Steroids oxidation, biochemical

Kitada, M., T. Kamataki, K. Itahashi, T. Rikihisa, and Y. Kanakubo (1987). Significance of cytochrome P-450 (P-450 HFLa) of human fetal livers in the steroid and drug oxidations. Biochem. Pharmacol. 36, 453—456. 

Bishop, G., Nomura, T., Yokota, T, Montoya, T., Castle, J., Harrison, K., Kushiro, T., Kamiya, Y, Yamaguchi, S., Bancos, S., Szatmari, A.M., and Szekeres, M. 2006. Dwarfism and cytochrome P450-mediated C-6 oxidation of plant steroid hormones. Biochem Soc Trans 34 1199-1201. 

Open-chain 1,5-polyenes (e.g. squalene) and some oxygenated derivatives are the biochemical precursors of cyclic terpenoids (e.g. steroids, carotenoids). The enzymic cyclization of squalene 2,3-oxide, which has one chiral carbon atom, to produce lanosterol introduces seven chiral centres in one totally stereoselective reaction. As a result, organic chemists have tried to ascertain, whether squalene or related olefinic systems could be induced to undergo similar stereoselective cyclizations in the absence of enzymes (W.S. Johnson, 1968, 1976). 

Recent syntheses of steroids apply efficient strategies in which open-chain or monocyclic educts with appropiate side-chains are stereoselectively cyclized in one step to a tri- or tetracyclic steroid precursor. These procedures mimic the biochemical synthesis scheme where acyclic, achiral squalene is first oxidized to a 2,3-epoxide containing one chiral carbon atom and then enzymatically cyclized to lanostetol with no less than seven asymmetric centres (W.S. Johnson, 1%8, 1976 E.E. van Tamden, 1968). 

The synthesis of triterpenoid saponins from the skeletons shown in Fig. 2 involves a series of further modifications that may include a variety of different oxidation and substitution events [9]. Very little is known about the enzymes and genes involved in the elaboration of the triterpenoid skeleton, although genetic and biochemical analysis of saponin-deficient mutants of plants is likely to accelerate the dissection of these processes [16]. Progress has been made in the characterisation of saponin glucosyltransferases (primarily for steroidal and steroidal alkaloid saponins), and the first of these enzymes (StSGT from potato) has been cloned. Since glycosylation at the C-3 hydroxyl position confers am-... 

A number of oxidation reactions of mono- and difluorosteroid compounds has been reported. In some reactions, the specific influence of a fluoro substituent on the reactivity has been observed the presence of a 9a-fluorine in a 11 /i-hydroxy-A4-3-oxo steroid causes completely stcreospecific alkaline epoxidation with hydrogen peroxide in a much slower reaction (4d vs 4 h) in comparison with the nonfluorinated analog.322 Most oxidations are accomplished by the highest selective biochemical (that is, by bacterial enzymatic) transformations. As the biochemical oxidation systems are not discussed in this section, only a list of selected transformations of steroids is presented in Table 21. For additional information see ref 323. 

Silva CM, Cidlowski JA. The effect of oxidation/reduction on the charge heterogeneity of the human glucocorticoid receptor. J Steroid Biochem Mol Biol 1992 41 1-10. 

Corvazier, E. and Maclouf, J. 1985. Interference of some flavonoids and non-steroidal antiinflammatory drugs with oxidative metabolism of arachidonic acid by human platelets and neutrophils. Biochem. Biophys. Acta 835, 315-321. 

Figure 16.4 Biosynthesis of various classes of steroid hormones. Reaction (A) is catalyzed by a cholesterol desmolase, which oxidizes the cholesterol side chain. Reactions (D) are catalyzed by 21-hydroxylases, which are defective in congenital adrenal hyperplasia. (Reproduced by permission from Schwarz V. A Clinical Companion to Biochemical Studies. Reading Freeman, 1978, p. 94.)...

I aradve microbial oxidations have long been practiced in organic synthesis, perhq>s most prominently in the steroidal field, and a number of comprehensive and specialized reviews have appeared. The most recent review, publi ed in 1981, covers most aspects of biochemical oxidations, and gives an ex-... 

Secondary steroidal alcohols react in preference to primary allylic alcohols in biochemical oxidations usingJihizopus arrhizus and Helicostylum piriforme or Cunninghamella blakesleeana. However, the reaction is complicated by hydroxylations in positions 6 (with Rhizopus arrhizus) and 9 (with Helicostylum piriforme or Cunninghamella blakesleeana) [1059]. 

The Baeyer-Villiger reaction is also effected by biochemical oxidation using the enzyme cyclohexanone oxygenase from Acinetobacter strain NCIB 9871. Cyclohexanone is thus converted into e-caprolactone [1043], and phenylacetone (l-phenyl-2-propanone) is transformed into benzyl acetate. The formation of benzyl acetate from phenylacetone involves the same migration as that in oxidation with peroxytrifluoroacetic acid (equation 387) [1034]. More examples of biochemical Baeyer-Villiger reactions occur in diketones and steroids see equation 397). 

Oxidations of steroidal keto alcohols to diketones are frequently accomplished biochemically. In addition, isomerization of double bonds, dehydrogenations, and hydroxylations often take place. 

Reversible acylation is important in biochemical reactions, and sulfur functions as an activator in many such processes. Coenzyme A (41) is an acyl group carrier which is involved in lipid oxidation and the biosynthesis of lipids and steroids. The active form of coenzyme A is the thiol ester (acyl coenzyme A) (42), which is more stable than coenzyme A (41) and hence functions as an efficient acyl group donor for a substrate RH (Scheme 26). 

As is the case for other steroids, the Hver is the primary site for the inactivation of estrogens. The main biochemical reactions are hydroxylation, oxidation, reduction, and methylation. Conjugation with glucuronic or sulfuric acid, which imparts more water solubility to these steroids and thus allows them to be eliminated rapidly through the... 

Snyder, G.D., Holmes, R.W., Bates, J.N., and Van Voorhis, B.J. (1996). Nitric oxide inhibits aromatase activity Mechanisms of action. J. Steroid Biochem. Molec. Biol. 58 63-69. 

Toell, A., Kroncke, K. D., Kleinert, H., and Carlberg, C. (2002) Orphan nuclear receptor binding site in the human inducible nitric oxide synthase promoter mediates responsiveness to steroid and xenobiotic ligands. J. Cell Biochem. 85, 72-82. 

Roy D, Bernhardt A, Strobel H, et al. Catalysis of the oxidation of steroid and stilbene estrogens to estrogen quinone metabolites by the 3-naphthotlavone-inducible cytochrome P450 1A family. Arch Biochem Biophys 1992 296 450-456. 

Brassinosteroids (BRs) are highly oxidized steroidal plant hormones and essential for normal plant growth. BR deficient mutants display strong dwarfism with curly, dark-green leaves in the light, and a deetiolated phenotype with short hypocotyl and open cotyledons in the dark. The characterization of BR-deficient mutants by biochemical studies and molecular genetic analysis has established the biosynthetic pathway for brassinoHde (BL), the biochemically most active BR. 

---