21.pii.biodegradation.10

21.pii.biodegradation.10 - Biodegradation Reactions Phase...

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Unformatted text preview: Biodegradation Reactions Phase II Introduction Glycosylation Sulfation Methylation Acetylation (Acylation) Amino Acid Conjugation Glutathione (Peptide) Conjugation Summary and Conclusions I. Introduction to Phase II Reactions Cofactors (biomolecules) of phase II enzymes react with xenobiotic functional groups (from phase I processes). Reactions greatly increase water solubility to further enhance chemical elimination. They also commonly detoxify a xenobiotic. Phase II reactions are often faster than phase I reactions. Three General Mechanisms Type I = reaction of a xenobiotic with a highenergy cofactor (glycosylation, sulfation, methylation, acetylation). xenobiotic + activated cofactor conjugated agent II = reaction of an activated xenobiotic with a cofactor (amino acid conjugation). activated xenobiotic + cofactor conjugated agent III = naturally reactive xenobiotic reacts with a cofactor (glutathione conjugation). Type Type II. Glycosylation (Type I) The major detoxification pathway of all organisms except cats. Cofactor: uridine diphosphate-glucuronic acid (UDP-glucuronic acid). Catalyzed by UDP-glucuronosyl transferases; energized by UTP. Location: microsomes of liver, kidney, intestine, skin, brain, spleen, and nasal mucosa. Vertebrates use glucuronic acid, invertebrates use glucose. UDPGA UTP + glucose-1 phosphate UDP-glucose + PPi UDP-glucose + 2 NAD + H2O UDPGA + 2 NADH2 UDPGA Examples of Glycosylation Site of glycosylation is an electron-rich nucleophilic heteroatom (O, N, S) on a xenobiotic. Conjugates are polar, water-soluble, and eliminated in urine (<254 dal) or bile (>254 dal). III. Sulfation (Type I) Nucleophilic attack of O or N of a xenobiotic with electrophilic S in 3'-phosphoadenosine-5"phosphosulfate (PAPS). Catalyzed by sulfotransferases, energized by ATP. Conjugates are mainly excreted in the urine (<254 dal). ATP + sulfate adenosine pyrophosphate + PPi adenosine pyrophosphate + ATP PAPS + ADP PAPS Examples of Sulfation Sulfation is a highaffinity, but lowcapacity process. Glycosylation is a low-affinity, but high capacity process. Acetaminophen at low doses undergoes sulfation Acetaminophen at high doses undergoes glycosylation. IV. Methylation (Type I) A common but minor pathway decreases water solubility. Nucleophilic attack of an electron-rich heteroatom (O, N, S) on an electrophilic methyl carbon. Cofactor: S-adenosyl methionine (SAM), energized by ATP. Functional groups are alcohols, amines, etc. Catalyzed by methyl transferases microsomes or cytosol. L-methionine + ATP SAM Examples of Methylation V. Acetylation (Acylation; Type I) 2 The major route for aromatic amines (R-NH ), 3 converted to amides (R-NH-COCH ). 2 The major route for hydrazines (R-NH-NH ), 3 converted to hydrazides (R-NH-NH-COCH ). Catalyzed by N-acetyl transferases, energized by Acetyl CoA ATP. VI. Amino Acid Conjugation (Type II) Conjugation of carboxylic acids with amines of amino acids such as glycine, glutamine and taurine. Substrate (not cofactor) is energized by ATP. Glutathione VII. Glutathione Conjugation (Type III) conjugates electrophilic xenobiotics. Nucleophilic attack of GS- onto an electrophilic C atom (also on electrophilic O, N, S heteroatoms). Cofactor: glutathione (glycine, glutamic acid, cysteine). Enzyme: glutathione S-transferases. Glutathione Conjugation Substrates are hydrophobic, contain strongly electrophilic atoms and can react nonenzymatically with GSH. GSTs increase reaction rate by de-protonating GSH GS-. GSTs and GSH account for 10% of total cellular proteins (GSH in erythrocytes). Conjugates are excreted via bile or converted to mercapturic acids to be excreted in urine. GSH Conjugation Reaction Types GSH displaces electronwithdrawing group such as a halide, sulfate, phosphate, nitro group, or sulfonate (all good leaving groups). GSH can also add to an activated double bond or strained ring facilitated by a nearby electronwithdrawing group (CN, -CHO, -COOR Mercapturic Acid Synthesis GSH first conjugates the xenobiotic. Glutamate is cleaved off. Glycine is cleaved off. The remaining cysteine conjugate is acetylated. The mercapturic acid (N-acetyl cysteine) conjugate Summary of Conjugation Processes VIII. Summary and Conclusions There are six basic phase II biodegradation reactions. Reactions occur only in biological systems. Reactions require cofactors, are enzyme catalyzed and require energy (i.e. ATP, UTP, or GTP). Reactions serve to detoxify and increase water solubility. Enzymes are in the hepatic endoplasmic reticulum or cytosol. ...
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21.pii.biodegradation.10 - Biodegradation Reactions Phase...

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