Steroids, biosynthesis examples

An example is adrenodoxin reductase (see chapter banner, p. 764), which passes electrons from NADPH to cytochrome P450 via the small redox protein adrenodoxin. This system functions in steroid biosynthesis as is indicated in Fig. 22-7.209a b Other flavin-dependent reductases have protective functions catalyzing the reduction of ascorbic acid radicals,210 211 toxic quinones,212-214 and peroxides.215-218... 

Enzymes involved in steroid biosynthesis have proved to be good targets, both for therapeutic intervention and for mechanism-based inactivators (2). Aromatase, for example, catalyzes the final, rate-limiting step in estrogen biosynthesis (Equation 17.55). Aromatase has proved susceptible to mechanism-based inhibitors such as formestane and ex-emestane. These are now both used in the treatment of breast cancer (210). 

Arthropoda.—Steroid biosynthesis seems to be absent from all of this phylum. Examples of the class Arachnida, Diplopoda, Crustacea, and Insecta have been examined. Steroid metabolism in insects has been reviewed. " It should be borne in mind that insects can synthesise some terpenoids [e.g. (32) and (46)], but there is an absolute dietary requirement for steroids. Phytosterols such as -sitosterol are converted back into cholesterol derivatives apparently by the reverse of side chain alkylation (86 R = Et) (85 R = CHMe)—> (85 R = CHj)— (84)— (74). In addition a A -double bond is introduced. Parasites, and other organisms naturally present, may contribute to some of these reactions. ... 

As in previous Reports this section is particularly concerned with non-vertebrate species and their ability to synthesize steroids from simple precursors. Further Protozoan studies have confirmed their ability to synthesize steroids. However, in the Porifera one species had this ability but another did not. Coelenter-ate examples again showed the absence of squalene or steroid biosynthesis. 

Cation-JT interactions are also prominent at the active sites of enzymes involving cationic substrates. Key examples include the blood coagulation serine proteases Factor Xa and thrombin, and a number of enzymes that use S-adenosyhnethionine. a sulfonium ion that serves as nature s ubiquitous methyl transfer agent. A spectacular series of examples is the array of enzymes that catalyze the cationic cyclizations of polyenes in a key step of terpene and steroid biosynthesis. It is now clear that... 

Powerful support for any biosynthetic pathway as well as detailed information on the reactions involved may be gained by isolation, purification and characterization of enzymes which will catalyse individual steps of biosynthesis. A number of examples are quoted in succeeding chapters. The most notable are associated with the polyketide synthetases (Section 3.2) and enzymes of steroid biosynthesis (Sections 4.2 and 4.4). 

During the course of steroid biosynthesis, conjugation of the molecule can influence its metabolism both quantitatively or qualitatively. Conjugation can direct a molecule into a certain type of metabolism rather than into another quantitatively for example, in the case of de-... 

Furthermore, attention must be drawn to the part played by squalene epoxide (2) as an initiator of steroid biosynthesis in eukaryotes. Antibiotics with oxirane rings, for example, oleandomycine, have also been isolated. 

Carbonyl condensation reactions are widely used in synthesis. One example of their versatility is the Robinson anuulation reaction, which leads to the formation of an substituted cyclohexenone. Treatment of a /3-diketone or /3-keto ester with an a,/3-unsaturated ketone leads first to a Michael addition, which is followed by intramolecular aldol cyclization. Condensation reactions are also used widely in nature for the biosynthesis of such molecules as fats and steroids. 

Processes of this kind are important in the biosynthesis of steroids and tetra- and pentacyclic terpenes. For example, squalene 2,3-oxide is converted by enzymatic catalysis to dammaradienol. 

Polyene cyclizations are of substantial value in the synthesis of polycyclic terpene natural products. These syntheses resemble the processes by which the polycyclic compounds are assembled in nature. The most dramatic example of biosynthesis of a polycyclic skeleton from a polyene intermediate is the conversion of squalene oxide to the steroid lanosterol. In the biological reaction, an enzyme not only to induces the cationic cyclization but also holds the substrate in a conformation corresponding to stereochemistry of the polycyclic product.17 In this case, the cyclization is terminated by a series of rearrangements. 

Alternative, also stereoselective, routes to allenic steroids take advantage of cationic cyclization reactions [108] or [2,3]-sigmatropic rearrangements [109]. For example, the allenic Michael acceptor 112 was prepared with 57% chemical yield by reaction of mestranol (111) with diethyl chlorophosphite and was found to inhibit the sterol biosynthesis of the pathogen responsible for Pneumocystis carinii pneumonia (PCP), the most abundant AIDS-related disease (Scheme 18.36) [110]. 

By far the most impressive example of electrophilic addition in natural prodnct formation is in the biosynthesis of steroids. The snbstrate sqnalene oxide is cyclized to lanosterol in a process catalysed by a single enzyme. Lanosterol is then converted into the primary animal-steroid cholesterol. Sqnalene oxide comes from sqnalene, which is itself formed throngh a combination of two molecules of farnesyl diphosphate. 

Membrane-located enzymes in the sER catalyze lipid synthesis. Phospholipid synthesis (see p. 170) is located in the sER, for example, and several steps in cholesterol biosynthesis (see p. 172) also take place there. In endocrine cells that form steroid hormones, a large proportion of the reaction steps involved also take place in the sER (see p. 376). 

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