Search results for PAH

Showing 14 results out of 14

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Protein (2 results from a total of 2)

PAH

Identifier: R-HSA-71066
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: PAH: P00439
Identifier: R-HSA-5649486
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: PAH: P00439

Complex (2 results from a total of 2)

Identifier: R-HSA-9631879
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-71068
Species: Homo sapiens
Compartment: cytosol

Reaction (6 results from a total of 6)

Identifier: R-HSA-5649483
Species: Homo sapiens
Compartment: cytosol
Inactivating mutations of cytosolic phenylalanine hydroxylase (PAH) block the normal reaction of phenylalanine, molecular oxygen and tetrahydrobiopterin to form tyrosine, water, and 4 alpha-hydroxytetrahydrobiopterin. Excess phenylalanine accumulates as a result, driving the formation of abnormally high levels of phenylpyruvate, and phenyllactate (Guldberg et al. 1996; Mitchell et al. 2011) in reactions not annotated here.
Identifier: R-HSA-5692232
Species: Homo sapiens
Compartment: cytosol
Polycyclic aromatic hydrocarbons (PAHs) are pro-carcinogens which require further metabolic activation to ellicit their harmful effects. Aldo-keto reductases (AKRs) such as alcohol dehydrogenase [NADP+] (AKR1A1) can catalyse the oxidation of proximate carcinogenic PAH trans-dihydrodiols to reactive and redox active PAH o-quinones. Redox-cycling of PAH o-quinones generate reactive oxygen species and subsequent oxidative DNA damage. The proximate PAH carcinogen benzo[a]pyrene-7,8-trans-dihydrodiol (BaPtDHD) is oxidised by AKR1A1 to yield BaP-7,8-catechol which is unstable and auto-oxidises to yield BaP-7,8-dione (Zhang et al. 2012).
Identifier: R-HSA-71118
Species: Homo sapiens
Compartment: cytosol
Inactivating mutations of cytosolic phenylalanine hydroxylase (PAH) block the normal reaction of phenylalanine, molecular oxygen and tetrahydrobiopterin to form tyrosine, water, and 4 alpha-hydroxytetrahydrobiopterin. Excess phenylalanine accumulates as a result, driving the formation of abnormally high levels of phenylpyruvate, and phenyllactate (Guldberg et al. 1996; Mitchell et al. 2011) in reactions not annotated here.
Identifier: R-HSA-561041
Species: Homo sapiens
Compartment: plasma membrane
The human gene SLC22A6 encodes organic anion transporter1 (OAT1). It was originally characterized in mouse as Novel Kidney Transcript (NKT). OAT1 is located on the basolateral membrane of the proximal tubule in human kidney as well as in the brain (Reid G et al, 1998; Lu R et al, 1999; Hosoyamada M et al, 1999). The human gene SLC22A7 encodes organic anion transporter 2 (OAT2) and is highly expressed in the liver and kidney (Sun W et al, 2001; Kobayashi Y et al, 2005). The human gene SLC22A8 encodes organic anion transporter 3 (OAT3) which is expressed mainly in the brain and kidney (Race JE et al, 1999; Bakhiya A et al, 2003).
OAT1-3 transport organic anions such as p-aminohippurate and drugs such as cimetidine and acyclovir. This transport is is coupled with an efflux of one molecule of endogenous dicarboxylic acid such as alpha-ketoglutarate (2-oxoglutarate). OAT2 is classified as both a transporter of organic anions and sulphate conjugates.
Identifier: R-HSA-8936849
Species: Homo sapiens
Compartment: cytosol
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that can control the expression of a diverse set of genes. Two major types of environmental compounds can activate AHR signaling: halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and polycyclic aromatic hydrocarbons (PAH) such as benzo(a)pyrene. Unliganded AHR forms a complex in the cytosol with two copies of 90kD heat shock protein (HSP90AB1) (Forsythe et al. 2001), one X-associated protein (AIP) (Meyer et al. 1998), and one p23 molecular chaperone protein (PTGES3) (Nguyen et al. 2012, Beischlag et al. 2008). Here, the binding of TCDD is shown.
Identifier: R-HSA-9670620
Species: Homo sapiens
Compartment: nucleoplasm
DAXX mutations identified in cancer are frequently nonsense and frameshift mutations that result in premature protein truncation. Mutant DAXX proteins are frequently lost or mis-localized and are usually undetectable in the nucleus. DAXX contains an ATRX-binding region that maps to PAH domains of DAXX, PAH1 and PAH2, which are located in the N-terminal portion of DAXX. At least the PAH1 domain is needed for binding to ATRX, and a recombinant construct consisting of amino acids 1-160 of DAXX, which includes the PAH1 domain, is able to bind to ATRX, but the binding is stronger if PAH2 domain is also included (if the recombinant DAXX construct consists of amino acids 1-260) (Tang et al. 2004). Minimally, amino acids 55-144 are required for DAXX binding to ATRX (Wang et al. 2017). All DAXX truncation mutants in which the stop codon occurs upstream of the amino acid 144 are annotated as candidate loss-of-function mutants. These include the following nonsense mutants:
DAXX K56*
DAXX E104*
DAXX C106*
DAXX S138*.
DAXX frameshift mutants in which the frameshift occurs upstream of the codon 144 are also annotated as candidates:
DAXX H26Tfs*118
DAXX A36Qfs*108
DAXX R48Vfs*93
DAXX E72Nfs*72
DAXX C74*
DAXX L98Vfs*13
DAXX A103Sfs*40.
Missense mutants of DAXX have not been functionally tested in the context of the full-length protein, just in the context of the DAXX fragment that consists of amino acids 55-144 (Wang et al. 2017) and are not shown here.

Chemical Compound (2 results from a total of 2)

Identifier: R-ALL-561068
Compartment: extracellular region
Primary external reference: ChEBI: p-aminohippuric acid: 104011
Identifier: R-ALL-561038
Compartment: cytosol
Primary external reference: ChEBI: 104011

Pathway (2 results from a total of 2)

Identifier: R-HSA-2160456
Species: Homo sapiens
Phenylalanine hydroxylase (PAH) normally catalyzes the conversion of phenylalanine to tyrosine. In the absence of functional PAH, phenylalanine accumulates to high levels in the blood and is converted to phenylpyruvate and phenyllactate (Clemens et al. 1990; Langenbeck et al. 1992; Mitchell et al. 2011). The extent of these conversions is modulated by genetic factors distinct from PAH, as siblings with the identical PAH defect can produce different amounts of them (Treacy et al. 1996).

Both L-amino acid oxidase (Boulland et al. 2004) and Kynurenine--oxoglutarate transaminase 3 (Han et al. 2004) can catalyze the conversion of phenylalanine to phenylpyruvate and lactate dehydrogenase can catalyze the conversion of the latter molecule to phenyllactate (Meister 1950), in reactions not annotated here.

Identifier: R-HSA-8937144
Species: Homo sapiens
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that belongs to the basic helix-loop-helix/PER-ARNT-SIM family of DNA binding proteins and controls the expression of a diverse set of genes. Two major types of environmental compounds can activate AHR signaling: halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and polycyclic aromatic hydrocarbons (PAH) such as benzo(a)pyrene. Unliganded AHR forms a complex in the cytosol with two copies of 90kD heat shock protein (HSP90AB1), one X-associated protein (AIP), and one p23 molecular chaperone protein (PTGES3). After ligand binding and activation, the AHR complex translocates to the nucleus, disassociates from the chaperone subunits, dimerises with the aryl hydrocarbon receptor nuclear translocator (ARNT) and transactivates target genes via binding to xenobiotic response elements (XREs) in their promoter regions. AHR targets genes of Phase I and Phase II metabolism, such as cytochrome P450 1A1 (CYP1A1), cytochorme P450 1B1 (CYP1B1), NAD(P)H:quinone oxidoreductase I (NQO1) and aldehyde dehydrogenase 3 (ALHD3A1). This is thought to be an organism's response to foreign chemical exposure and normally, foreign chemicals are made less reactive by the induction and therefore increased activity of these enzymes (Beischlag et al. 2008).

AHR itself is regulated by the aryl hydrocarbon receptor repressor (AHRR, aka BHLHE77, KIAA1234), an evolutionarily conserved bHLH-PAS protein that inhibits both xenobiotic-induced and constitutively active AHR transcriptional activity in many species. AHRR resides predominantly in the nuclear compartment where it competes with AHR for binding to ARNT. As a result, there is competition between AHR:ARNT and AHRR:ARNT complexes for binding to XREs in target genes and AHRR can repress the transcription activity of AHR (Hahn et al. 2009, Haarmann-Stemmann & Abel 2006).
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