dependent form in cyanobacteria and plants (Fd-GOGAT,

) displays a single-subunit structure corresponding to the large bacterial subunit.

3. Pyridine-linked form in both photosynthetic and nonphotosynthetic eukaryotes (eukaryotic GOGAT or NADH-GOGAT,

) displays a single-subunit structure corresponding to the fusion of the small and the large bacterial subunits (

).

4. The archaeal type with stand-alone proteins corresponding to the N-terminal, FMN-binding, and the C-terminal domains of the large subunit (

,

), and to the small subunit.
Methane/phenol monooxygenase, hydroxylase component (MP_mOase_hydro)
Type: Family

This group represents the hydroxylase component of aromatic and alkene monooxygenases such as methane monooxygenase (

) phenol 2-monooxygenase (

), toluene-4-monooxygenase (

) from Pseudomonas mendocina, and alkene monooxygenase (

) from Xanthobacter autotrophicus. Aromatic and alkene monooxygenase hydroxylases (AAMH) are composed of two copies each of three subunits (alpha 2 beta 2 gamma 2), and all three subunits are almost completely α-helical, with the exception of two β hairpin structures in the alpha subunit. The active site of each alpha subunit contains one dinuclear iron centre, housed in a four-helix bundle .

Methane monooxygenase is a multicomponent enzyme found in methanotrophic bacteria that catalyzes the hydroxylation of methane and higher alkenes (as large as octane). Phenol monooxygenase, found in a diverse group of bacteria, catalyses the hydroxylation of phenol, chloro- and methyl-phenol and naphthol. Both enzyme systems consist of three components: the hydroxylase, a coupling protein and a reductase . The toluene-4-monooxygenase multicomponent enzyme system catalyzes the O
2
- and NADH-dependent hydroxylation of toluene to form p-cresol . The alkene monooxygenase system catalyzes the O
2
- and NADH-dependent epoxidation of short chain (C2 to C6) alkenes to their corresponding epoxides .

Please see the following relevant references: .
Bifunctional aldehyde-alcohol dehydrogenase (Bifunc_Ald-ADH)
Type: Family

This enzyme has two NAD+-dependent activities: alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ACDH) . It controls ethanol and acetate production under aerobic conditions . The N-terminal region of the protein is highly homologous to aldehyde:NAD(+) oxidoreductases, whereas the C-terminal region is homologous to a family of Fe(2+)-dependent ethanol:NAD(+) oxidoreductases. In Escherichia coli, this fusion protein also functions as a pyruvate formate lyase deactivase . In Streptococcus pneumoniae, blocking of alcohol dehydrogenase activity leads to enhanced susceptibility to antimicrobials such as erythromycin, which suggests a potential of inhibitors of this enzyme as adjuvants to antibiotics .