Enzyme-catalyzed steroid transformation

Table 2 Enzyme-Catalyzed Steroid Transformations in Water-Organic Solvent Two-Phase Systems by Hydroxy Steroid Dehydrogenases (HSDH)... 

In the biogenesis of steroids, the enzyme-catalyzed polycyclization of squalene (225) produces the tetracyclic substance lanosterol (225) which is eventually converted into cholesterol (227) Eschenmoser, Stork, and their co-workers (80-82) have proposed that the squalene-1anosterol conversion can be rationalized on the basis of stereoelectronic effects. The stereochemical course of this biological cyclization (83, 84) can be illustrated by considering the transformation of squalene oxide (228) (an intermediate in the biosynthesis of cholesterol (83, 84)) into dammaradienol 229. This transfor-... 

Scope - There is an enzyme-catalyzed equivalent for almost every type of chemically catalyzed reaction.Thousands of microbiological and enzymic transformations of chemical significance have now been documented in excellent monographs. These reviews cover the field in general as well as specialized areas such as steroids, alkaloids, and terpenes. These provide access to much of the published data. Current awareness is also easily maintained. So far, the use of intact microorganisms in organic syntheses has been dominant. However, wholly or partly purified and immobilized enzymes are gaining rapidly in importance. 

Lipides, 238, 239, 241-243, 261 Lipidosis, 239, 242, 243 Lobry de Bruyn-Alberda van Ekenstein transformation, 63, 291 acid catalysis of, 79 aldolization in, 77 base catalysis of, 79-81 catalysis of, by metal ions, 81 dealdolization in, 77 dehydration reactions in, 73 enzyme-catalyzed, 66, 70 formation of reductones in, 79 of or-hydroxy aldehydes, 71 mechanism of, 84 of noncarbohydrate a-ketols, 71 non-enzymic, 66, 67, 83 in paper chromatography, 81 rearrangement of carbon chain, 79 scope of, 65 of steroids, 72 use of, for synthesis, 82 Lyxonic acid, 3-deoxy-D-, 300 Lyxose, D-, condensation of, with urea, 218... 

The conversion of 3a,7a,12a-trihydroxy-5)5-cholestanoic acid into cholic acid (cholyl coenzyme A) occurs by means of a /9-oxidation with release of propionic acid (propionyl coenzyme A) (Fig. 2). Although no definite experimental evidence is available, it may be assumed that the reactions involve the coenzyme-A esters of the steroid acids. Only one of the intermediates in the /9-oxidation of 3a,7a,12a-trihydroxy-5/9-cholestanoic acid has been isolated. Masui and Staple (88,89) have shown that the mitochondrial fraction of rat liver homogenate supplemented with the 100,000g supernatant fluid catalyzes the conversion of 3a,7a,12a-trihydroxy-5/9-cholestanoic acid into one of the two C-24 epimers of 3a,7a,12a,24-tetrahydroxy-5/9-choles-tanoic acid. It is probable that the C-24 isomer formed is the 24a-hydroxy compound (89,90). The transformation of 3a,7a,12a,24a-tetrahydroxy-5/9-cholestanoic acid into cholic acid is catalyzed by the 100,000g supernatant fluid of rat liver homogenate (89). No studies have yet been carried out to compare the enzymes catalyzing /9-oxidation of 3a,7a,12a-trihydroxy-5/9-... 

It is probably true that any class of enzyme-catalyzed reaction presently known, or to be discovered, will eventuaUy find an illustration in the microbial transformation of steroids. At the present time examples of all of the listed cat ories are known. 

The history of cytochrome P450 (P450) really began with studies on the metabolism of drags, carcinogens, and steroids. The early research in these fields necessarily involved animal models, but the intent was always to imderstand the human systems in the context of the enzymes catalyzing the observed transformations. 

Transformation of lanosterol to cholesterol (Figure 19-16) is a complex, multistep process catalyzed by enzymes of the endoplasmic reticulum (microsomes). A cytosolic sterol carrier protein is also required and presumably functions as a carrier of steroid intermediates from one catalytic site to the next but may also affect activity of the enzymes. The reactions consist of removal of the three methyl groups attached to C4 and C14, migration of the double bond from the 8,9- to the 5,6-position, and saturation of the double bond in the side chain. Conversion of lanosterol to cholesterol occurs principally via 7-dehydrocholesterol and to a minor extent via desmosterol. 

Our laboratory is concerned with targeting potential insecticides that disrupt normal development and metamorphosis in insects. Juvenile hormones (JHs), acting in concert with the steroid hormone ecdysone, are believed to control the timing of the larval-larval molts, larval-pupal and pupal-adult transformations of the insects. It has been demonstrated that the events leading to pupation are initiated by reduction of the JH titer in the hemolymph. In addition to a cessation of biosynthesis, this reduction in JH titer is controlled by degradative metabolism (16,17). Hydrolysis of the epoxide and ester functionalities present in active JH are two routes of degradation and subsequent inactivation of JH (18). The primary route of JH metabolism in the hemolymph of last stadium lepidopterous larvae is ester hydrolysis, and it is catalyzed by the enzyme juvenile hormone esterase (JHE). JHE has been shown to... 

Excess cholesterol can also be metabolized to CE. ACAT is the ER enzyme that catalyzes the esterification of cellular sterols with fatty acids. In vivo, ACAT plays an important physiological role in intestinal absorption of dietary cholesterol, in intestinal and hepatic lipoprotein assembly, in transformation of macrophages into CE laden foam cells, and in control of the cellular free cholesterol pool that serves as substrate for bile acid and steroid hormone formation. ACAT is an allosteric enzyme, thought to be regulated by an ER cholesterol pool that is in equilibrium with the pool that regulates cholesterol biosynthesis. ACAT is activated more effectively by oxysterols than by cholesterol itself, likely due to differences in their solubility. As the fatty acyl donor, ACAT prefers endogenously synthesized, monounsaturated fatty acyl-CoA. 

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