20.PII.Biodegradation.11

20.PII.Biodegradation.11 - Biodegradation Reactions –...

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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) via phase II enzymes fuse with xenobiotic functional groups (from phase I processes) Greatly increase water solubility to further enhance chemical elimination 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 activated cofactor (glycosylation, sulfation, methylation, acetylation): xenobiotic + activated cofactor conjugated agent Type II = reaction of an activated xenobiotic with a cofactor (amino acid conjugation): activated xenobiotic + cofactor conjugated agent Type III = both are naturally reactive (glutathione conjugation): reactive xenobiotic + reactive cofactor conjugated agent II. Glycosylation (Type I) The major detoxification pathway of all organisms except cats Cofactor: UDP-glucuronic acid (energized by UTP) Catalyzed by UDP-glucuronosyl transferases Location: microsomes of liver, kidney, intestine, skin, brain, etc. 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) 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, low-capacity process Glycosylation is a low-affinity, high capacity process Acetaminophen at low doses undergoes sulfation Acetaminophen at high doses undergoes glycosylation IV. Methylation (Type I) A 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 Major route for aromatic amines (R-NH ), converted 3 to amides (R-NH-COCH ) 2 Major route for hydrazines (R-NH-NH ), converted 3 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 is energized by ATP Glutathione 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) Enzymes: glutathione S-transferases VII. Glutathione Conjugation (Type III) 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, or sulfonate (good leaving groups) GSH also adds to an activated double bond or strained ring facilitated by a nearby electronwithdrawing group (–CN, -CHO, -COOR Mercapturic Acid Synthesis GSH first conjugates xenobiotic Glutamate and glycine are cleaved off Remaining cysteine conjugate is acetylated The mercapturic acid (N-acetyl cysteine) conjugate is excreted in urine Summary of Conjugation Processes VIII. Summary and Conclusions There are six phase II biodegradation reactions Reactions occur only in biological systems Require cofactors, are enzyme catalyzed and require energy (i.e. ATP, UTP or GTP) Serve to detoxify and increase water solubility Enzymes are in the hepatic endoplasmic reticulum or cytosol ...
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This note was uploaded on 03/10/2011 for the course ETX 102A taught by Professor Ronaldtjeerdema during the Winter '10 term at UC Davis.

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20.PII.Biodegradation.11 - Biodegradation Reactions –...

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