SII-SWORD/CoKE huggingface dataset:
Chloride channel ClC-4 (Cl_channel-4)
Type: Family

Chloride channels (CLCs) constitute an evolutionarily well-conserved family of voltage-gated channels that are structurally unrelated to the other known voltage-gated channels. They are found in organisms ranging from bacteria to yeasts and plants, and also to animals. Their functions in higher animals likely include the regulation of cell volume, control of electrical excitability and trans-epithelial transport . Some members are plasma membrane Cl channels, while others are Cl/H exchangers .

The first member of the family (CLC-0) was expression-cloned from the electric organ of Torpedo marmorata , and subsequently nine CLC-like proteins have been cloned from mammals. They are thought to function as multimers of two or more identical or homologous subunits, and they have varying tissue distributions and functional properties. To date, CLC-0, CLC-1, CLC-2, CLC-4 and CLC-5 have been demonstrated to form functional Cl-channels; whether the remaining isoforms do so is either contested or unproven. One possible explanation for the difficulty in expressing activatable Cl-channels is that some of the isoforms may function as Cl-channels of intracellular compartments, rather than of the plasma membrane. However, they are all thought to have a similar transmembrane (TM) topology, initial hydropathy analysis suggesting 13 hydrophobic stretches long enough to form putative TM domains . Recently, the postulated TM topology has been revised, and it now seems likely that the CLCs have 10 (or possibly 12) TM domains, with both N-and C-termini residing in the cytoplasm .

A number of human disease-causing mutations have been identified in the genes encoding CLCs. Mutations in CLCN1, the gene encoding CLC-1, the major skeletal muscle Cl-channel, lead to both recessively and dominantly-inherited forms of muscle stiffness or myotonia . Similarly, mutations in CLCN5, which encodes CLC-5, a renal Cl-channel, lead to several forms of inherited kidney stone disease . These mutations have been demonstrated to reduce or abolish CLC function.

CLC-4 was initially identified as a putative member of the CLC family following mapping of the human Xp22.3 chromosome region . Together with CLC-5 and CLC-3, it forms a distinct branch of the CLC gene family. Initial expression studies of CLC-4 did not yield measurable Cl
-
currents; however, recent studies of human CLC-4 have revealed that it gives rise to Cl
-
currents that rapidly activate at positive voltages, and are sensitive to extracellular pH, with currents decreasing when pH falls below 6.5 .
Chloride channel ClC-5 (Cl_channel-5)
Type: Family

Chloride channels (CLCs) constitute an evolutionarily well-conserved family of voltage-gated channels that are structurally unrelated to the other known voltage-gated channels. They are found in organisms ranging from bacteria to yeasts and plants, and also to animals. Their functions in higher animals likely include the regulation of cell volume, control of electrical excitability and trans-epithelial transport . Some members are plasma membrane Cl channels, while others are Cl/H exchangers .

The first member of the family (CLC-0) was expression-cloned from the electric organ of Torpedo marmorata , and subsequently nine CLC-like proteins have been cloned from mammals. They are thought to function as multimers of two or more identical or homologous subunits, and they have varying tissue distributions and functional properties. To date, CLC-0, CLC-1, CLC-2, CLC-4 and CLC-5 have been demonstrated to form functional Cl-channels; whether the remaining isoforms do so is either contested or unproven. One possible explanation for the difficulty in expressing activatable Cl-channels is that some of the isoforms may function as Cl-channels of intracellular compartments, rather than of the plasma membrane. However, they are all thought to have a similar transmembrane (TM) topology, initial hydropathy analysis suggesting 13 hydrophobic stretches long enough to form putative TM domains . Recently, the postulated TM topology has been revised, and it now seems likely that the CLCs have 10 (or possibly 12) TM domains, with both N-and C-termini residing in the cytoplasm .

A number of human disease-causing mutations have been identified in the genes encoding CLCs. Mutations in CLCN1, the gene encoding CLC-1, the major skeletal muscle Cl-channel, lead to both recessively and dominantly-inherited forms of muscle stiffness or myotonia . Similarly, mutations in CLCN5, which encodes CLC-5, a renal Cl-channel, lead to several forms of inherited kidney stone disease . These mutations have been demonstrated to reduce or abolish CLC function.

CLC-5, with 746 amino acid residues, is a member of the CLC family that shows most similarity to the CLC-3 and CLC-4 channels, to which it is ~80% identical at the amino acid level. It is predominantly expressed in the kidney, but can be found in the brain and liver . As mentioned above, mutations in the CLCN5 gene cause certain hereditary kidney stone diseases, including Dent's disease, an X-chromosome linked syndrome characterised by proteinuria, hypercalciuria, and kidney stones (nephrolithiasis), leading to progressive renal failure. When the native protein is expressed, it gives rises to strongly outwardly-rectifying Cl
-
currents; however, the mutated channel forms show loss-of-function . Recent studies have suggested that CLC-5 may play an important role in endocytosis in renal proximal tubule cells (probably by providing a shunt for the potential generated by the H
+
-ATPase), and that disruption of this function may impair endocytosis, accounting for the proteinuria observed in Dent's disease .
Chloride channel ClC-6 (Cl_channel-6)
Type: Family

Chloride channels (CLCs) constitute an evolutionarily well-conserved family of voltage-gated channels that are structurally unrelated to the other known voltage-gated channels. They are found in organisms ranging from bacteria to yeasts and plants, and also to animals. Their functions in higher animals likely include the regulation of cell volume, control of electrical excitability and trans-epithelial transport . Some members are plasma membrane Cl channels, while others are Cl/H exchangers .

The first member of the family (CLC-0) was expression-cloned from the electric organ of Torpedo marmorata , and subsequently nine CLC-like proteins have been cloned from mammals. They are thought to function as multimers of two or more identical or homologous subunits, and they have varying tissue distributions and functional properties. To date, CLC-0, CLC-1, CLC-2, CLC-4 and CLC-5 have been demonstrated to form functional Cl-channels; whether the remaining isoforms do so is either contested or unproven. One possible explanation for the difficulty in expressing activatable Cl-channels is that some of the isoforms may function as Cl-channels of intracellular compartments, rather than of the plasma membrane. However, they are all thought to have a similar transmembrane (TM) topology, initial hydropathy analysis suggesting 13 hydrophobic stretches long enough to form putative TM domains . Recently, the postulated TM topology has been revised, and it now seems likely that the CLCs have 10 (or possibly 12) TM domains, with both N-and C-termini residing in the cytoplasm .

A number of human disease-causing mutations have been identified in the genes encoding CLCs. Mutations in CLCN1, the gene encoding CLC-1, the major skeletal muscle Cl-channel, lead to both recessively and dominantly-inherited forms of muscle stiffness or myotonia . Similarly, mutations in CLCN5, which encodes CLC-5, a renal Cl-channel, lead to several forms of inherited kidney stone disease . These mutations have been demonstrated to reduce or abolish CLC function.

CLC-6 (also known as H(+)/Cl(-) exchange transporter 6) is a CLC that, together with CLC-7, forms a distinct branch of the CLC gene family. CLC-6 consists of 869 amino acids residues (human isoform)
and is ~45% identical to CLC-7 (at the amino acid level). Analysis of human CLC-6 mRNAs reveals that transcripts of the encoding gene (CLCN6) are alternatively-spliced, resulting in the expression of four different CLC-6 isoforms (CLC-6a to CLC-6d). These show different levels of abundance and tissue distribution patterns, with one, CLC-6c, apparently being a kidney-specific isoform . The functionality of CLC-6 has been proven but its exact biophysical properties remain unknown . This protein seems to be mostly expressed in neurons of the central and peripheral nervous systems .
H(+)/Cl(-) exchange transporter 7 (CIC-7)
Type: Family

CLC-7 is a CLC that functions as antiporter and contributes to the acidification of the lysosome lumen and may be involved in maintaining lysosomal pH .

Chloride channels (CLCs) constitute an evolutionarily well-conserved family of voltage-gated channels that are structurally unrelated to the other known voltage-gated channels. They are found in organisms ranging from bacteria to yeasts and plants, and also to animals. Their functions in higher animals likely include the regulation of cell volume, control of electrical excitability and trans-epithelial transport . Some members are plasma membrane Cl channels, while others are Cl/H exchangers .

The first member of the family (CLC-0) was expression-cloned from the electric organ of Torpedo marmorata , and subsequently nine CLC-like proteins have been cloned from mammals. They are thought to function as multimers of two or more identical or homologous subunits, and they have varying tissue distributions and functional properties. To date, CLC-0, CLC-1, CLC-2, CLC-4 and CLC-5 have been demonstrated to form functional Cl-channels; whether the remaining isoforms do so is either contested or unproven. One possible explanation for the difficulty in expressing activatable Cl-channels is that some of the isoforms may function as Cl-channels of intracellular compartments, rather than of the plasma membrane. However, they are all thought to have a similar transmembrane (TM) topology, initial hydropathy analysis suggesting 13 hydrophobic stretches long enough to form putative TM domains . Recently, the postulated TM topology has been revised, and it now seems likely that the CLCs have 10 (or possibly 12) TM domains, with both N-and C-termini residing in the cytoplasm .

A number of human disease-causing mutations have been identified in the genes encoding CLCs. Mutations in CLCN1, the gene encoding CLC-1, the major skeletal muscle Cl-channel, lead to both recessively and dominantly-inherited forms of muscle stiffness or myotonia . Similarly, mutations in CLCN5, which encodes CLC-5, a renal Cl-channel, lead to several forms of inherited kidney stone disease . These mutations have been demonstrated to reduce or abolish CLC function.
Chloride channel ClC-K (Cl_channel-K)
Type: Family

Chloride channels (CLCs) constitute an evolutionarily well-conserved family of voltage-gated channels that are structurally unrelated to the other known voltage-gated channels. They are found in organisms ranging from bacteria to yeasts and plants, and also to animals. Their functions in higher animals likely include the regulation of cell volume, control of electrical excitability and trans-epithelial transport . Some members are plasma membrane Cl channels, while others are Cl/H exchangers .

The first member of the family (CLC-0) was expression-cloned from the electric organ of Torpedo marmorata , and subsequently nine CLC-like proteins have been cloned from mammals. They are thought to function as multimers of two or more identical or homologous subunits, and they have varying tissue distributions and functional properties. To date, CLC-0, CLC-1, CLC-2, CLC-4 and CLC-5 have been demonstrated to form functional Cl-channels; whether the remaining isoforms do so is either contested or unproven. One possible explanation for the difficulty in expressing activatable Cl-channels is that some of the isoforms may function as Cl-channels of intracellular compartments, rather than of the plasma membrane. However, they are all thought to have a similar transmembrane (TM) topology, initial hydropathy analysis suggesting 13 hydrophobic stretches long enough to form putative TM domains . Recently, the postulated TM topology has been revised, and it now seems likely that the CLCs have 10 (or possibly 12) TM domains, with both N-and C-termini residing in the cytoplasm .

A number of human disease-causing mutations have been identified in the genes encoding CLCs. Mutations in CLCN1, the gene encoding CLC-1, the major skeletal muscle Cl-channel, lead to both recessively and dominantly-inherited forms of muscle stiffness or myotonia . Similarly, mutations in CLCN5, which encodes CLC-5, a renal Cl-channel, lead to several forms of inherited kidney stone disease . These mutations have been demonstrated to reduce or abolish CLC function.

Two highly similar members of the CLC family have been cloned that appear to be kidney-specific isoforms. These are known as CLC-Ka and CLC-Kb in humans and are ~90% identical (at the amino acid level); in other species, they are named CLC-K1 and CLC-K2 . Within species, the two isoforms show differing distribution patterns in the kidney, possibly suggesting diferent roles in renal function. To date, attempts at functional expression of CLC-K isoforms have not yielded measurable Cl
-
currents; however, that they play a key role in normal kidney function had been made clear by the fact that naturally occurring mutations in the human gene CLCNKB (encoding CLC-Kb) lead to a form of Bartter's syndrome, an inherited kidney disease characterised by hypokalaemic alkalosis . Similarly, transgenic mice, whose CLC-K1 channel has been rendered dysfunctional by targeted gene disruption, develop overt diabetes, suggesting that these channels are important for urinary concentration .
Chloride channel ClC-plant (Cl_channel_pln)
Type: Family

Chloride channels (CLCs) constitute an evolutionarily well-conserved family of voltage-gated channels that are structurally unrelated to the other known voltage-gated channels. They are found in organisms ranging from bacteria to yeasts and plants, and also to animals. Their functions in higher animals likely include the regulation of cell volume, control of electrical excitability and trans-epithelial transport . Some members are plasma membrane Cl channels, while others are Cl/H exchangers .

The first member of the family (CLC-0) was expression-cloned from the electric organ of Torpedo marmorata , and subsequently nine CLC-like proteins have been cloned from mammals. They are thought to function as multimers of two or more identical or homologous subunits, and they have varying tissue distributions and functional properties. To date, CLC-0, CLC-1, CLC-2, CLC-4 and CLC-5 have been demonstrated to form functional Cl-channels; whether the remaining isoforms do so is either contested or unproven. One possible explanation for the difficulty in expressing activatable Cl-channels is that some of the isoforms may function as Cl-channels of intracellular compartments, rather than of the plasma membrane. However, they are all thought to have a similar transmembrane (TM) topology, initial hydropathy analysis suggesting 13 hydrophobic stretches long enough to form putative TM domains . Recently, the postulated TM topology has been revised, and it now seems likely that the CLCs have 10 (or possibly 12) TM domains, with both N-and C-termini residing in the cytoplasm .

A number of human disease-causing mutations have been identified in the genes encoding CLCs. Mutations in CLCN1, the gene encoding CLC-1, the major skeletal muscle Cl-channel, lead to both recessively and dominantly-inherited forms of muscle stiffness or myotonia . Similarly, mutations in CLCN5, which encodes CLC-5, a renal Cl-channel, lead to several forms of inherited kidney stone disease . These mutations have been demonstrated to reduce or abolish CLC function.

In plants, chloride channels contribute to a number of plant-specific functions, such as regulation of turgor, stomatal movement, nutrient transport and metal tolerance. By contrast with Cl
-
channels in animal cells, they are also responsible for the generation of action potentials. The best documented examples are the chloride channels of guard cells, which control opening and closing of stomata. Recently, four homologous proteins that belong to the CLC family have been cloned from Arabidopsis thaliana (Mouse-ear cress) . Hydropathy analysis suggests that they have a similar membrane topology to other CLC proteins, with up to 12 TM domains. Expression in Xenopus oocytes failed to generate measurable Cl
-
currents, although protein analysis suggested they had been synthesised and inserted into cell membranes. However, similar CLC proteins have since been cloned from other plants, and one, CIC-Nt1 (from tobacco), has been demonstrated to form funtional Cl
-
channels, suggesting that at least some of these proteins do function as Cl
-
channels in plants .
Glycoside hydrolase family 36 (Glyco_hydro_36)
Type: Family

O-Glycosyl hydrolases (

) are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycosyl hydrolases, based on sequence similarity, has led to the definition of 85 different families . This classification is available on the CAZy (CArbohydrate-Active EnZymes) website.

Glycoside hydrolase family 36 (

) occur in prokaryotes, eukaryotes, and archaea with a wide range of hydrolytic activities, including alpha-galactosidase, alpha-N-acetylgalactosaminidase, stachyose synthase, and raffinose synthase . All GH36 enzymes cleave a terminal carbohydrate moiety from a substrate that varies considerably in size, depending on the enzyme, and may be either a starch or a glycoprotein. GH36 members are retaining enzymes that cleave their substrates via an acid/base-catalyzed, double-displacement mechanism involving a covalent glycosyl-enzyme intermediate . Two aspartic acid residues have been identified as the catalytic nucleophile and the acid/base, respectively.

Proteins in this entry also include AgaSK, a bifunctional protein that contains two domains: one closely related to alpha-galactosidases from glycoside hydrolase family GH36 and the other containing a nucleotide-binding motif. It can hydrolyze melibiose and raffinose to galactose and either glucose or sucrose, respectively, and can specifically phosphorylate sucrose on the C6 position of glucose in the presence of ATP .
Flavin monooxygenase (FMO) 1 (Flavin_mOase_1)
Type: Family

Flavin-containing monooxygenases (FMOs) constitute a family of xenobiotic- metabolising enzymes . Using an NADPH cofactor and FAD prosthetic group, these microsomal proteins catalyse the oxygenation of nucleophilic nitrogen, sulphur, phosphorous and selenium atoms in a range of structurally diverse compounds. FMOs have been implicated in the metabolism of a number of pharmaceuticals, pesticides and toxicants. In man, lack of hepatic FMO-catalysed trimethylamine metabolism results in trimethylaminuria (fish odour syndrome). Five mammalian forms of FMO are now known and have been designated FMO1-FMO5 .

Human FMO1 mRNA is more abundant in foetal than in adult liver, indicating that the enzyme is subject to developmental regulation in man . The deduced amino sequence contains putative FAD- (GxGxxG) and NADP
+
-binding (GxGxxA) sites, a 'FATGY' motif that has also been observed in a range of siderphore biosynthetic enzymes , and a C-terminal hydrophobic segment that is believed to anchor the monooxygenase to the microsomal membrane . The human sequence shares 88 and 86% identity, respectively, with pig and rabbit 'hepatic' forms of FMO, but is only 58% similar to the abbit 'pulmonary' FMO .
Flavin monooxygenase (FMO) 2 (Flavin_mOase_2)
Type: Family

Flavin-containing monooxygenases (FMOs) constitute a family of xenobiotic- metabolising enzymes . Using an NADPH cofactor and FAD prosthetic group, these microsomal proteins catalyse the oxygenation of nucleophilic nitrogen, sulphur, phosphorous and selenium atoms in a range of structurally diverse compounds. Five mammalian forms of FMO are now known and have been designated FMO1-FMO5 .

Cavia porcellus (Guinea pig) and Oryctolagus cuniculus (Rabbit) both express two variants of 'lung' FMO, observed as three distinct phenotypes based on mobility differences in SDS-PAGE . The coding regions of the guinea pig variants differ at only two positions, both of which result in amino acid substitutions . Similarly, the nucleotide and amino acid sequences of the rabbit variants differ at only two positions. The amino sequence contains putative FAD- (GxGxxG) and NADP
+
- binding (GxGxxA) sites, a 'FATGY' motif that has also been observed in a range of siderphore biosynthetic enzymes , and a C-terminal hydrophobic segment that is believed to anchor the monooxygenase to the microsomal membrane . The activities of the enzymes are characteristic of the lung FMO, and the mobilities of the expressed enzymes are the same as those observed for the variants present in guinea pig pulmonary microsomal preparations . Both rabbit and guinea pig lung FMO are associated with a single gene. Rabbit lung FMO exists in tight association with the calcium-binding protein, calreticulin . It is thought that complexation of calreticulin with rabbit lung FMO could account for some of the unusual physical properties of this FMO enzyme form.
Flavin monooxygenase (FMO) 3 (Flavin_mOase_3)
Type: Family

Flavin-containing monooxygenases (FMOs) constitute a family of xenobiotic- metabolising enzymes . Using an NADPH cofactor and FAD prosthetic group, these microsomal proteins catalyse the oxygenation of nucleophilic nitrogen, sulphur, phosphorous and selenium atoms in a range of structurally diverse compounds. Five mammalian forms of FMO are now known and have been designated FMO1-FMO5 .

The mRNA encoding FMO3 is abundant in adult liver and is also present, in low abundance, in some foetal tissues. Thus, like FMO1, FMO3 is subject to developmental and tissue-specific regulation, with a developmental switch in the expression of the genes taking place in the liver . The deduced amino acid sequence of human FM03 includes the putative FAD- (GxGxxG) and NADP
+
pyrophosphate-binding (GxGxxA) sites characteristic of mammalian FMOs , a 'FATGY' motif that has also been observed in a range of siderphore biosynthetic enzymes , and a C-terminal hydrophobic segment that is believed to anchor the monooxygenase to the microsomal membrane . Mutations in human FMO3 impair N-oxygenation of xenobiotics and are responsible for the trimethylaminuria phenotype . Three disease-causing mutations have been identified. Nonsense and missense mutations are associated with a severe phenotype and are also implicated in impaired metabolism of other nitrogen- and sulphur-containing substrates, including biogenic amines, both clinically and when mutated proteins expressed from cDNA are studied in vitro . Human FMO3 thus plays a critical role in the metabolism of xenobiotic substrates and endogenous amines.