Steroid hormone biosynthetic pathways

For an organism to eliminate a lipophilic, chemically inert xenobiotic, it is usually hrst necessary to oxidize it to a more polar form. In addition, many biosynthetic pathways that produce steroid hormones, prostaglandins, leukotrienes, etc. involve oxidative steps. Organisms have evolved many enzymes to carry out these oxidations. Oxidation can occur by addition of oxygen (without addition of hydrogen which would represent hydration), removal of hydrogen atoms (without removal of oxygen which would represent dehydration), or simply removal of electrons. 

Urea ((NH2)2CO), a small and highly water soluble molecule, is an end product of amine and ammonia nitrogen metabolism and as such represents an example of biodetoxification (Section 6.4). The process is discussed in this section because it illustrates a genuine de novo biosynthetic pathway rather than detoxification involving chemical modification, via phase I and phase II reactions, of a pre-existing molecule as is the case for haem or steroid hormones. 

NADPH provides reducing power for biosynthetic reactions, and ribose 5-phosphate is a precursor for nucleotide and nucleic acid synthesis. Rapidly growing tissues and tissues carrying out active biosynthesis of fatty acids, cholesterol, or steroid hormones send more glucose 6-phosphate through the pentose phosphate pathway than do tissues with less demand for pentose phosphates and reducing power. 

We begin with an account of the main steps in the biosynthesis of cholesterol from acetate, then discuss the transport of cholesterol in the blood, its uptake by cells, the normal regulation of cholesterol synthesis, and its regulation in those with defects in cholesterol uptake or transport. We next consider other cellular components derived from cholesterol, such as bile acids and steroid hormones. Finally, an outline of the biosynthetic pathways to some of the many compounds derived from isoprene units, which share early steps with the pathway to cholesterol, illustrates the extraordinary versatility of isoprenoid condensations in biosynthesis. 

Stereospecific 2,3-epoxidation of squalene. followed by a non-concerted carbocationic cyclization and a seiies of carbocationic rearrangements, forms lanosterol (26) in the first steps dedicated solely toward steroid synthesis. Cholesterol is the principal starting material for steroid hormone biosynthesis ill animals. The cholesterol biosynthetic pathway is composed of at least 30 enzymatic reactions. Lanosterol and squalene appear to he normal constituents, in trace amounis. in tissues that are actively synthesizing cholesterol,... 

The excessive production of thyroid hormone in Graves disease is associated with an enlarged thyroid gland, but in this case a circulating immunoglobulin that mimics the activity of thyroid stimulating hormone (TSH) is implicated. Finally, we saw in an earlier section how an inappropriate steroid hormone may be secreted in excessive amounts when specific enzymes in the adrenal steroid biosynthetic pathway are present at inadequate levels. 

The foregoing discussion has attempted to trace the ways in which cholesterol, derived from plasma lipoproteins, is converted into the various steroid hormones and how these are secreted back into the blood. Of necessity, many details have had to be omitted but it is hoped that this up-date has shown the complexities of steroid biosynthetic pathways and that earlier classical ideas have had to be modified as greater knowledge of intermediates, isoenzymes and multiple forms of cyt P-450s has become available. Perspectives for future studies are indeed exciting. 

Adrenodoxin Hie enzyme is used in the synthesis of steroid hormones from cholesterol. It is used for the introduction of oxygen atoms into cholesterol in the biosynthetic pathways for aldosterone, the glucocorticoids, and the sex hormones. 

Steroid hormones in mammals are biosynihesixed from cholesterol. which in turn is made in vivo from acetyl-coenrym A (acetyl-CoA) via the mevalonate pathway. Although humans do obtain approximately 300 mg of choleslcnil [ei day in their diets, a greater amount (about I g) is hiiKynlhc-.sized per day. A schematic outline of these biosynthetic paih-ways is shown in Figure 23-. >. 

Figure 34-2. General biosynthetic pathway of the steroid hormones.

Like all steroids, brassinosteroids derive from a single common precursor mevalonic acid. Some phytohormones are synthesized totally or in part via the isoprenoid pathway, such as absdsic acid, gibberellins and cytokinins. The importance of this biosynthetic pathway in processes involved with cell cycle regulation and tumorigenesis in mammals is well documented. Having in mind the similarities between certain regulatory systems in plants and animals the question arose whether brassinosteroids as putative plant steroid hormones would show a specific effect on plant tumor cells. 

Enzymes of the biosynthetic pathway of steroid hormones can also be demonstrated effectively in immunohistochemical formats. Among the enzymes that have been localized are P450scc (cholesterol side chain cleavage), 3 3-hydroxysteroid dehydrogenase, 21-hydroxylase, 17a-hydroxylase, and lip-hydroxylase. " To date, however, there have been relatively few studies evaluating antibodies to these enzymes as diagnostic reagents. 

Cholesterol is primarily restricted to eukaryotic cells where it plays a number of roles. Undoubtedly, the most primitive function is as a structural component of membranes. Its metabolism to bile acids and the steroid hormones is relatively recent in the evolutionary sense. In this chapter, the pathway of cholesterol biosynthesis will be divided into segments which correspond to the chemical and biochemical divisions of this biosynthetic route. The initial part of the pathway is the 3-step conversion of acetyl-CoA to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). The next is the reduction of this molecule to mevalonate, considered to be the rate-controlling step in the biosynthesis of polyisoprenoids. From thence, a series of phosphorylation reactions both activate and decarboxylate mevalonate to isopen tenyl pyrophosphate, the true isoprenoid precursor. After a rearrangement to the allylic pyrophosphate, dimethylallyl pyrophosphate, a sequence of l -4 con-... 

The conjugation and inactivation pathways are similar to those used by the hver to inactivate many of its own metabolic waste products. These pathways are intimately related to the biosynthetic cascades that exist in the liver. The liver can synthesize the precursors that are required for conjugation and inactivation reactions from other compounds. For example, sulfation is used by the liver to clear steroid hormones from the circulation. The sulfate used for this purpose can be obtained from the degradation of cysteine or methionine. 

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