Phase II of biotransformation is concerned with conjugation, that is using groups from cofactors to react with functional groups present or introduced from phase I on the compound. The enzymes involved are a set of transferases which perform the transfer of the cofactor group to the substrate. The resultant conjugation results in greatly increasing the excretory potential of compounds. Although most conjugations result in pharmacological inactivation or detoxification, some can result in bioactivation. Most of the phase II enzymes are located in the cytosol except UDP-glucuronosyltransferases (UGT), which are microsomal. Phase II reactions are typically much faster than phase I reactions therefore the rate-limiting step for biotransformation of a compound is usually the phase I reaction. Phase II metabolism can deal with all the products of phase I metabolism, be they reactive (Type I substrate) or unreactive/poorly active (Type II substrate) compounds. With the exception of glutathione, the conjugating species needs to be made chemically reactive after synthesis. The availability of the cofactor in the synthesis may be a rate-limiting factor in some phase II pathways as it may prevent the formation of enough conjugating species to deal with the substrate or it's metabolite. As many substrates and/or their metabolites are chemically reactive, their continued presence may lead to toxicity.
View original pathway at:Reactome.
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Reiter C, Mwaluko G, Dunnette J, Van Loon J, Weinshilboum R.; ''Thermolabile and thermostable human platelet phenol sulfotransferase. Substrate specificity and physical separation.''; PubMedEurope PMCScholia
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Glatt H.; ''Sulfotransferases in the bioactivation of xenobiotics.''; PubMedEurope PMCScholia
Bosma PJ, Seppen J, Goldhoorn B, Bakker C, Oude Elferink RP, Chowdhury JR, Chowdhury NR, Jansen PL.; ''Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man.''; PubMedEurope PMCScholia
Falany CN, Krasnykh V, Falany JL.; ''Bacterial expression and characterization of a cDNA for human liver estrogen sulfotransferase.''; PubMedEurope PMCScholia
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Vessey DA, Lau E, Kelley M, Warren RS.; ''Isolation, sequencing, and expression of a cDNA for the HXM-A form of xenobiotic/medium-chain fatty acid:CoA ligase from human liver mitochondria.''; PubMedEurope PMCScholia
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Fieger CB, Sassetti CM, Rosen SD.; ''Endoglycan, a member of the CD34 family, functions as an L-selectin ligand through modification with tyrosine sulfation and sialyl Lewis x.''; PubMedEurope PMCScholia
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Dupret JM, Grant DM.; ''Site-directed mutagenesis of recombinant human arylamine N-acetyltransferase expressed in Escherichia coli. Evidence for direct involvement of Cys68 in the catalytic mechanism of polymorphic human NAT2.''; PubMedEurope PMCScholia
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Li X, Anderson RJ.; ''Sulfation of iodothyronines by recombinant human liver steroid sulfotransferases.''; PubMedEurope PMCScholia
Mungrue IN, Pagnon J, Kohannim O, Gargalovic PS, Lusis AJ.; ''CHAC1/MGC4504 is a novel proapoptotic component of the unfolded protein response, downstream of the ATF4-ATF3-CHOP cascade.''; PubMedEurope PMCScholia
Griffith OW, Bridges RJ, Meister A.; ''Evidence that the gamma-glutamyl cycle functions in vivo using intracellular glutathione: effects of amino acids and selective inhibition of enzymes.''; PubMedEurope PMCScholia
LeGros HL, Halim AB, Geller AM, Kotb M.; ''Cloning, expression, and functional characterization of the beta regulatory subunit of human methionine adenosyltransferase (MAT II).''; PubMedEurope PMCScholia
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Castonguay R, Halim D, Morin M, Furtos A, Lherbet C, Bonneil E, Thibault P, Keillor JW.; ''Kinetic characterization and identification of the acylation and glycosylation sites of recombinant human gamma-glutamyltranspeptidase.''; PubMedEurope PMCScholia
Sakakibara Y, Suiko M, Pai TG, Nakayama T, Takami Y, Katafuchi J, Liu MC.; ''Highly conserved mouse and human brain sulfotransferases: molecular cloning, expression, and functional characterization.''; PubMedEurope PMCScholia
Ritter JK, Chen F, Sheen YY, Tran HM, Kimura S, Yeatman MT, Owens IS.; ''A novel complex locus UGT1 encodes human bilirubin, phenol, and other UDP-glucuronosyltransferase isozymes with identical carboxyl termini.''; PubMedEurope PMCScholia
Tang L, Singh R, Liu Z, Hu M.; ''Structure and concentration changes affect characterization of UGT isoform-specific metabolism of isoflavones.''; PubMedEurope PMCScholia
van Haren MJ, Sastre Toraño J, Sartini D, Emanuelli M, Parsons RB, Martin NI.; ''A Rapid and Efficient Assay for the Characterization of Substrates and Inhibitors of Nicotinamide N-Methyltransferase.''; PubMedEurope PMCScholia
Knop JK, Hansen RG.; ''Uridine diphosphate glucose pyrophosphorylase. IV. Crystallization and properties of the enzyme from human liver.''; PubMedEurope PMCScholia
Girard JP, Baekkevold ES, Amalric F.; ''Sulfation in high endothelial venules: cloning and expression of the human PAPS synthetase.''; PubMedEurope PMCScholia
Polekhina G, Board PG, Gali RR, Rossjohn J, Parker MW.; ''Molecular basis of glutathione synthetase deficiency and a rare gene permutation event.''; PubMedEurope PMCScholia
Fuda H, Lee YC, Shimizu C, Javitt NB, Strott CA.; ''Mutational analysis of human hydroxysteroid sulfotransferase SULT2B1 isoforms reveals that exon 1B of the SULT2B1 gene produces cholesterol sulfotransferase, whereas exon 1A yields pregnenolone sulfotransferase.''; PubMedEurope PMCScholia
West MB, Wickham S, Quinalty LM, Pavlovicz RE, Li C, Hanigan MH.; ''Autocatalytic cleavage of human gamma-glutamyl transpeptidase is highly dependent on N-glycosylation at asparagine 95.''; PubMedEurope PMCScholia
Teramoto T, Fujikawa Y, Kawaguchi Y, Kurogi K, Soejima M, Adachi R, Nakanishi Y, Mishiro-Sato E, Liu MC, Sakakibara Y, Suiko M, Kimura M, Kakuta Y.; ''Crystal structure of human tyrosylprotein sulfotransferase-2 reveals the mechanism of protein tyrosine sulfation reaction.''; PubMedEurope PMCScholia
Kerr SC, Fieger CB, Snapp KR, Rosen SD.; ''Endoglycan, a member of the CD34 family of sialomucins, is a ligand for the vascular selectins.''; PubMedEurope PMCScholia
Javitt NB, Lee YC, Shimizu C, Fuda H, Strott CA.; ''Cholesterol and hydroxycholesterol sulfotransferases: identification, distinction from dehydroepiandrosterone sulfotransferase, and differential tissue expression.''; PubMedEurope PMCScholia
Carrithers SL, Hoffman JL.; ''Sequential methylation of 2-mercaptoethanol to the dimethyl sulfonium ion, 2-(dimethylthio)ethanol, in vivo and in vitro.''; PubMedEurope PMCScholia
Jakobsson PJ, Mancini JA, Ford-Hutchinson AW.; ''Identification and characterization of a novel human microsomal glutathione S-transferase with leukotriene C4 synthase activity and significant sequence identity to 5-lipoxygenase-activating protein and leukotriene C4 synthase.''; PubMedEurope PMCScholia
Zhou Y, Zheng J, Li Y, Xu DP, Li S, Chen YM, Li HB.; ''Natural Polyphenols for Prevention and Treatment of Cancer.''; PubMedEurope PMCScholia
Radominska A, Comer KA, Zimniak P, Falany J, Iscan M, Falany CN.; ''Human liver steroid sulphotransferase sulphates bile acids.''; PubMedEurope PMCScholia
Rossjohn J, McKinstry WJ, Oakley AJ, Verger D, Flanagan J, Chelvanayagam G, Tan KL, Board PG, Parker MW.; ''Human theta class glutathione transferase: the crystal structure reveals a sulfate-binding pocket within a buried active site.''; PubMedEurope PMCScholia
Kamiyama S, Sasaki N, Goda E, Ui-Tei K, Saigo K, Narimatsu H, Jigami Y, Kannagi R, Irimura T, Nishihara S.; ''Molecular cloning and characterization of a novel 3'-phosphoadenosine 5'-phosphosulfate transporter, PAPST2.''; PubMedEurope PMCScholia
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
Cytosolic, non-specific peptidase (CNDP2) can hydrolyse cysteinylglycine (CysGly) to release cysteine (L-Cys) and glycine (Gly) (Tuefel et al. 2003). CNDP2 is functional as a homodimer and requires 2 Mn2+ ion per subunit.
Glutathione is exported out of the cell to be made available for membrane-bound gamma-glutamyl transpeptidases (GGTs). Cells that have GGTs can utilize translocated glutathione. The exact transport mechanism is uncertain (Griffith and Meister, 1979; Griffith et al, 1979).
Gamma-glutamylcyclotransferase (GGCT) homodimer (Bae et al. 2008) catalyses the formation of 5-oxoproline from gamma-glutamylcysteine (gGluCys), therby playing a role in glutathione homeostasis (Oakley et al. 2008).
5-oxoprolinase catalyzes the cleavage of 5-oxoproline to form L-glutamate, coupled to the hydrolysis of ATP to ADP and inorganic phosphate (Chen et al, 1998).
The hydrolysis product of glutathione, cysteinylglycine (CysGly) is transported back into the cell to replenish the precursor resevoir for the resynthesis of glutathione. The exact mechanism of uptake is unknown (Griffith et al. 1978).
Cytosolic sulfotransferase 1A1 (SULT1A1), in dimeric form, can sulfonate the widely used analgesic and antipyretic drug paracetamol (PARA aka acetaminophen). Around 20-30% of PARA is metabolised via sulfonation by the liver (Parkinson 1995, Yamazoe et al. 1995, Strott 2002).
Methylation is the major biotransformation route of thiopurine drugs such as 6-mercaptopurine (6MP), used in the treatment of inflammatory diseases such as rheumatoid arthritis and childhood acute lymphoblastic leukemia. 6MP and its thioguanine nucleotide metabolites are principally inactivated by thiopurine methyltransferase (TPMT)-catalysed S-methylation.
Defects in TPMT can cause thiopurine S methyltransferase deficiency (TPMT deficiency; MIM:610460). Patients with intermediate or no TPMT activity are at risk of toxicity such as myelosuppression after receiving standard doses of thiopurine drugs. Inter individual differences in response to these drugs are largely determined by genetic variation at the TPMT locus. TPMT exhibits an autosomal co dominant phenotype: About one in 300 people in Caucasian, African, African-American, and Asian populations are TPMT deficient. Approximately 6-10% of people in these populations inherit intermediate TPMT activity and are heterozygous at the TPMT locus. The rest are homozygous for the wild type allele and have high levels of TPMT activity. (Remy 1963, Weinshilboum et al. 1999, Couldhard & Hogarth 2005, Al Hadithy et al. 2005, Azimi et al. 2014).
N-acetylation occurs in two sequential steps via a ping-pong Bi-Bi mechanism. In the first step, the acetyl group from acetyl-CoA is transferred to a conserved cysteine residue (position 68) in the active site of NAT, with consequent release of coenzyme-A. In the second step, the acetyl group is transferred to the acceptor substrate and the enzyme returns to its initial state.
At the beginning of this reaction, 1 molecule of 'PAPS', and 1 molecule of 'Phenol' are present. At the end of this reaction, 1 molecule of 'Phenyl sulfate', and 1 molecule of 'PAP' are present.
This reaction takes place in the 'cytosol' and is mediated by the 'aryl sulfotransferase activity' of 'SULT1A1 homodimer'.
N-hydroxy-4-aminobiphenyl (NHABP) is a genotoxic metabolite of an industrial carcinogen no longer used in the rubber industry. It can be sulfonated in the liver by cytosolic sulfotransferase 1A1 (SULT1A1) (Yamazoe et al. 1999, Weinshilboum et al. 1997, Strott 2002).
The principal conjugate of bilirubin in bile is bilirubin diglucuronide (BDG). The monomeric forms of UGT1A1 (Bilirubin UDP-glucuronyltransferase 1) only conjugates the first step of bilirubin conjugation to form the monoglucuronide. A tetrameric form of UGT1A1 can transfer glucuronic acid (GlcA) to bilirubin (BIL) and bilirubin monoglucuronide (BMG) to form both the monoglucuronide and the diglucuronide (BDG) conjugates respectively (Peters & Jansen 1986, Gorden et al. 1983, Choudhury et al. 1981, Fevery et al. 1971). UGT1A4 is also able to catalyse the formation of BDG (Ritter et al. 1992).
Bilirubin (BIL) is a breakdown product of heme. Its accumulation in the blood can be fatal. It is highly lipophilic and thus requires conjugation to become more water soluble to aid excretion. Both UGT1A1 and 4 can transfer glucuronic acid (GlcA) to bilirubin to form either its monoglucuronide (BMG) or diglucuronide (BDG) conjugates (Bosma et al. 1994, Ritter et al. 1992). Mutations of the UGT1A1 gene cause complete loss or partial activity for bilirubin glucuronidation.
The catecholamine neurotransmitter dopamine (DA) is predominantly (>95%) conjugated with sulfate (dopamine 3-O-sulfate, DAOS) in human blood circulation. Human SULT1A3 and SULT1A4 are the major sulfotransferases that sulfonate DA (as well as other catecholamines and phenols) (Reiter et al. 1983, Johnson et al. 1980, Thomae et al. 2003, Hildebrandt et al. 2004).
Benzoate and ATP react with coenzyme A to form benzoyl CoA, AMP, and pyrophosphate (Vessey et al. 1999, 2003). Two human CoA ligases have been characterized that catalyze this reaction efficiently in vitro: acyl-CoA synthetase medium-chain family member 1 (BUCS1) (Fujino et al. 2001) and xenobiotic/medium-chain fatty acid:CoA ligase (Vessey et al. 2003). Their relative contributions to benzoate metabolism in vivo are unknown.
Salicylate and ATP react with coenzyme A to form salicylate CoA, AMP, and pyrophosphate in a reaction catalyzed by xenobiotic/medium-chain fatty acid:CoA ligase (Vessey et al. 2003).
UDP-glucose dehydrogenase (UGDH) catalyzes the conversion of UDP-glucose to UDP-glucuronic acid. The cytosolic enzyme is active as a hexamer and performs two successive oxidations to convert the 6'-hydroxyl of UDP-glucose to a carboxylate with concurrent reduction of 2 mol of NAD+ to NADH.
The first step in the formation of glutathione is the ligation of glutamate with cysteine, catalysed by the dimeric protein glutamate-cysteine ligase, GCL (Gipp et al. 1995, Misra & Griffith 1998).
The UDP-glucuronic acid/UDP-N-acetylgalactosamine transporter (SLC35D1) in hexameric form transports both UDP-glucuronic acid (UDP-GlcA) and UDP-N-acetylgalactosamine (UDP-GalNAc) from the cytosol into the ER lumen across the ER membrane (Muraoka et al. 2001). These substrates participate in glucuronidation and/or chondroitin sulfate biosynthesis.
A methyl group from 5-methyltetrahydrofolate is transferred to homocysteine (HCYS) via a meCbl intermediate, forming methionine (L-Met) (Leclerc et al. 1996).
In the second step of PAPS biosynthesis, adenylyl sulfate (APS) is phosphorylated to 3'-phosphoadenylyl sulfate (PAPS), catalyzed by the APS kinase domains of the bifunctional enzymes PAPS synthases 1 and 2 (PAPSS1 and 2). PAPSS2 is essential for the sulfation of glycosaminoglycan chains of proteoglycans, a necessary post-translational modification. Defective PAPSS2 results in undersulfation of proteoglycans which causes spondyloepimetaphyseal dysplasia Pakistani type (SEMD-PA; MIM:612847), a bone disease characterized by epiphyseal dysplasia with mild metaphyseal abnormalities. Mutations resulting in SEMD-PA include S438*, T48R and R329* (Ahmad et al. 1998, ul Haque et al. 1998, Noordam et al. 2009).
S-adenosylmethionine (AdoMet, SAM) is an essential metabolite in all cells. AdoMet is a precursor in the synthesis of polyamines. Methionine adenosyltransferases (MAT) catalyse the only known AdoMet biosynthetic reaction from methionine (L-Met) and ATP. In mammalian tissues, three different forms of MAT (MAT I, MAT III and MAT II) have been identified that are the product of two different genes (MAT1A and MAT2A). MAT1A binds 1 K+ and 2 Mg2+ (or Co2+, not shown here) in tetrameric or dimeric form (Corrales et al. 2002, Mato et al. 1997).
In the first step of PAPS biosynthesis, ATP and sulfate react to form adenylyl sulfate (APS) and pyrophosphate (PPi), catalyzed by the ATP sulfurylase domains of the bifunctional enzymes PAPS synthases 1 and 2 (PAPSS1 and 2). PAPSS2 is essential for the sulfation of glycosaminoglycan chains in proteoglycans, a necessary post translational modification. Defective PAPSS2 results in undersulfation of the glycosaminoglycan chains in proteoglycans which causes spondyloepimetaphyseal dysplasia Pakistani type (SEMD PA; MIM:612847), a bone disease characterized by epiphyseal dysplasia with mild metaphyseal abnormalities. Mutations resulting in SEMD PA include S438*, T48R and R329* (Ahmad et al. 1998, ul Haque et al. 1998, Noordam et al. 2009).
In the second step in the formation of glutathione, gamma-glutamylcysteine (gGluCys) ligates with glycine (Gly) to form glutathione (GSH) (Gali & Board 1995). This reaction is catalysed by glutathione synthetase (GSS), a homodimeric enzyme present in the cytosol which requires one Mg2+ cofactor per subunit for activity (Polekhina et al. 1999).
Adenosylhomocysteinase (AHCY) is a tetrameric, NAD+-bound, cytosolic protein that regulates all adenosylmethionine-(AdoMet) dependent transmethylations by hydrolysing the feedback inhibitor adenosylhomocysteine (AdoHcy) to homocysteine (HCYS) and adenosine (Ade-Rib) (Turner et al. 1998, Yang et al. 2003).
Typical O-centred substrates were chosen as examples for these isozymes. Many UDP-glucuronosyltransferases (UGTs) can transfer the glucuronyl moiety (GlcA) from UDP-GlcA to the O-centre functional group of many substrates to form 4-O-glucuronides (Casarett & Doull 1995, Babu et al. 1996).
N-acetylation occurs in two sequential steps via a ping-pong Bi-Bi mechanism. In the first step, the acetyl group from acetyl-CoA is transferred to a conserved cysteine residue (position 68) in the active site of NAT, with consequent release of coenzyme-A. In the second step, the acetyl group is transferred to the acceptor substrate and the enzyme returns to its initial state.
Typical NAT 1 substrates were chosen as examples. They are sulfanilamide, 4-aminosalicylate, 4-aminobenzoate and N-hydroxy 4-aminobiphenyl (Hong et al. 2017).
The glutathione S-transferases (GSTs) catalyze the nucleophilic attack by reduced glutathione (GSH) on nonpolar compounds that contain an electrophilic carbon, nitrogen, or sulphur atom. Their substrates include halogenonitrobenzenes, arene oxides, quinones, and alpha, beta-unsaturated carbonyls. Three major families of proteins are widely distributed in nature. Two of these, the cytosolic and mitochondrial GST, comprise soluble enzymes that are only distantly related whilst the third family comprises microsomal GST, referred to as membrane-associated proteins in eicosanoid and glutathione (MAPEG) metabolism.
At least 16 cytosolic GST subunits exist in human which are all in a dimeric form. Based on amino acid sequence similarities, seven classes of cytosolic GST are recognized in mammalian species; Alpha, Mu, Pi, Sigma, Theta, Omega, and Zeta (2–5). As well as being homodimers, the Alpha and Mu classes are also able to form heterodimers so a large number of isozymes are possible from all cytosolic GST subunits (Sinning et al. 1993, LeTrong et al. 2002, Ahmad et al. 1993, Pastore et al. 1998, Tars et al. 2010, Bruns et al. 1999, Balogh et al. 2010, Morel et al. 2002, Li et al. 2005, Patskovsky et al. 2006, Raghunathan et al. 1994, Patskovsky et al. 1999, Comstock et al. 1994, Board et al. 2000, Zhou et al. 2011, Zhou et al. 2012, Sun et al. 2011, Tars et al. 2006, Rossjohn et al. 1998, Polekhina et al. 2001, Inoue et al. 2003). Typical electrophilic substrates are chosen as examples for which the majority of the cytosolic GST isozymes act on.
The microsomal glutathione S-transferases (MGSTs) catalyse the nucleophilic attack by reduced glutathione (GSH) on nonpolar compounds that contain an electrophilic C, N, or S atom. Three major families of proteins are widely distributed in nature. The cytosolic and mitochondrial GST families comprise soluble enzymes that are only distantly related whilst the third family comprises microsomal GST, referred to as membrane-associated proteins in eicosanoid and glutathione (MAPEG) metabolism. Three members of this family function as detoxification enzymes, MGST1-3 (DeJong et al. 1988, Kelner et al. 1996, Jakobsson et al. 1996, Jakobsson et al. 1997). Electron crystallography studies in rat Mgst1 indicate these enzymes function as homotrimers (Holm et al. 2002). Both aflatoxin B1 exo- and endo-epoxides (AFXBO and AFNBO) conjugate with glutathione. These conjugates are eventually excreted in urine as mercapturic acids.
Six SULT enzymes, SULT1A1 (Li et al. 2001), 1A3 (Kester, Kaptein et al. 1999), 1B1 (Wang et al. 1998), 1C1 (Li et al. 2000), 1E1 (Li and Anderson 1999; Kester, van Dijk et al. 1999), and 2A1 (Li and Anderson 1999), can catalyze the sulfonation of 3,3'-diiodothyronine (T2) in vitro or in tissue culture model systems. These six enzymes also catalyze the sulfonation of 3,5,3'-triiodothyronine (T3).
The sulfonation of pregnenolone (PREG) is catalyzed by both the a and b isoforms of SULT2B1, although the a isoform is more active in assays in vitro (Fuda et al. 2002; Meloche and Falany 2001).
3,5,3'-Triiodothyronine (T3) 4-sulfate is a major metabolite of T3 in humans (LoPresti and Nicoloff 1994), and seven SULT enzymes, SULT1A1 (Li et al. 2001), 1A3 (Kester, Kaptein et al. 1999), 1B1 (Wang et al. 1998), 1C1 (Li et al. 2000), 1E1 (Li and Anderson 1999; Kester, van Dijk et al. 1999), 2A1 (Li and Anderson 1999), and 4A1 (Sakakibara et al. 2002) can catalyze this reaction in vitro or in tissue culture model systems. All of these enzymes except SULT4A1 also catalyze the sulfonation of 3,3'-diiodothyronine (T2).
PAP is generated as a byproduct of sulfonation reactions in vivo; its hydrolysis to AMP and orthophosphate returns its constituents to the pool of molecules available for cytosolic nucleotide metabolism. Bisphosphate 3'-nucleotidase 1catalyzes this reaction efficiently in vitro; whether other nucleotidases also play a role in PAP breakdown in vivo is unknown.
The 3-hydroxyl groups of a number of sterols can undergo sulfonation. Cholesterol sulfate is particularly abundant in the body, and may have both regulatory and biosynthetic functions (Strott and Higashi 2003). Its synthesis is catalyzed by the b isoform of SULT2B1 (Fuda et al. 2002; Javitt et al. 2001).
Sulfonation of dehydroepiandrosterone (DHEA) is catalyzed by SULT1E1 (Aksoy et al. 1994), SULT2A1 (Radominska et al. 1990) and the a and b isoforms of SULT2B1 (Meloche and Falany 2001).
The sulfonation of the xenobiotic p-nitrophenol (4-nitrophenol) can be catalyzed by five well-characterized SULT enzymes, 1A1 (Brix et al. 1998), 1A2 (Brix et al. 1998; Zhu et al. 1996), 1C2 (Sakakibara et al. 1998), and 4A1 (Sakakibara et al. 2002).
Sulfonation of estrone is catalyzed by SULT1E1 (Aksoy et al. 1994; Falany et al. 1995), and also by SULT2A1 (Comer et al. 1993), although the efficiency of SULT2A1 catalysis is unknown.
Sulfonation of the xenobiotic N-hydroxy-2-acetylaminofluorene converts it to a potent carcinogen. SULT1A2 (Glatt 2000) and SULT1C1 and 1C2 (Sakakibara et al. 1998) catalyze this reaction.
Phenylacetate and ATP react with coenzyme A to form phenylacetyl CoA, AMP, and pyrophosphate (Vessey et al. 1999). Two human CoA ligases have been characterized that catalyze this reaction efficiently in vitro: acyl-CoA synthetase medium-chain family member 1 (BUCS1) (Fujino et al. 2001) and xenobiotic/medium-chain fatty acid:CoA ligase (Vessey et al. 2003). Their relative contributions to phenylacetate metabolism in vivo are unknown.
Phenylacetyl CoA and glutamine react to form phenylacetyl glutamine and Coenzyme A. The enzyme that catalyzes this reaction has been purified from human liver mitochondria and shown to be a distinct polypeptide species from glycine-N-acyltransferase (Webster et al. 1976). This human glutamine-N-acyltransferase activity has not been characterized by sequence analysis at the protein or DNA level, however, and thus cannot be associated with a known human protein in the annotation of phenylacetate conjugation.
Glutathione S-transferase Kappa isozyme (GSTK1) is widely expressed in human tissues and exists as a dimer in mitochondria and peroxisomes. It has high activity towards aryl halides such as the model substrate 1-chloro-2,4-dinitrobenzene (CDNB) to which it can conjugate with glutathionate (GS-) from glutathione (GSH) (Morel et al. 2004). Mouse, rat and human possess only one GST Kappa isozyme.
The SLC26A1 and 2 genes encode proteins that facilitate sulfate (SO4(2-)) uptake into cells (Alper & Sharma 2013). The mechanism by which these transporters work is unclear but may be enhanced by extracellular halides or acidic pH environments, cotransporting protons electroneutrally. Both can transport SO4(2-) (as well as oxalate and Cl-) across the basolateral membrane of epithelial cells. SLC26A1 encodes the sulfate anion transporter 1 (SAT1) (Regeer et al. 2003) and is most abundantly expressed in the liver and kidney, with lower levels expressed in many other parts of the body. SLC26A2 is ubiquitously expressed and encodes a sulfate transporter (Diastrophic dysplasia protein, DTD, DTDST) (Hastbacka et al. 1994). This transporter provides sulfate for sulfation of glycosaminoglycan chains in proteoglycans needed for cartilage development. Defects in SLC26A2 are implicated in the pathogenesis of several human chondrodysplasias.
S-adenosylmethionine (AdoMet, SAM) is an essential metabolite in all cells. AdoMet is a precursor in the synthesis of polyamines. Methionine adenosyltransferases (MAT) catalyse the only known AdoMet biosynthetic reaction from methionine (L-Met) and ATP. In mammalian tissues, three different forms of MAT (MAT I, MAT III and MAT II) have been identified that are the product of two different genes (MAT1A and MAT2A). A third gene, MAT2B has been identified and its protein product is known to associate as a regulatory subunit with catalytic MAT2A (LeGros et al. 2000, Halim et al. 1999).
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).
S-formylglutathione hydrolase (ESD, esterase D) is a homodimeric enzyme in the ER lumen of red blood cells that can hydrolyse S-formylglutathione (S-FGSH) to glutathione (GSH) and formate (Hopkinson et al. 1973, Eiberg & Mohr 1986). It is also able to hydrolyse 4-methylumbelliferyl acetate (not shown here).
Mycophenolic acid (MPA) is the active metabolite of the immunosuppressant drug mycophenolate mofetil (MMF) and is primarily metabolised by glucuronidation to a phenolic glucuronide (MPAG) and an acyl glucuronide (AMPAG), a potential immunotoxic metabolite. Mitochondrial mycophenolic acid acyl-glucuronide esterase (ABHD10) deglucuronidates AMPAG thereby ABHD10 could play a role in the protection against acyl glucuronide-induced toxicity (Iwamura et al. 2012).
Alpha/beta hydrolase domain-containing protein 14B (ABHD14B) can hydrolyse the model substrate p-nitrophenyl butyrate (PNPB) to p-nitrophenol (PNP) and butyric acid (BUT) (Padmanabhan et al. 2004). Its physiological substrate is unknown.
Arsenic is a groundwater contaminant and methylation is an important reaction in its biotransformation. The arsenite(3-) salt form can be methylated by arsenite methyltransferase (AS3MT), transfering a methyl group from the high energy donor S-adenosyl-L-methionine (AdoMet) (Wood et al. 2006). Methylarsonite is also a substrate and it is converted into the much less toxic compound dimethylarsinate (cacodylate).
Arsenic is a groundwater contaminant and methylation is an important reaction in its biotransformation. The arsenite(3-) salt form can be methylated by arsenite methyltransferase (AS3MT), transfering a methyl group from the high energy donor S-adenosyl-L-methionine (AdoMet) (Wood et al. 2006). Methylarsonite is also a substrate and it is converted into the much less toxic compound dimethylarsinate (cacodylate).
Glutathione S-transferase omega-1 (GSTO1 aka monomethylarsonic acid reductase, MMA(V) reductase) is a bifunctional enzyme that has glutathione S-transferase activity and also takes part in the biotransformation of inorganic arsenic. It mediates the reduction of methylarsonate to methylarsonite (Zakharyan et al. 2001).
Glutathione-specific gamma-glutamylcyclotransferases 1 and 2 (CHAC1 and 2) catalyse the specific cleavage of glutathione (GSH) into 5-oxoproline (OPRO) and a cysteinylglycine (CysGly) dipeptide. GSH acts a redox buffer in cells and its depletion is an important factor for apoptosis, oxidative stress and progression of cancer. CHAC1 and 2 act as proapototic agents with implications for human health and disease (Mungrue et al. 2009, Crawford et al. 2015).
Inorganic arsenic (iAs) compounds are human carcinogens. The most toxic arsenic metabolite is monomethylarsonous acid (MMAIII). Arsenic (3+) methyltransferase (AS3MT) is the primary enzyme responsible for methylating MMAIII to the less toxic dimethylarsonic acid (DMAA). A human ortholog of yeast MTQ2, HemK methyltransferase family member 2 (aka N(6)-adenine-specific DNA methyltransferase 1, N6AMT1), is also able to methylate MMAIII using S-adenosyl L-methionine as methyl donor (Ren et al. 2011). N6AMT1 forms a heterodimer with multifunctional methyltransferase subunit TRM112-like protein (TRMT112) (Figaro et al. 2008).
Cytosolic UDP-glucose pyrophosphorylase 2 (UGP2) catalyzes the reaction of UTP and glucose 1-phosphate to form UDP glucose and pyrophosphate (Knop and Hansen 1970; Duggleby et al. 1996). UGP2 is inferred to occur in the cell as a homooctamer from studies of its bovine homologue (Levine et al. 1969).
The human gene SLC35B2 encodes the adenosine 3'-phospho 5'-phosphosulfate transporter 1 (PAPST1) (Ozeran et al. 1996, Kamiyama et al. 2003). In human tissues, PAPST1 is highly expressed in the placenta and pancreas and present at lower levels in the colon and heart. The human gene SLC35B3 encodes a human PAPS transporter gene that is closely related to PAPST1. Called PAPST2, it is predominantly expressed in the colon (Kamiyama et al. 2006). Both proteins can transport PAPS from the cytosol to the Golgi lumen.
At the beginning of this reaction, 1 molecule of 'H+', 1 molecule of '6-Methylmercaptopurine', 1 molecule of 'Oxygen', and 1 molecule of 'NADPH' are present. At the end of this reaction, 1 molecule of 'NADP+', 1 molecule of '6-Mercaptopurine', 1 molecule of 'Formaldehyde', and 1 molecule of 'H2O' are present.
This reaction takes place in the 'smooth endoplasmic reticulum' and is mediated by the 'oxygen binding activity' of 'Cytochrome P450 1A2 '.
Isoflavones are a class of dietary polyphenols called phytoestrogens which are found in soy and soy foods, alfalfa sprouts and red clover. They possess biological activities ranging from anticancer to cardiovascular protective effects (Zhou et al. 2016). Despite their health claims, making these compounds into chemo-preventive or chemo-therapeutic agents is complicated by their low bioavailabilities (<5%), the result of extensive first-pass metabolism by phase II enzymes including UGTs and SULTs (Hu 2007). Four UDP-glucuronosyltransferase 1A (UGT1A) isoforms share the responsibility of metabolising various isoflavones. UGT1A10 is mainly expressed in the intestine and is located on the ER membrane of these cells. It can transfer the glucuronyl moiety from UDP-GlcA to the isoflavone glycitein (GCTN) to form glycitein 4-O-glucuronide (GCTN4OG) (Tang et al. 2009).
GGT (gamma-glutamyl transpeptidase) dimers associated with the plasma membrane (Hanigan & Frierson 1996) hydrolyze extracellular glutathione (GSH) to form cysteinylglycine (CysGly) and glutamate (L-Glu). GGT1 has been extensively characterized. The active dimeric form of the enzyme is generated by autohydrolysis (West et al. 2011) and in vitro can catalyze both the reaction of GSH with water annotated here, and the reaction of GSH with a free amino acid or dipeptide to generate a gamma-glutamyl-amino acid and cysteinylglycine (Castonguay et al. 2007; Pawlak et al. 1989; Tate & Ross 1977; Thompson & Meister 1976). Based on amino acid sequence similarity, Heisterkamp et al. (2008) identified five additional dimeric proteins, GGT2, 3P, 5, 6, and 7, likely to catalyze the same reactions. West et al. (2013), however, found that GGT2 had no catalytic activity in vitro.
Sulfur is an essential element in all lifeforms used in the synthesis of sulfur-containing amino acids, maintenance of cellular redox states and detoxifying toxic compounds. 3'-phosphoadenosine 5'-phosphosulfate (PAPS) is the active form of sulfur used in these reactions, which consume PAPS, producing 3'-phosphoadenosine 5'-phosphate (PAP). PAP is degraded to 5′-AMP (AMP) by 3′-nucleotidase family. Mammals encode two 3′-nucleotidases, the Golgi-resident inositol monophosphatase 3 (IMPAD3 aka PAP phosphatase, gPAPP) and the cytosolic bisphosphate 3′-nucleotidase 1 (BPNT1, described in its own reaction). Both require Mg2+ as cofactor and both are inhibited by lithium (Hudson et al. 2013).
Podocalyxin-like protein 2 (PODXL2 aka endoglycan) acts as a ligand for vascular selectins which mediate the rapid rolling of leukocytes over vascular surfaces. PODXL2 interacts with selectins through sulfation on two tyrosine residues (97 and 118) (Fieger et al. 2003, Kerr et al. 2008) and O-linked carbohydrate structures within its acidic amino-terminal region (latter not shown here). Protein-tyrosine sulfotransferases 1 and 2 (TPST1 and TPST2) are Golgi membrane-resident proteins which catalyse the transfer of sulfate from 3'-phospho-5'-adenylyl sulfate (PAPS) to tyrosine residues within acidic motifs of polypeptides such as PODXL2 (Ouyang et al. 1998, Danan et al. 2008, Teramoto et al. 2013).
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Defects in TPMT can cause thiopurine S methyltransferase deficiency (TPMT deficiency; MIM:610460). Patients with intermediate or no TPMT activity are at risk of toxicity such as myelosuppression after receiving standard doses of thiopurine drugs. Inter individual differences in response to these drugs are largely determined by genetic variation at the TPMT locus. TPMT exhibits an autosomal co dominant phenotype: About one in 300 people in Caucasian, African, African-American, and Asian populations are TPMT deficient. Approximately 6-10% of people in these populations inherit intermediate TPMT activity and are heterozygous at the TPMT locus. The rest are homozygous for the wild type allele and have high levels of TPMT activity. (Remy 1963, Weinshilboum et al. 1999, Couldhard & Hogarth 2005, Al Hadithy et al. 2005, Azimi et al. 2014).
This reaction takes place in the 'cytosol' and is mediated by the 'aryl sulfotransferase activity' of 'SULT1A1 homodimer'.
At least 16 cytosolic GST subunits exist in human which are all in a dimeric form. Based on amino acid sequence similarities, seven classes of cytosolic GST are recognized in mammalian species; Alpha, Mu, Pi, Sigma, Theta, Omega, and Zeta (2–5). As well as being homodimers, the Alpha and Mu classes are also able to form heterodimers so a large number of isozymes are possible from all cytosolic GST subunits (Sinning et al. 1993, LeTrong et al. 2002, Ahmad et al. 1993, Pastore et al. 1998, Tars et al. 2010, Bruns et al. 1999, Balogh et al. 2010, Morel et al. 2002, Li et al. 2005, Patskovsky et al. 2006, Raghunathan et al. 1994, Patskovsky et al. 1999, Comstock et al. 1994, Board et al. 2000, Zhou et al. 2011, Zhou et al. 2012, Sun et al. 2011, Tars et al. 2006, Rossjohn et al. 1998, Polekhina et al. 2001, Inoue et al. 2003). Typical electrophilic substrates are chosen as examples for which the majority of the cytosolic GST isozymes act on.
(Padmanabhan et al. 2004). Its physiological substrate is unknown.
This reaction takes place in the 'smooth endoplasmic reticulum' and is mediated by the 'oxygen binding activity' of 'Cytochrome P450 1A2 '.