* Biosynthesis of Cholesterol, Steroids and IsoprenoidsCommon tetracyclic steroid frame containing the 1,2-cyclopentanoperhydrophenanthrene ring skeleton. The first known sterol, cholesterol, was discovered by French chemists as a crystalline component of human gallstones over years ago. InFrancois Poulletier de La Salle observed an alcohol-soluble portion of bile stones, which 10 years later was reported cholesterll De Fourcroy to be identical to a waxy material in the fat of putrefied biosynthesis of cholesterol steroids and isoprenoids referred to as adipocire. The correct formula C 27 H 45 O—, which here shows that it has a hydroxyl group although it contains 46 hydrogen atoms of cholesterol was proposed in by F. Reinitze, yet it took biosynthesis of cholesterol steroids and isoprenoids 30 years to establish the biosyntuesis steric representation of the molecule, efforts that led to winstrol injectable side effects Nobel Prizes in chemistry for Wieland and Windaus The first connection between cholesterol and human health appeared in xteroids Vogel showed that cholesterol was present in arterial plaques.
* Biosynthesis of Cholesterol, Steroids and Isoprenoids - ppt video online download
We now turn our attention to the synthesis of the fundamental lipid cholesterol. This steroid modulates the fluidity of animal cell membranes Section All 27 carbon atoms of cholesterol are derived from acetyl CoA in a three-stage synthetic process Figure Thirteen Nobel Prizes have been awarded to scientists who devoted major parts of their careers to cholesterol. Ever since it was isolated from gallstones in , cholesterol has exerted an almost hypnotic fascination for scientists from the most diverse areas of science and medicine….
Cholesterol is a Janus-faced molecule. The very property that makes it useful in cell membranes, namely its absolute insolubility in water, also makes it lethal. The results of isotope-labeling experiments reveal the source of carbon atoms in cholesterol synthesized from acetate labeled in its methyl group blue or carboxylate atom red.
Stage one is the synthesis of isopentenyl pyrophosphate, an activated isoprene unit that is the key building block of cholesterol. Stage two is the condensation of six molecules of isopentenyl pyrophosphate to form squalene. In stage three, squalene cyclizes in an astounding reaction and the tetracyclic product is subsequently converted into cholesterol. The first stage in the synthesis of cholesterol is the formation of isopentenyl pyrophosphate from acetyl CoA. This intermediate is reduced to mevalonate for the synthesis of cholesterol Figure Recall that mitochondrial 3-hydroxymethylglutaryl CoA is processed to form ketone bodies Section Fates of 3-HydroxyMethylglutaryl CoA.
In mitochondria, it is converted into acetyl CoA and acetoacetate. The synthesis of mevalonate is the committed step in cholesterol formation. The enzyme catalyzing this irreversible step, 3-hydroxymethylglutaryl CoA reductase HMG-CoA reductase , is an important control site in cholesterol biosynthesis, as will be discussed shortly.
HMG- CoA reductase is an integral membrane protein in the endoplasmic reticulum. Mevalonate is converted into 3-isopentenyl pyrophosphate in three consecutive reactions requiring ATP Figure Decarboxylation yields isopentenyl pyrophosphate, an activated isoprene unit that is a key building block for many important biomolecules throughout the kingdoms of life.
We will return to a discussion of this molecule later in the chapter. Synthesis of Isopentenyl Pyrophosphate. This activated intermediate is formed from mevalonate in three steps, the last of which includes a decarboxylation.
Squalene is synthesized from isopentenyl pyrophosphate by the reaction sequence. This stage in the synthesis of cholesterol starts with the isomerization of isopentenyl pyrophosphate to dimethylallyl pyrophosphate. These isomeric C 5 units condense to form a C 10 compound: The same kind of reaction takes place again: The resulting C 15 compound is called farnesyl pyrophosphate. The same enzyme, geranyl transferase, catalyzes each of these condensations.
Condensation Mechanism in Cholesterol Synthesis. The mechanism for joining dimethylallyl pyrophosphate and isopentenyl pyrophosphate to form geranyl pyrophosphate. The same mechanism is used to add an additional isopentenyl pyrophosphate to form farnesyl more The last step in the synthesis of squalene is a reductive tail-to-tail condensation of two molecules of farnesyl pyrophosphate catalyzed by the endoplasmic reticulum enzyme squalene synthase.
The reactions leading from C 5 units to squalene, a C 30 isoprenoid, are summarized in Figure One molecule of dimethyallyl pyrophosphate and two molecules of isopentenyl pyrophosphate condense to form farnesyl pyrophosphate. The tail-to-tail coupling of two molecules of farnesyl pyrophosphate yields squalene. The final stage of cholesterol biosynthesis starts with the cyclization of squalene Figure Squalene is first activated by conversion into squalene epoxide 2,3-oxidosqualene in a reaction that uses O 2 and NADPH.
Squalene epoxide is then cyclized to lanosterol by oxidosqualene cyclase Figure This remarkable transformation proceeds in a concerted fashion. The enzyme holds squalene epoxide in an appropriate conformation and initiates the reaction by protonating the epoxide oxygen. The carbocation formed spontaneously rearranges to produce lanosterol. Lanosterol is converted into cholesterol in a multistep process by the removal of three methyl groups, the reduction of one double bond by NADPH, and the migration of the other double bond Figure The formation of the steroid nucleus from squalene begins with the formation of squalene epoxide.
This intermediate is protonated to form a carbocation that cyclizes to form a tetracyclic structure, which rearranges to form lanosterol. The structure of an enzyme homologous to oxidosqualene cyclase shows a central cavity lined primarily with hydrophobic side chains shown in red in which the cyclization reaction takes place. Lanosterol is converted into cholesterol in a complex process. By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.