Ho

▲ FIGURE 18-7 Cholesterol biosynthetic pathway. The regulated rate-controlling step In cholesterol biosynthesis Is the conversion of p-hydroxy-p-methylglutaryl CoA (HMG-CoA) Into mevalonic acid by HMG-CoA reductase, an ER-membrane protein. Mevalonate is then converted into isopentenyl pyrophosphate (IPP), which has the basic five-carbon isoprenoid is catalyzed by HMG-CoA reductase, an ER integral membrane protein, even though both its substrate and its product are water soluble. The water-soluble catalytic domain of HMG-CoA reductase extends into the cytosol, but its eight transmembrane segments firmly embed the enzyme in the ER membrane and act as a regulatory domain. Five of the transmembrane segments compose the so-called sterol-sensing domain. As described later, homologous domains are found in other proteins taking part in cholesterol transport and regulation.

Mevalonate, the 6-carbon product formed by HMG-CoA reductase, is converted in several steps into the 5-carbon iso-prenoid compound isopentenyl pyrophosphate (IPP) and its stereoisomer dimethylallyl pyrophosphate (DMPP). These reactions are catalyzed by cytosolic enzymes, as are the subsequent reactions in which six IPP units condense to yield squalene, a branched-chain 30-carbon intermediate. Enzymes bound to the ER membrane catalyze the multiple reactions that convert squalene into cholesterol in mammals or into related sterols in other species.

Because an excessive accumulation of cholesterol can lead to the formation of damaging cholesterol crystals, the production and accumulation of cholesterol is tightly

Squalene

Vitamin D " Bile acids

Cholesterol Steroid hormones Cholesterol esters Modified proteins (hedgehog)

structure. IPP can be converted into cholesterol and into many other lipids, often through the polyisoprenoid intermediates shown here. Some of the numerous compounds derived from isoprenoid intermediates and cholesterol itself are indicated. See text for discussion.

Acetyl CoA + acetoacetyl CoA

HMG-CoA

HMG-CoA reductase

Mevalonate 1

Isopentenyl pyrophosphate

Isopentenyl adenosine ^ Many other isoprenoids

Dolichol Haem

Ubiquinone Farnesyl pyrophosphate ^ Vitamins (A, E, K) Chlorophyll

Lipid-anchored proteins (Ras)

controlled. For example, cholesteryl esters (see Figure 18-6) are formed from excess cholesterol and stored as cytosolic lipid droplets. Acyl.cholesterol acyl transferase (ACAT), the enzyme that esterifies fatty acyl CoAs to the hydroxyl group of cholesterol, is located in the ER membrane. Substantial amounts of cholesteryl ester droplets are usually found only in cells that produce steroid hormones and in foam cells, which contribute to atherosclerotic disease in artery walls. Intracellular lipid droplets, whether composed of cholesteryl esters or triglycerides, have an outer protein coat that serves as an interface between the aqueous environment of the cytosol and the lipid. The coat proteins on lipid droplets in mammalian cells are called perilipins or perilipin-related proteins, while the oleosins and their related proteins coat the surfaces of lipid droplets called oil bodies in plants.

Many Bioactive Molecules Are Made from Cholesterol and Its Biosynthetic Precursors

In addition to its structural role in membranes, discussed in Chapter 5, cholesterol is the precursor for several important bioactive molecules. They include bile acids (see Figure 18-6), which are made in the liver and help emulsify dietary fats for digestion and absorption in the intestines, steroid hormones produced by endocrine cells (e.g., adrenal gland, ovary, testes), and vitamin D produced in the skin and kidneys. Arthropods need cholesterol or other sterols to produce membranes and ecdysteroid hormones, which control development; however, they cannot make the precursor sterols themselves and must obtain these compounds in their diet. Another critical function of cholesterol is its covalent addition to Hedgehog protein, a key signaling molecule in embryonic development (Chapter 15).

Isopentenyl pyrophosphate and other isoprenoid intermediates in the cholesterol pathway also serve as precursors for more than 23,000 biologically active molecules. Some of these molecules are discussed in other chapters: various hemes, including the oxygen-binding component of hemoglobin and electron-carrying components of cytochromes (see Figure 8-15a); ubiquinone, a component of the mitochondrial electron-transport chain (see Figure 8-16); chlorophylls, the light-absorbing pigments in chloroplasts (see Figure 8-31); and dolichol, a polyisoprenoid in the ER membrane that plays a key role in the glycosylation of proteins (see Figure 16-17).

Isoprenoid derivatives are particularly abundant in plants in which they form fragrances and flavors, rubber and latex, hormones and pheromones, various defensive molecules, the active ingredient in marijuana, the cardioprotective natural drug digitalis, anticancer drugs such as taxol, and many others. Given the importance of iso-prenoids as biosynthetic precursors, it is not surprising that a second, mevalonate-independent pathway for IPP synthesis evolved in eubacteria (e.g., E. coli), green algae, and higher plants. In plants, this pathway is located in organelles called plastids and operates to synthesize carotenoids, phytol (the isoprenoid side chain of chlorophyll), and other isoprenoids. I

Cholesterol and Phospholipids Are Transported Between Organelles by Golgi-Independent Mechanisms

As already noted, the final steps in the synthesis of cholesterol and phospholipids take place primarily in the ER, although some of these membrane lipids are produced in mitochondria and peroxisomes (plasmalogens). Thus the plasma membrane and the membranes bounding other organelles (e.g., Golgi, lysosomes) must obtain these lipids by means of one or more intracellular transport processes. For example, in one important pathway, phosphatidylserine made in the ER is transported to the inner mitochondrial membrane where it is decarboxylated to phosphatidylethanolamine, some of which either returns to the ER for conversion into phosphatidylcholine or moves to other organelles.

Membrane lipids do accompany both soluble (luminal) and membrane proteins during vesicular trafficking through the Golgi-mediated secretory pathway (see Figure 17-1). However, several lines of evidence suggest that there is substantial interorganelle movement of cholesterol and phos-pholipids through other, Golgi-independent mechanisms. For example, chemical inhibitors of the classic secretory pathway and mutations that impede vesicular traffic in this pathway do not prevent cholesterol or phospholipid transport between membranes, although they do disrupt the transport of proteins and Golgi-derived sphingolipids. Furthermore, membrane lipids produced in the ER cannot move to mitochondria by means of classic secretory transport vesicles, inasmuch as no vesicles budding from ER membranes have been found to fuse with mitochondria.

Three mechanisms have been proposed for the transport of cholesterol and phospholipids from their sites of synthesis to other membranes independently of the Golgi-mediated secretory pathway (Figure 18-8). First, some Golgi-independent transport is most likely through membrane-limited vesicles or other protein-lipid complexes. The second mechanism entails direct protein-mediated contact of ER or ER-derived membranes with membranes of other organelles. In the third mechanism, small lipid-transfer proteins facilitate the exchange of phospholipids or cholesterol between different membranes. Although such transfer proteins have been identified in assays in vitro, their role in intracellular movements of most phospholipids is not well defined. For instance, mice with a knockout mutation in the gene encoding the phos-phatidylcholine-transfer protein appear to be normal in most respects, indicating that this protein is not essential for cellular phospholipid metabolism.

One well-established component of the intracellular cholesterol-transport system is the steroidogenic acute regulatory (StAR) protein. This protein, which is encoded in nuclear DNA, controls the transfer of cholesterol from the cholesterol-rich outer mitochondrial membrane to the cholesterol-poor inner membrane, where it undergoes the first steps in its enzymatic conversion into steroid hormones. StAR-mediated cholesterol transport is a key regulated, ratecontrolling step in steroid hormone synthesis. StAR contains

Phospholipid

Cholesterol

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