20.pi.biodegradation.10

20.pi.biodegradation.10 - Biodegradation Reactions Phase I...

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Unformatted text preview: Biodegradation Reactions Phase I Introduction to Biodegradation Reactions Cytochrome P450 Monooxygenases Examples of P450-Catalyzed Reactions Hydrolases Summary and Conclusions Oxidation I. Introduction to Biodegradation Reactions bonds. Reduction gain of electrons or loss of oxygen bonds. Hydrolysis reaction with water (a nucleophile). loss of electrons or gain of oxygen Role of Biodegradation in Homeostasis Homeostasis an organism's ability to maintain stable internal conditions although the outside world is continuously changing. Hepatic biodegradation maintains homeostasis during exposure to small foreign molecules (pesticides, drugs, etc.). Immune system maintains homeostasis during exposure to large foreign molecules (proteins, etc.) and small organisms (bacteria, viruses). General Strategy and Benefits Reactions often directly detoxify a chemical. Reactions usually increase water solubility of a chemical. II. Cytochrome P450 Monooxygenases Cytochrome P450 Reaction One oxygen atom is incorporated into the substrate, while the other oxygen atom is reduced to water. The electrons ultimately reduce one oxygen to water. 2 The electron donor is NADPH . Cytochrome P450 Reaction Mechanism At high O2 tensions both electrons are used to 2 reduce one oxygen atom into H O. At low O tensions both electrons are incorporated 2 into the substrate, thus reducing it. Other Oxidations Alcohol and aldehyde dehydrogenases oxidize alcohols (methanol, ethanol) to aldehydes (formaldehyde, acetaldehyde) then carboxylic acids (formic, acetic acids). Other Oxidations Flavin monooxygenases oxidize nucleophilic nitrogen, sulfur and phosphorous heteroatoms. Result is a coordinate covalent bond with oxygen. Designated by an arrow, but sometimes mistakenly by a double bond (since they have III. Examples of P450 Catalyzed Reactions Epoxidation results from addition of oxygen across a double bond. Unstable, it often results in an electrophilic carbocation. May covalently bond nucleic acids and proteins. May be deactivated by hydrolysis. Oxidative dealkylation reactions are common. Initiated by oxidation of a carbon adjacent to N, O or S. Results in dealkylation of the N, O or S. Examples Continued Examples Continued N oxidations are also common. Resultant Nhydroxy product can be first step in activation to electrophilic + nitrenium ion (N ). Examples Continued S and P oxidations are also common. Catalyzed by P450s, result is a coordinate covalent bond (an arrow). Both electrons from one atom contribute to the covalent bond giving it double-bond character. Examples Continued Reductions are catalyzed by P450s under low 2 O tensions. Instead of O 2 serving as the electron acceptor (to form water), the substrate does, and is thus Examples Continued Reductive dehalogenation is commonly catalyzed by either P450s or reductases (such as in microbes). Perchloroethylene is commonly reduced by microbes under anaerobic conditions to ethane or 2 IV. Hydrolases Catalyze nucleophilic substitution reactions involving H2O as the weak nucleophile. Also occur abiotically. Carboxylesterases act on carboxylic acid esters, thioesters, phosphoric acid esters and acid anhydrides. Amidases act on amides (or peptide bonds). Epoxide hydrolases act on aliphatic and aromatic Examples Continued Hydrolysis is one way electrophilic carbocations can be deactivated. Strong electrophiles, they easily react with water. Resulting product is a dihydrodiol. V. Summary and Conclusions There are three basic phase I reactions oxidation, reduction and hydrolysis. They are enzyme-catalyzed versions of the abiotic reactions. They usually both detoxify and increase water solubility. Enzymes in hepatic endoplasmic reticulum or cytosol. Oxidations catalyzed by P450s, FMOs or dehydrogenases. Reductions catalyzed by reductases or P450s 2 ...
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This note was uploaded on 06/29/2011 for the course GENETICS 101 taught by Professor Debrakimbrell during the Summer '09 term at UC Davis.

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20.pi.biodegradation.10 - Biodegradation Reactions Phase I...

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