Chapter 24

Lipid Biosynthesis

Biochemistry

by

Reginald Garrett and Charles Grisham

Outline

1. How Are Fatty Acids Synthesized?2. How Are Complex Lipids Synthesized?3. How Are Eicosanoids Synthesized, and What

Are Their Functions?4. How Is Cholesterol Synthesized?5. How Are Lipids Transported Throughout the

Body?6. How Are Bile Acids Biosynthesized?7. How Are Steroid Hormones Synthesized and

Utilized?

24.1 – How Are Fatty Acids Synthesized?

The Biosynthesis and Degradation Pathways are Different

• As in cases of glycolysis/gluconeogenesis and glycogen synthesis/breakdown, fatty acid synthesis and degradation go by different routes

• There are five major differences between fatty acid breakdown and biosynthesis

The Differences Between fatty acid biosynthesis and breakdown

1. Intermediates in synthesis are linked to -SH groups of acyl carrier proteins (as compared to -SH groups of CoA)

2. Synthesis in cytosol; breakdown in mitochondria

3. Enzymes of synthesis are one polypeptide (fatty acid synthase) in animals

4. Biosynthesis uses NADPH/NADP+; breakdown uses NADH/NAD+ & FAD

5. Stereochemistry (D--hydroxyacyl)

Activation by Malonyl-CoAAcetate Units are Activated for Transfer in Fatty

Acid Synthesis by Malonyl-CoA• Fatty acids are built from 2-C units -- acetyl-CoA• Acetate units are activated for transfer by

conversion to malonyl-CoA• Decarboxylation of malonyl-CoA and reducing

power of NADPH drive chain growth• Chain grows to 16-carbons (palmitate)• Other enzymes add double bonds and more Cs

The sources of Acetyl-CoA• Amino acid degradation produces cytosolic

acetyl-CoA

• Fatty acid oxidation produces mitochondrial acetyl-CoA

• Glycolysis yields cytosolic pyruvate which is converted to acetyl-CoA in mitochondria

• Citrate-malate-pyruvate shuttle provides cytosolic acetate units and reducing equivalents for fatty acid synthesis

The reducing power: NAPDH

• Produced by malic enzyme

• Produced in pentose phosphate pathway (chapter 22)

The "ACC enzyme" commits acetate to fatty acid synthesis

Acetyl-CoA Carboxylase

• Carboxylation of acetyl-CoA to form malonyl-CoA is the irreversible, committed step in fatty acid biosynthesis

• ACC uses bicarbonate and ATP (& biotin)– E.coli enzyme has three subunits– Animal enzyme is one polypeptide with all three

functions - biotin carboxyl carrier, biotin carboxylase and transcarboxylase

Figure 24.2(a) The acetyl-CoA carboxylase reaction produces malonyl-CoA for fatty acid synthesis. (b) A mechanism for the acetyl-CoA carboxylase reaction. Bicarbonate is activated for carboxylation reactions by formation of N-carboxybiotin. ATP drives the reaction forward, with transient formation of a carbonylphosphate intermediate (Step 1). In a typical biotin-dependent reaction, nucleophilic attack by the acetyl-CoA carbanion on the carboxyl carbon of N-carboxybiotin - a transcarboxylation - yields the carboxylated product (Step 2).

Malonyl-CoA

Figure 24.3In the acetyl-CoA carboxylase reaction, the biotin ring, on its flexible tether, acquires carboxyl groups from carbonylphosphate on the carboxylase subunit and transfers them to acyl-CoA molecules on the transcarboxylase subunits.

Acetyl-CoA Carboxylase

ACC forms long, active filamentous polymers from inactive protomers

• As a committed step, ACC is carefully regulated

• Palmitoyl-CoA (product) favors monomers• Citrate favors the active polymeric form

CitrateInactive protomers active polymer

Acyl-CoA

Figure 24.4Models of the acetyl-CoA carboxylase polypeptide, with phosphorylation sites indicated, along with the protein kinases responsible. Phosphorylation at Ser1200 is primarily responsible for decreasing the affinity for citrate.

Phosphorylation of ACC modulates activation by citrate and inhibition by

palmitoyl-CoA • Unphosphorylated E has high affinity for

citrate and is active at low [citrate]

• Unphosphorylated E has low affinity for palm-CoA and needs high [palm-CoA] to inhibit

• Phosphorylated E has low affinity for citrate and needs high [citrate] to activate

• Phosphorylated E has high affinity for palm-CoA and is inhibited at low [palm-CoA]

Figure 24.5The activity of acetyl-CoA carboxylase is modulated by phosphorylation and dephosphorylation. The dephospho form of the enzyme is activated by low [citrate] and inhibited only by high levels of fatty acyl-CoA. In contrast, the phosphorylated form of the enzyme is activated only by high levels of citrate, but is very sensitive to inhibition by fatty acyl-CoA.

The acyl carrier protein carry the intermediates in fatty acid synthesis

• ACP is a 77 residue protein in E. coli - with a phosphopantetheine

• The same functional group of CoA

Fatty Acid Synthesis

• Acetyl-CoA-ACP transacylases (ATase)• Malonyl-CoA-ACP transacylases (MTase)• -ketoacyl-ACP synthase (KSase)• -ketoacyl-ACP reductase (KRase)• -hydroxyacyl-ACP dehydratase (DH)• Enoyl-ACP reductase (ERase)• Thioesterase (TEase) in animals

Figure 24.7The pathway of palmitate synthesis from acetyl-CoA and malonyl-CoA. Acetyl and malonyl building blocks are introduced as acyl carrier protein conjugates. Decarboxylation drives the-ketoacyl-ACP synthase and results in the addition of two-carbon units to the growing chain. Concentrations of free fatty acids are extremely low in most cells, and newly synthesized fatty acids exist primarily as acyl-CoA esters.

Fatty Acid Synthesis in Bacteria and Plants

• The separate enzymes in bacteria and plants• Pathway initiated by formation of acetyl-ACP

and malonyl-ACP by transacylases • Decarboxylation drives the condensation of

acetyl-CoA and malonyl-CoA by KSase• Next three steps look very similar to the fatty

acid oxidation in reverse • Only differences: D configuration and NADPH

Fatty Acid Synthesis

Acetyl-CoA + 7 malonyl-CoA + 14 NAPDH + 14 H+

Palmitoyl-CoA + 7 HCO3- + 14 NAPD+ + 7 CoA-SH

The formation of malonyl-CoA:

7 Acetyl-CoA + 7 HCO3- + 7 ATP4-

7 malonyl-CoA + 7 ADP3- + 7Pi2- +7H+

The overall reaction:8 Acetyl-CoA + 7 ATP4- + 14 NAPDH + 14 H+

Palmitoyl-CoA + 14 NAPD+ + 7 CoA-SH + 7 ADP3- + 7Pi2-

In yeast: 66

Figure 24.8In yeast, the functional groups and enzyme activities required for fatty acid synthesis are distributed between - and -subunits.

(213 KD)

(203 KD)

Fatty Acid Synthase in Animals

Fatty Acid Synthase - a multienzyme complex

• Dimer of 250 kD multifunctional polypeptides– Domain 1: AT, MT & KSase– Domain 2: ACP, KRase, DH, ERase– Domain 3: Thioesterase

Figure 24.9Fatty acid synthase in animals contains all the functional groups and enzyme activities on a single multifunctional subunit. The active enzyme is a head-to-tail dimer of identical subunits. (Adapted from Wakil, S. J., Stoops, J. K., and Joshi, V. C., 1983.Fatty acid synthesis and its regulation. Annual Review of Biochemistry 52:537-579.)

Figure 24.10Acetyl units are covalently linked to a serine residue at the active site of the acetyl transferase in eukaryotes. A similar reaction links malonyl units to the malonyl transferase.

Further Processing of FAs

Additional elongation & desaturation • Additional elongation occurs in

mitochondria and the surface of ER• The reducing coenzyme for the second step

is NADH, whereas the reductant for the fourth step is NADPH.

• In ER, involving malonyl-CoA

Figure 24.12Elongation of fatty acids in mitochondria is initiated by the thiolase reaction. The -ketoacyl intermediate thus formed undergoes the same three reactions (in reverse order) that are the basis of -oxidation of fatty acids. Reduction of the -keto group is followed by dehydration to form a double bond. Reduction of the double bond yields a fatty acyl-CoA that is elongated by two carbons. Note that the reducing coenzyme for the second step is NADH, whereas the reductant for the fourth step is NADPH.

( in mitochondria)

Further Processing of FAsIntroduction of cis double bonds

• E.coli add double bonds during the fatty acid synthesis

• After four normal cycles, -hydroxydecanoyl thioester dehydrase forms a double bond to the thioester

• O2-independent

Figure 24.13Double bonds are introduced into the growing fatty acid chain in E. coli by specific dehydrases. Palmitoleoyl-ACP is synthesized by a sequence of reactions involving four rounds of chain elongation, followed by double bond insertion by -hydroxydecanoyl thioester dehydrase and three additional elongation steps. Another elongation cycle produces cis-vaccenic acid.

Further Processing of FAsIntroduction of cis double bonds

• Eukaryotes add double bond until the fatty acyl chain has reached its full length (usually 16 to 18 carbons)

• Desaturase• Cytochrome b5 reductase & Cytochrome b5 • All three proteins are ssociated with the ER

membrane• NADH & O2 are required; O2-dependent

Figure 24.14The conversion of stearoyl-CoA to oleoyl-CoA in eukaryotes is catalyzed by stearoyl-CoA desaturase in a reaction sequence that also involves cytochrome b5 and cytochrome b5 reductase. Two electrons are passed from NADH through the chain of reactions as shown, and two electrons are also derived from the fatty acyl substrate. linoleic acid in eukaryotes. This is the only means by which animals can synthesize fatty acids with double bonds at positions beyond C-9.

• Mammals cannot synthesize most polyunsaturated fatty acids– Essential fatty acids– Introduce double bonds between the double bond at

the 8- or 9- position and the carboxyl group– form a double bond at 5-position (6) if one already

exists at the 8-position (9)

Arachidonic acid

• mammals can also add double bonds to unsaturated fatty acids

• synthesized from linoleic acid in eukaryotes

• The precursor for prostaglandins and other biologically active derivatives

Figure 24.15Arachidonic acid is synthesized from linoleic acid in eukaryotes. This is the only means by which animals can synthesize fatty acids with double bonds at positions beyond C-9.

Regulation of Fatty Acid Synthesis

Allosteric modifiers, phosphorylation and hormones

• Allosteric regulation – Malonyl-CoA blocks the carnitine acyltransferase

and thus inhibits -oxidation– Citrate activates acetyl-CoA carboxylase– Fatty acyl-CoAs inhibit acetyl-CoA carboxylase

Figure 24.16Regulation of fatty acid synthesis and fatty acid oxidation are coupled as shown. Malonyl-CoA, produced during fatty acid synthesis, inhibits the uptake of fatty acylcarnitine (and thus fatty acid oxidation) by mitochondria. When fatty acyl-CoA levels rise, fatty acid synthesis is inhibited and fatty acid oxidation activity increases. Rising citrate levels (which reflect an abundance of acetyl-CoA) similarly signal the initiation of fatty acid synthesis.

Regulation of FA Synthesis

• Phosphorylation and hormones– Citrate activation and acyl-CoA inhibition of ACC

are dependent on the phosphorylation state– Phosphorylation causes inhibition of fatty acid

biosynthesis

• Hormone signals regulate ACC and fatty acid biosynthesis– Glucagon activates lipases/inhibits ACC– Insulin inhibits lipases/activates ACC

Figure 24.17Hormonal signals regulate fatty acid synthesis, primarily through actions on acetyl-CoA carboxylase. Availability of fatty acids also depends upon hormonal activation of triacylglycerol lipase.

24.2 – How Are Complex Lipids Synthesized?

Complexed lipids:1. Glycerolipid

– Triacylglycerols– Glycerophospholipids

2. Sphingolipids

Phospholipids (membrane components)1. Glycerophospholipids 2. Sphingolipids

Synthetic pathways depend on different organism

• Sphingolipids and triacylglycerols only made in eukaryotes

• Phosphatidylethanolamine (PE) accounts for 75% of phospholipids in E.coli– No PC, PI, sphingolipids, cholesterol in E.coli– But some bacteria do produce PC

Glycerolipid Biosynthesis

Glycerolipids are synthesized by phosphorylation & acylation of glycerol

• Phosphatidic acid (PA) is the precursor for all other glycerolipids in eukaryotes

• Eukaryotic systems can also utilize DHAP as a starting point

Figure 24.18Synthesis of glycerolipids in eukaryotes begins with the formation of phosphatidic acid, which may be formed from dihydroxyacetone phosphate or glycerol as shown.

Unsatuated Fatty Acid

Satuated Fatty Acid

Glycerolipid Biosynthesis

• PA is converted either to DAG or CDP-DAG

• DAG is a precursor for synthesis of TAG, phosphatidylethanolamine (PE) and phosphatidylcholine (PC)

• TAG is synthesized mainly in adipose tissue, liver, and intestines

Figure 24.19Diacylglycerol and CDP-diacylglycerol are the principal precursors of glycerolipids in eukaryotes. Phosphatidylethanolamine and phosphatidylcholine are formed by reaction of diacylglycerol with CDP-ethanolamine or CDP-choline, respectively.

Glycerolipid Biosynthesis

• PE synthesis – begins with phosphorylation of ethanolamine to

form phosphoethanolamine– Transfer of a cytidylyl group from CTP to from

CDP-ethanolamine– Phosphoethanolamine transferase link

phosphoethanolamine to the DAG

• Synthesis of PC is entirely analogous

• PC can also be converted from PE by methylation reactions

Figure 24.21The interconversion of phosphatidylethanolamine and phosphatidylserine in mammals.

• Exchange of ethanolamine for serine converts PE to PS (phosphatidylserine)

Other PLs from CDP-DAG

Figure 24.22• CDP-diacylglycerol is used in eukaryotes to

produce:– Phosphatiylinositol (PI) in one step

• 2-8% in animal membrane• Breakdown to form inositol-1,4,5-triphosphate &

DAG (second messengers)

– Phosphatiylglycerol (PG) in two steps– Cardiolipin in three steps

Figure 24.22CDP-diacylglycerol is a precursor of phosphatidylinositol, phosphatidylglycerol, and cardiolipin in eukaryotes.

Plasmalogen Biosynthesis

Dihydroxyacetone phosphate (DHAP) is the precursor to the plasmalogens

• Acylation of DHAP• Exchange reaction produces the ether

linkage by long-chain alcohol (acyl-CoA reductase)

• Ketone reduction• Acylation again• CDP-ethanolamine delivers the head group• A desaturase produces the double bond in

the alkyl chain

Figure 24.23Biosynthesis of plasmalogens in animals. (1) Acylation at C-1 is followed by (2) exchange of the acyl group for a long-chain alcohol.(3) Reduction of the keto group at C-2 is followed by (4 and 5) transferase reactions, which add an acyl group at C-2 and a polar head-group moiety, and a (6) desaturase reaction that forms a double bond in the alkyl chain. The first two enzymes are of cytoplasmic origin, and the last transferase is located at the endoplasmic reticulum.

Acyl-CoA

Acyl-CoA reductase

Figure 24.24Platelet-activating factor, formed from 1-alkyl-2-lysophosphatidylcholine by acetylation at C-2, is degraded by the action of acetylhydrolase.

Sphingolipid BiosynthesisHigh levels made in neural tissue

1. Initial reaction is a condensation of serine and palmitoyl-CoA (by 3-ketosphinganine synthase)

– 3-ketosphinganine synthase is PLP-dependent

2. Ketone is reduced with help of NADPH3. Acylation to form N-acyl-sphinganine4. Desaturated to form ceramide• Ceramide is precursor for other sphingolipids

Figure 24.25Biosynthesis of sphingolipids in animals begins with the 3-ketosphinganine synthase reaction, a PLP-dependent condensation of palmitoyl-CoA and serine. Subsequent reduction of the keto group, acylation, and desaturation (via reduction of an electron acceptor, X) form ceramide, the precursor of other sphingolipids.

Sphingolipid BiosynthesisCeramide is precursor for other sphingolipids

• Sphingomyelin– Rich in myelin sheath– Insulates nerve axons– By transfer of phosphocholine from PC

• Cerebrosides– Glycosylation of ceramide– Galactosylceramide makes up ~15% of the lipid of

myelin sheath

• Gangliosides – Cerebrosides contain one or more sialic acid

Figure 24.26Glycosylceramides (such as galactosylceramide), gangliosides, and sphingomyelins are synthesized from ceramide in animals.

Gangliosides

1. UDP-glucose

2. UDP-galactose

3. UDP-N-acetylgalactosamine

4. CMP-sialic acid

(N-acetylneuraminidate)

24.3 – How Are Eicosanoid Synthesized and What Are Their Functions?

• Eicosanoid are all derived from 20-carbon fatty acid (arachidonic acid)

• Eicosanoids are local hormones1. Exert their effect at very low concentration2. Usually act near their sites of synthesis

• PLA2 releases arachidonic acid from phospholipids (PC)

• Can be released by PLC & DAG lipase

Figure 24.27Arachidonic acid, derived from breakdown of phospholipids (PL), is the precursor of prostaglandins, thromboxanes, and leukotrienes. The letters used to name the prostaglandins are assigned on the basis of similarities in structure and physical properties. The class denoted PGE, for example, consists of -hydroxyketones that are soluble in ether, whereas PGF denotes 1,3-diols that are soluble in phosphate buffer. PGA denotes prostaglandins possessing ,-unsaturated ketones. The number following the letters refers to the number of carbon - carbon double bonds. Thus, PGE2 contains two double bonds.

Specificities of phospholipases A1, A2, C, and D.

Eicosanoids are local hormones• Eicosanoids include

– Prostaglandins (PG)– Thromboxanes (Tx)– Leukotrienes– Other hydroxyeicosanoic acid

• Tissue injury and inflammation triggers arachidonate release and eicosanoid synthesis

• All PGs are cyclopentanoic acids • Initiated by PGH synthase associated with

the ER

• PGH synthase• Prostaglandin

endoperoxide synthase• Cyclooxygenase

• Catalyzes simultineous oxidation and cyclization of arachidonic acid

Two isoforms in animals

(a) COX-1: normal, physiological production of PG

(b) COX-2: induced by cytokines, mitogens, and endotoxins in inflammatory cells

(a) COX-1 (b) COX-2

Aspirin & NSAIDs

• Aspirin and other nonsteroid anti-inflammatory drugs (NSAIDs) inhibit the cyclooxygenase– Aspirin covalently– Others noncovalently

Specifically inhibition of COX2

24.4 – How Is Cholesterol Synthesized?

Occurs primarily in the liver

• The most prevalent steroid in animal cells is cholesterol

• Serve as cell membranes, precursor of bile acids and steroid hormones, and vitamin D3

Occurs primarily in the liver

• Biosynthesis begins in the cytosol with the synthesis of mevalonate from acetyl-CoA

1. First step is a thiolase reaction

2. Second step makes HMG-CoA

3. Third step produces 3R-mevalonate • HMG-CoA reductase• The rate-limiting step in cholesterol

biosynthesis• HMG-CoA reductase is site of action

of cholesterol-lowering drugs

Figure 24.32A reaction mechanism for HMG-CoA reductase. Two successive NADPH-dependent reductions convert the thioester, HMG-CoA, to a primary alcohol.

Regulation of HMG-CoA ReductaseAs rate-limiting step, it is the principal site of

regulation in cholesterol synthesis1. Phosphorylation by cAMP-dependent

kinases inactivates the reductase2. Degradation of HMG-CoA reductase -

half-life is 3 hrs and depends on cholesterol level: High [cholesterol] means a short half-time

3. Gene expression (mRNA production) is controlled by cholesterol levels: If [cholesterol] is low, more mRNA is made

Figure 24.33HMG-CoA reductase activity is modulated by a cycle of phosphorylation and dephosphorylation.

Squalene is synthesized from Mevalonate

• Six-carbon mevalonate makes 5-carbon isopentenyl pyrophosphate and dimethylallyl pyrophosphate

• Condensation of these two 5-carbon intermediates produces geranyl pyrophosphate (10-carbon)

• Addition of another isopentenyl pyrophosphate yields farnesyl pyrophosphate

• Two farnesyl pyrophosphates link to form squalene

Figure 24.34The conversion of mevalonate to squalene.

• Bloch and Langdon were first to show that squalene is derived from acetate units and that cholesterol is derived from squalene

geranyl pyrophosphate

Cholesterol from Squalene

At the endoplasmic reticulum membrane• Squalene monooxygenase converts

squalene to squalene-2,3-epoxide• 2,3-oxidosqualene:lanosterol cyclase

converts the epoxide to lanosterol• Though lanosterol looks like cholesterol, 20

more steps are required to form cholesterol• All at/in the endoplasmic reticulum

membrane

Figure 24.35Cholesterol is synthesized from squalene via lanosterol. The primary route from lanosterol involves 20 steps, the last of which converts 7-dehydrocholesterol to cholesterol. An alternative route produces desmosterol as the penultimate intermediate.

Inhibiting Cholesterol SynthesisMerck and the Lovastatin story...

• HMG-CoA reductase is the key - the rate-limiting step in cholesterol biosynthesis

• Lovastatin (mevinolin) blocks HMG-CoA reductase and prevents synthesis of cholesterol

• Lovastatin is an (inactive) lactone• In the body, the lactone is hydrolyzed to

mevinolinic acid, a competitive inhibitor of the reductase, Ki = 0.6 nM

HB page 797The structures of (inactive ) lovastatin, (active) mevinolinic acid, mevalonate, and synvinolin.

24.5 – How Are Lipids Transported Throughout the Body?

Lipoproteins are the carriers of most lipids in the body

• Lipoprotein - a cluster of lipids, often with a monolayer membrane (phospholipids), together with an apolipoprotein

• HDL & VLDL are assembled primarily in the ER of liver cells (some in intestines)

• Chylomicrons form in the intestines

• LDL not made directly, but is made from VLDL

• LDL appears to be the major circulatory complex for cholesterol & cholesterol esters

Lipoproteins

Lipoproteins• Chylomicrons carry TAG & cholesterol

esters from intestine to other tissues• VLDLs carry lipid from liver• Mostly in the capillaries of muscle and

adipose cells, lipoprotein lipases hydrolyze triglycerides from lipoproteins, making the lipoproteins smaller and raising their density

• Thus chylomicrons and VLDLs are progressively converted to IDL and then LDL, which either return to the liver for reprocessing or are redirected to adipose tissues and adrenal glands

Figure 24.38Lipoprotein components are synthesized predominantly in the ER of liver cells. Following assembly of lipoprotein particles (red dots) in the ER and processing in the Golgi, lipoproteins are packaged in secretory vesicles for export from the cell (via exocytosis) and released into the circulatory system.

Lipoproteins

• LDLs are main carriers of cholesterol and cholesterol esters

• Newly formed HDL contains virtually no cholesterol esters– Cholesterol esters are accumulated through the

action lecithin:cholesterol acyltransferase (LCAT)

• HDLs function to return cholesterol and cholesterol esters to the liver

Figure 24.39Endocytosis and degradation of lipoprotein particles. (ACAT is acyl-CoA cholesterol acyltransferase.)

The LDL Receptor

A complex plasma membrane protein• LDL binding domain on N-terminus• N-linked and O-linked oligosaccharide domains• A single TMS• A cytosolic domain essential to aggregation of

receptors in the membrane during endocytosis• Dysfunctions in or absence of LDL receptors

lead to familial hypercholesterolemia

Figure 24.40The structure of the LDL receptor. The amino-terminal binding domain is responsible for recognition and binding of LDL apoprotein. The O-linked oligosaccharide-rich domain may act as a molecular spacer, raising the binding domain above the glycocalyx. The cytosolic domain is required for aggregation of LDL receptors during endocytosis.

24.6 – How Are Bile Acids Biosynthesized?

Carboxylic acid derivatives of cholesterol• Essential for the digestion of food, especially for

solubilization of ingested fats • Synthesized from cholesterol in the liver, stored in

the gallbladder, and secreted as need into the intestine

• Cholic acid conjugates with taurine and glycine to form taurocholic and glycocholic acids

• First step is oxidation of cholesterol by a mixed-function oxidase (7-hydroxylase)

24.7 – How Are Steroid Hormones Synthesized and Utilized?

Desmolase (in mitochondria) converts cholesterol to pregnenolone, precursor to all others

• Pregnenolone migrates from mitochondria to ER where progesterone is formed

• Progesterone is a branch point - it produces sex steroids (testosterone and estradiol), and corticosteroids (cortisol and aldosterone)

Figure 24.43The steroid hormones are synthesized from cholesterol, with intermediate formation of pregnenolone and progesterone. Testosterone, the principal male sex hormone steroid, is a precursor to -estradiol. Cortisol, a glucocorticoid, and aldosterone, a mineralocorticoid, are also derived from progesterone.

(27C) (21C)

(19C)

(18C)

aromatase

Figure 24.44The structure of stanozolol, an anabolic steriod.

• Anabolic steroids are illegal and dangerous