Isoprene steroid biosynthesis

Why is HMG-CoA so important in cholesterol biosynthesis The starting material for steroid biosynthesis is acetyl-GoA. Isoprene units are formed from acetyl-GoA in the early stages of a lengthy process that leads ultimately to cholesterol. HMG-GoA is a key intermediate, and its formation is a target of cholesterol-lowering drugs. 

Steroids are a class of organic compounds that contain a characteristic arrangement of four cycloalkane rings joined to each other. All steroids are synthesized inside cells either from the sterols lanosterol (in animals and microorganisms) or from cycloartenol (in plants). Both lanosterol and cycloartenol are derived from the cycli-zation of the triterpene squalene (six isoprene units, 30C) [3-5]. In other words, squalene is the biochemical precursor to the whole family of steroids. Among all of the steroid biosynthesis, steroid hormone biosynthesis is the most concerned. 

D-Mevalonic acid is the fundamental intermediate in the biosynthesis of the terpenoids and steroids, together classed as poly-isoprenoids. The biogenetic isoprene unit is isopentenyl pyrophosphate which arises by enzymic decarboxylation-dehydration of mevalonic acid pyrophosphate. D-Mevalonic acid is almost quantitatively incorporated into cholesterol synthesized by rat liver homogenates. 

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. 

Isoprene is also a precursor of steroids and terpenes. This relationship becomes clear when we examine the biosynthesis of these compounds (see chapter 20). Vitamin A is either biosynthesized from /3-carotene (see fig. S2.4) or absorbed in the diet. Vitamin A is stored in the liver predominantly as an ester of palmitic acid. For many decades, it has been... 

The ultimate precursor of all the carbon atoms in cholesterol and in the other steroids that are derived from cholesterol is the acetyl group of acetyl-GoA. There are many steps in the biosynthesis of steroids. The condensation of three acetyl groups produces mevalonate, which contains six carbons. Decarboxylation of mevalonate produces the five-carbon isoprene unit frequently encountered in the structure of lipids. The involvement of isoprene imits is a key point in the biosynthesis of steroids and of many other compounds that have the generic name terpenes. Vitamins A, E, and K come from reactions involving terpenes that humans cannot carry out. That is why we must consume these vitamins in our diets vitamin D, the remaining lipid-soluble vitamin, is derived from cholesterol (Section 8.8). Isoprene units are involved in the biosynthesis of ubiquinone (coenzyme Q) and of derivatives of proteins and tRNA with specific five-carbon units attached. Isoprene units are often added to proteins to act as anchors when the protein is attached to a membrane. 

Biosynthesis In contrast to steroids and terpenes, there is no equivalent to the isoprene rule for alkaloids as a useful aid for structure determination and biogenetic investigations. It is generally accepted today that A. are formed in cyclization, condensation, and dimerization reactions from amino acids and biogenic amines with biogenic aldehydes and ketones. 

Squalene [(a//- )-2,6,10,15,19,23-hexamethyl-2.6, 10,14,18,22-tetracosahexaene]. The most important aliphatic, acyclic triterpene, C30H50, Mr 410.73, mp. -4.8 to -5.2 C, bp. 284-285°C, formula, see steroids. S. was first isolated from fish liver oils and later detected in plant oils and human fat. It is composed of 6 isoprene units and is formed from activated acetate ( acetyl-CoA) via mevalonic acid. It is an intermediate in the biosynthesis of all cyclic triterpenoids and thus also of the steroids. Its enzymatic cyclization to IanosteroI or cycloartenoI requires molecular oxygen and proceeds through (35)-squalene 2,3-epoxide. lit. Annu. Rev. Biochem. 14,555-585 (1982)"Chem. Soc. Rev. 20,129-147 (1991) - Kaiier, No. 34 Nat. Prod. Rep. 2, 525 - 5W (1985) Phytochemisby 27,628 (1988) (biosy nthe-sis) Stryer 1995,692-695.-/HS290/29 CASHI-02-4]... 

Poly(c -l,4-isoprene) belongs to the family of polyisoprenoids, which are the most structurally diverse and abundant natural products known, with more than 23,000 primary and secondary metabolites. This huge family comprises, for example, sterols which display not only structural functions (control of biological membrane fluidity) but also hormonal functions (steroid hormones). Key phyto-hormones, such as abscisic acid, gibberellins and cytokinins, are isoprenoids too. Moreover, isoprenoids are used in protein prenylation, which is a key step in the activation and the localization of metabolic enzymes in many organisms. The first common step of all isoprenoid biosynthesis pathways is the formation of isopentenyl diphosphate (IPP). ... 

Originally only compounds with 10 carbon atoms (monoterpenes) were considered as T, and the oxygen-containing T. were classified as camphors. According to the mechanism of biosynthesis, however, all compounds derived from active isoprene are now classified as T. or isoprenes, including steroids, carotenoids, etc. 

There is an extraordinarily important class of molecules called steroids. The carbon framework common to all steroids is three cyclohexanes and a cyclopentane fused together (Fig. 12.77).This arrangement is often referred to as three rooms and a bath. Steroids are formed in Nature from isoprene units. We will start our summary of the biosynthesis with two units of farnesyl pyrophosphate, which can be enzymatically coupled in a tail-to-tail fashion to give the symmetrical triterpene called squalene (Fig. 12.78). 

Acetyl Coenzyme A 993 Fats, Oils, and Fatty Acids 994 Fatty Acid Biosynthesis 997 Phospholipids 999 Waxes 1001 Prostaglandins 1002 Nonsteroidal Antiinflammatory Drugs (NSAIDs) and COX-2 Inhibitors 1004 Terpenes The Isoprene Rule 1005 Isopentenyl Diphosphate The Biological Isoprene Unit 1008 Carbon-Carbon Bond Formation in Terpene Biosynthesis 1008 24.10 The Pathway from Acetate to Isopentenyl Diphosphate 1011 Steroids Cholesterol 1013 Vitamin D 1016... 

What is the nature of the substance with the Cs chain Let us recall the S3mthesis of isoprene, the starting point for carotenoids and terpenes, from acetate we see that this synthesis leads to the Cs arrangement we are seeking. Arguments have been advanced previously to implicate the iso-prenoid, squalene, in the biosynthesis of steroids. Squalene is not limited solely to the tissues of the selachians. Traces have been foimd everywhere in animal tissues where it has been sought. When we consider that isoprene units, as we have already indicated, are derived from acetate, we may represent squalene as in Fig. 62 and compare it with Fig. 61. 

The junction between isoprene units is not random, but most often is formed through the so-called head-to-tail coupling as shown in Fig. 8.1. In certain cases, a tail-to-tail coupling occurs, also shown in Fig. 8.1. This coupling is a characteristic feature of the central coupling used to form the carotenoids and the triterpenoid squalene (2) (Fig. 8.3) which is the precursor for the steroids. The explanation of the coupling systems hes in the biosynthesis as described in Figs. 8.3 and 8.4. 

The product of the reaction above, the acetoacetyl derivative of the acyl carrier protein, is the starting point for the biosynthesis of other compounds besides fatty acids. Steroids derive from a sequence of enzyme-catalyzed Claisen-like condensations that produce the branched five-carbon skeleton of 2-methyl-1,3-butadiene (isoprene), the building block of... 

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