Acetyl-CoA cholesterol

Glucose (from food or synthesised within acetyl-CoA cholesterol... 

Cholesterol and cholesteryl ester synthesis acetyl-CoA----> cholesterol----> cholesteryl esters... 

Pyruvate dehydrogenase produces acetyl CoA which can be used in synthesis of FAs. Enoyl CoA hydratase is an enzyme of the p-oxidation pathway and does not produce acetyl CoA. The three glycogenic amino acids are alanine, serine and glycine they cannot be directly converted to acetyl CoA. The ketogenic amino acid isoleucine may be converted directly to acetyl CoA. Cholesterol is synthesized from acetyl CoA. However, cholesterol cannot be degraded in the body and is disposed of by excretion in bile. 

Ketone body synthesis occurs only in the mitochondrial matrix. The reactions responsible for the formation of ketone bodies are shown in Figure 24.28. The first reaction—the condensation of two molecules of acetyl-CoA to form acetoacetyl-CoA—is catalyzed by thiolase, which is also known as acetoacetyl-CoA thiolase or acetyl-CoA acetyltransferase. This is the same enzyme that carries out the thiolase reaction in /3-oxidation, but here it runs in reverse. The second reaction adds another molecule of acetyl-CoA to give (i-hydroxy-(i-methyl-glutaryl-CoA, commonly abbreviated HMG-CoA. These two mitochondrial matrix reactions are analogous to the first two steps in cholesterol biosynthesis, a cytosolic process, as we shall see in Chapter 25. HMG-CoA is converted to acetoacetate and acetyl-CoA by the action of HMG-CoA lyase in a mixed aldol-Claisen ester cleavage reaction. This reaction is mechanistically similar to the reverse of the citrate synthase reaction in the TCA cycle. A membrane-bound enzyme, /3-hydroxybutyrate dehydrogenase, then can reduce acetoacetate to /3-hydroxybutyrate. 

Write a balanced, stoichiometric reaction for the synthesis of cholesterol from acetyl-CoA. 

HMG-CoA-Reductase Inhibitors. Figure 1 Mechanism of action of statins - cholesterol synthesis pathway. The conversion of acetyl CoA to cholesterol in the liver. The step of cholesterol biosynthesis inhibited by HMG-CoA reductase inhibitors (statins) is shown. 

Acetyl-CoA is also used as the precursor for biosynthesis of long-chain fatty acids steroids, including cholesterol and ketone bodies. 

The biosynthesis of cholesterol may be divided into five steps (l) Synthesis of mevalonate occurs from acetyl-CoA (Figure 26-1). (2) Isoprenoid units are formed... 

Figure 26-3. Biosynthesis of cholesterol. The numbered positions are those of the steroid nucleus and the open and solid circles indicate the fate of each of the carbons in the acetyl moiety of acetyl-CoA. Asterisks Refer to labeling of squalene in Figure 26-2.

Cholesterol is synthesized in the body entirely from acetyl-CoA. Three molecules of acetyl-CoA form mevalonate via the important regulatory reaction for the pathway, catalyzed by HMG-CoA reductase. Next, a five-carbon isoprenoid unit is formed, and six of these condense to form squalene. Squalene undergoes cychzation to form the parent steroid lanos-terol, which, after the loss of three methyl groups, forms cholesterol. 

FIGURE 9. Endogenous lipoprotein metabolism. In liver cells, cholesterol and triglycerides are packaged into VLDL particles and exported into blood where VLDL is converted to IDL. Intermediate-density lipoprotein can be either cleared by hepatic LDL receptors or further metabolized to LDL. LDL can be cleared by hepatic LDL receptors or can enter the arterial wall, contributing to atherosclerosis. Acetyl CoA, acetyl coenzyme A Apo, apolipoprotein C, cholesterol CE, cholesterol ester FA, fatty acid HL, hepatic lipase HMG CoA, 3-hydroxy-3-methyglutaryl coenzyme A IDL, intermediate-density lipoprotein LCAT, lecithin-cholesterol acyltransferase LDL, low-density lipoprotein LPL, lipoprotein lipase VLDL, very low-density lipoprotein. 

Biosynthesis of cholesterol from acetyl-CoA proceeds, assisted by the enzymes of endoplasmic reticulum and hyaloplasm, in many tissues and organs. This pro-cess is especially active in the liver of adult humans. 

Thus, the tissue cholesterol can be synthetized from any materials whose break-down leads to acetyl-CoA. These include carbohydrates, amino acids, fatty acids, and glycerol. 

Cholesterol is an essential component of mammalian membranes. It is obtained from the diet or can be synthesized from acetyl-CoA. 

In common with cholesterol synthesis described in the next section, fatty acids are derived from glucose-derived acetyl-CoA. In the fed state when glucose is plentiful and more than sufficient acetyl-CoA is available to supply the TCA cycle, carbon atoms are transported out of the mitochondrion as citrate (Figure 6.8). Once in the cytosol, citrate lyase forms acetyl-CoA and oxaloacetate (OAA) from the citrate. The OAA cannot re-enter the mitochondrion but is converted into malate by cytosolic malate dehydrogenase (cMDH) and then back into OAA by mitochondrial MDH (mMDH) Acetyl-CoA remains in the cytosol and is available for fatty acid synthesis. 

Acetyl-CoA is at the product of fatty acid catabolism and may be derived from amino acids and carbohydrates (via pyruvate). Acetyl-CoA is the precursor of fatty acids, cholesterol and ketone bodies. 

Cholesterol All cells, liver is especially Mainly cytosol but acetyl-CoA 6.3.2.3... 

Cholesterol is required for membrane synthesis, steroid synthesis, and in the liver, bile acid synthesis. Most cells derive their cholesterol from LDL or HDL, but some cholesterol may be synthesized de novo. Most de novo synthesis occurs in the liver, vfhere cholesterol is synthesized from acetyl CoA in the cytoplasm. The citrate shutde carries mitochondrial acetyl CoA into the cytoplasm, and NADPH is provided by the HMP shunt and malic enzyme. Important points are noted in Figure 1-15-9,... 

About 1 g of cholesterol is ingested by adults each day in developed countries. A similar amount enters the lumen via the bile, synthesised from acetyl-CoA in the liver, is also released from sloughed epithelial cells. Absorption of cholesterol also occurs from the mixed micelles. Within the enterocyte, it is esterified and the cholesterol ester is incorporated into the chylomicrons. 

Pyruvate for acetyl-CoA which is precursor for several compounds (cholesterol, specific fatty acids, dolichol). 

Epididymis Carnitine Inositol Phosphatidylcholine Cholesterol Glycoproteins Facihtates acetyl-CoA oxidation by spermatozoa (Chapter 9) Precursor for formation of phosphatidyhnositol bisphosphate Buffer to maintain pH and a source of chohne Stabilises membranes They coat the surface of the sperm to protect against IgA... 

Figure 19.8 A brief summary of the pathways for formation and secretion of oestradiol and progesterone within the cells of the follicle. Cholesterol is taken up by thecal cells in a complex with low density lipoprotein. In the thecal cells, cholesterol is converted to testosterone which is released to be taken up by granulosa cells where it is converted into oestradiol. For synthesis of progesterone in the granulosa cells, cholesterol is synthesised de novo within the cells from acetyl-CoA. In the follicle the enzyme aromatase, which produces the aromab c ring in the female sex hormones, is restricted to the granulosa cells. The reacrions that are stimulated by LH and FSH increase synthesis and, therefore, secretion of testosterone and increased synthesis of oestrogens and progesterone.

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