Metabolism stereochemistry

Degraded Carotenoids Physical Methods Separation and Assay N.M.R. Spectroscopy Mass Spectrometry Chiroptical Methods Electronic Absorption Spectroscopy Infrared and Resonance Raman Spectroscopy Other Spectroscopic Techniques Miscellaneous Physical Chemistry Photoreceptor Pigments Biosynthesis and Metabolism Stereochemistry Enzyme Systems Inhibition and Regulation... 

Miscellaneous Spectroscopy and Physical Chemistry Photoreceptor Pigments Biosynthesis and Metabolism Stereochemistry Pathways... 

Vermeulen, N.P.E. and Breimer, D.D. (1983) Stereoselective drug and xenobiotic metabolism. Stereochemistry and Biological Activity of Drugs. Blackwell Scientific Publications, Oxford. 

Cahill, R., D. H. G. Crout, M. B. Mitchell, and U. S. Muller Isoleucine Biosynthesis and Metabolism Stereochemistry of the Formation of L-isoleucine and of its conversion into Senecic and Isatinecic Acids in Senecio Species. J. Chem. Soc., Chem. Commun. 1980, 419. 

Divalent sulfur compounds are achiral, but trivalent sulfur compounds called sulfonium stilts (R3S+) can be chiral. Like phosphines, sulfonium salts undergo relatively slow inversion, so chiral sulfonium salts are configurationally stable and can be isolated. The best known example is the coenzyme 5-adenosylmethionine, the so-called biological methyl donor, which is involved in many metabolic pathways as a source of CH3 groups. (The S" in the name S-adenosylmethionine stands for sulfur and means that the adeno-syl group is attached to the sulfur atom of methionine.) The molecule has S stereochemistry at sulfur ana is configurationally stable for several days at room temperature. Jts R enantiomer is also known but has no biological activity. 

One of the steps in fat metabolism is the hydration of crotonate to yield 3-hydroxybutvrate. The reaction occurs by addition of —OH to the Si face at CM, followed by protonation at C2, also from the Si face. Draw the product of the reaction, showing the stereochemistry of each step. 

Cerniglia CE, JR Althus, EE Evans, JP Freeman, RK Mitchum, SK Yang (1983) Stereochemistry and evidence for an arene oxide-NIH shift pathway in the fungal metabolism of naphthalene. Chem-Biol Interactions 44 119-132. 

It was shown that microsomal epoxide hydrolase-catalyzed trans-addition of water to BaP 9,10-epoxide occurs stereospecifically at the C-9 position (15). Since BaP is metabolized essentially to an optically pure 9R,10R-dihydrodiol (13 and L5 Table I), the 9,10-epoxide formed in BaP metabolism must have 9S,10R absolute stereochemistry (Figure 1). Similarly, the 7,8-epoxide formed in BaP metabolism is hydrated specifically at the C-8 position to form the 7R,8R-dihydrodiol (14.21). Hence the enzymatically formed 7,8-epoxide intermediate has 7R,8S absolute stereochemistry (Figure 1). Although the 7R,8R-dihydrodiol is formed almost exclusively from BaP metabolism in rat liver microsomes (Table I) and in bovine bronchial explants (25). the 7S,8S-dihydrodiol is also formed from BaP metabolism in mouse skin epidermis in vivo (5). 

Peroxyl radicals are the species that propagate autoxidation of the unsaturated fatty acid residues of phospholipids (50). In addition, peroxyl radicals are intermediates in the metabolism of certain drugs such as phenylbutazone (51). Epoxidation of BP-7,8-dihydrodiol has been detected during lipid peroxidation induced in rat liver microsomes by ascorbate or NADPH and during the peroxidatic oxidation of phenylbutazone (52,53). These findings suggest that peroxyl radical-mediated epoxidation of BP-7,8-dihydrodiol is general and may serve as the prototype for similar epoxidations of other olefins in a variety of biochemical systems. In addition, peroxyl radical-dependent epoxidation of BP-7,8-dihydrodiol exhibits the same stereochemistry as the arachidonic acid-stimulated epoxidation by ram seminal vesicle microsomes. This not only provides additional... 

Young, D. W., Stereochemistry of Metabolic Reactions of Amino Acids, 21, 381. 

K. H. Dudley, S. B. Roberts, Dihydropyrimidase. Stereochemistry of the Metabolism of Some 5-Alkylhydantoins. Drug Metab. Dispos. 1978, 6, 133-139. 

The possibility of nucleophilic attack on different carbons in the resonance-stabilized carbocation facilitates another modification exploited by nature during terpenoid metabolism. This is a change in double-bond stereochemistry in the allylic system. The interconversions of geranyl diphosphate, linalyl diphosphate, and neryl diphosphate provide neat but satisfying examples of the chemistry of simple allylic carbocations. 

Note that harsher conditions may lead to further changes, e.g. epimerization at C-3 in fmctose, plus isomerization, or even reverse aldol reactions (see Section 10.3). In general, basic conditions must be employed with care if isomerizations are to be avoided. To preserve stereochemistry, it is usual to ensure that free carbonyl groups are converted to acetals or ketals (glycosides, see Section 12.4) before basic reagents are used. Isomerization of sugars via enediol intermediates features prominently in the glycolytic pathway of intermediary metabolism (see Box 10.1). 

Biosynthesis and Metabolism.—Pathways and Reactions. Two reviews of carotenoid biosynthesis discuss, respectively, the early steps and the later reactions." The former paper deals with the mechanism of formation of phytoene and the series of desaturation reactions by which phytoene is converted into lycopene, and also describes in detail the biosynthesis of bacterial C30 carotenoids. The second paper" presents details of the mechanism and stereochemistry of cyclization and the other reactions that involve the carotenoid C-1 —C-2 double bond and the later modifications, especially the introduction of oxygen functions. 

Metabolic transformations are characterized by high speed and yield, as well as high regio-, diastereo-and enantio-specificity. Errors in the stereochemistry of the molecules that serve to construct the genetic material are smaller than for the planetary motions. With secondary metabolites, however, enantiomerically inq)ure con unds are also encoimtered, typkally with monoterpenes and alkaloids from terrestrial plants even ant dal pathways in the same organism have been found, albeit as rare events (Guella 1998). 

The importance of the stereochemistry of the nitrosamine function in the mutagenicity and carcinogenicity of these compounds has not been demonstrated and yet there is considerable indirect evidence that such a stereochemical dependence may be important. It is evident that the metabolism can be related to a stereochemical factor for unsyrametrical nitrosamines. These, of course, give either of two oxygenated metabolites, and there is evidence that only one of these is mutagenic in some cases (23, 24). Thus, the metabolism may be at least regiospecific, if not stereospecific, relative to the nitrosamine function. 

Minor changes in the stereochemistry and substitution pattern of the steran skeleton result in vastly different yet specific physiological and pharmacological effects, which in turn influence developmental, metabolic, and behavioral phenomena. The organic chemistry and biochemistry of steroids is the subject of many excellent books and an enormous amount of research and patent literature. This chapter compares and contrasts the structure and mode of action of various steroids, their role in regulating hormonal secretion, and the timing of this regulatory action. 

Thus the partition coefficient, the stereochemistry, and the functional groups present on a molecule may all influence the particular metabolic transformation, which takes place, and these factors are discussed in more detail later. 

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