Biochemistry, 4th Edition P80 docx

In the cholesterol synthesis pathway, subsequent reactions, including HMG-CoA reductase and the following kinase reactions, pull the thiolase-catalyzed con-densation forward.. The first t

that the thiolase reaction is more or less reversible but slightly favors the cleavage

re-action In the cholesterol synthesis pathway, subsequent reactions, including

HMG-CoA reductase and the following kinase reactions, pull the thiolase-catalyzed

con-densation forward However, in the case of fatty acid synthesis, a succession of eight

thiolase condensations would be distinctly unfavorable from an energetic

perspec-tive Given the necessity of repeated reactions in fatty acid synthesis, it makes better

energetic sense to use a reaction that is favorable in the desired direction

Squalene Is Synthesized from Mevalonate

The biosynthesis of squalene involves conversion of mevalonate to two key 5-carbon

intermediates, isopentenyl pyrophosphate and dimethylallyl pyrophosphate, which join to

yield farnesyl pyrophosphate and then squalene A series of four reactions converts

mevalonate to isopentenyl pyrophosphate and then to dimethylallyl pyrophosphate

(Figure 24.34) The first three steps each consume an ATP, two for the purpose of

forming a pyrophosphate at the 5-position and the third to drive the decarboxylation

CRITICAL DEVELOPMENTS IN BIOCHEMISTRY

The Long Search for the Route of Cholesterol Biosynthesis

colleagues at Merck Sharpe & Dohme isolated mevalonic acid and also showed that mevalonate was the precursor of isoprene units The search for the remaining details (described in the text) made the biosynthesis of cholesterol one of the most enduring and challenging bioorganic problems of the 1940s, 1950s, and 1960s Even today, several of the enzyme mechanisms remain poorly understood

C H

CH3

C CH2

CH2

OH

(

(a)

(b)

Isoprene

Squalene

Lanosterol

Many steps)

Cholesterol

䊱 (a) An isoprene unit and a scheme for head-to-tail linking of isoprene units (b) The

cycliza-tion of squalene to form lanosterol, as proposed by Bloch and Woodward.

Heilbron, Kamm, and Owens suggested as early as 1926 that

squa-lene is a precursor of cholesterol That same year, H J Channon

demonstrated that animals fed squalene from shark oil produced

more cholesterol in their tissues Bloch and Rittenberg showed in

the 1940s that a significant amount of the carbon in the tetracyclic

moiety and in the aliphatic side chain of cholesterol was derived

from acetate In 1934, Sir Robert Robinson suggested a scheme for

the cyclization of squalene to form cholesterol before the

biosyn-thetic link between acetate and squalene was understood Squalene

is actually a polymer of isoprene units, and Bonner and Arreguin

suggested in 1949 that three acetate units could join to form

five-carbon isoprene units (see figure a).

In 1952, Konrad Bloch and Robert Langdon showed

conclu-sively that labeled squalene is synthesized rapidly from labeled

ace-tate and also that cholesterol is derived from squalene Langdon, a

graduate student of Bloch’s, performed the critical experiments in

Bloch’s laboratory at the University of Chicago while Bloch spent

the summer in Bermuda attempting to demonstrate that

radio-actively labeled squalene would be converted to cholesterol in

shark livers As Bloch himself admitted, “All I was able to learn was

that sharks of manageable length are very difficult to catch and

their oily livers impossible to slice” (Bloch, 1987)

In 1953, Bloch, together with the eminent organic chemist

R B Woodward, proposed a new scheme (see figure b) for the

cy-clization of squalene (Together with Fyodor Lynen, Bloch

re-ceived the Nobel Prize in Medicine or Physiology in 1964 for his

work.) The picture was nearly complete, but one crucial question

remained: How could isoprene be the intermediate in the

trans-formation of acetate into squalene? In 1956, Karl Folkers and his

754 Chapter 24 Lipid Biosynthesis

HMG-CoA

reductase kinase

(inactive)

P

HMG-CoA

reductase

kinase kinase

HPO4–

HMG-CoA reductase kinase phosphatase

HMG-CoA

reductase kinase

(active)

HPO4–

HMG-reductase phosphatase

P

HMG-CoA reductase (inactive)

HMG-CoA reductase (active)

ATP

ADP

ATP

H2O

CoA

FIGURE 24.33 HMG-CoA reductase activity is modulated

by a cycle of phosphorylation and dephosphorylation.

CH2OH

H3C C

OH –OOC

H3C C OH

CH2O

CH2

H3C C

H2C

H

CH2O

H3C

H3C

P

+ +

P

P P

P P

CH2 CH2

CH2 CH2

P

P P

P P

CH2

H

H3C

H3C

CH2

CH2

H

CH2

H

CH2O P P

P P

+

+

2

H3C

H3C

ATP + H2O

ATP

ADP

ATP

ADP

NADP+

NADPH H +

Mevalonate

Mevalonate kinase

5-Pyrophosphomevalonate

Phosphomevalonate

kinase

Pyrophosphomevalonate

decarboxylase

Isopentenyl pyrophosphate

Isopentenyl pyrophosphate isomerase

Dimethylallyl pyrophosphate

Isopentenyl pyrophosphate

Isopentenyl pyrophosphate

Farnesyl pyrophosphate

Squalene FIGURE 24.34 The conversion of mevalonate to squalene In the last step, two farnesyl-PP condense to form squalene.

and double bond formation in the third step Pyrophosphomevalonate decarboxylase

phosphorylates the 3-hydroxyl group, and this is followed by trans elimination of

the phosphate and carboxyl groups to form the double bond in isopentenyl

pyro-phosphate Isomerization of the double bond yields the dimethylallyl pyropyro-phosphate

Condensation of these two 5-carbon intermediates produces geranyl pyrophosphate;

ad-dition of another 5-carbon isopentenyl group gives farnesyl pyrophosphate Both steps

in the production of farnesyl pyrophosphate occur with release of pyrophosphate,

hy-drolysis of which drives these reactions forward Note too that the linkage of isoprene

units to form farnesyl pyrophosphate occurs in a head-to-tail fashion This is the

gen-eral rule in biosynthesis of molecules involving isoprene linkages The next step—the

joining of two farnesyl pyrophosphates to produce squalene—is a “tail-to-tail”

con-densation and represents an important exception to the general rule

HUMAN BIOCHEMISTRY

Statins Lower Serum Cholesterol Levels

Chemists and biochemists have long sought a means of reducing

serum cholesterol levels to reduce the risk of heart attack and

car-diovascular disease Because HMG-CoA reductase is the

rate-limiting step in cholesterol biosynthesis, this enzyme is a likely drug

target Mevinolin, also known as lovastatin (see accompanying

fig-ure), was isolated from a strain of Aspergillus terreus and developed

at Merck Sharpe & Dohme for this purpose It is now a widely

pre-scribed cholesterol-lowering drug Dramatic reductions of serum

cholesterol are observed at dosages of 20 to 80 mg per day

Lovastatin is administered as an inactive lactone After oral

in-gestion, it is hydrolyzed to the active mevinolinic acid, a competitive

inhibitor of the reductase with a KIof 0.6 nM Mevinolinic acid is

thought to behave as a transition-state analog (see Chapter 14) of the tetrahedral intermediate formed in the HMG-CoA reductase re-action (see figure)

Derivatives of lovastatin have been found to be even more potent

in cholesterol-lowering trials Synvinolin lowers serum cholesterol

levels at much lower dosages than lovastatin Lipitor, shown bound

at the active site of HMG-CoA reductase, is the most-prescribed drug

in the United States, with annual sales of $9 billion

O R

CH3

H

CH3 O

O

O

CH3

(a)

CH3

R

H O

O HO

1 R=H Mevinolin (Lovastatin, MEVACOR ®)

2 R=CH3Synvinolin (Simvastatin, ZOCOR ®)

CH3

H

CH3

O

CH3

CH3

H OH

HO

COO–

H OH

HO

COO–

Mevinolinic acid

OH

HO

COO–

H3C

Mevalonate

HO

COO–

H3C

H OH

SCoA

Tetrahedral intermediate

in HMG-CoA reductase mechanism

CH

CH3

CH2

F

CH3 NHC

N

Lipitor ®

(Atorvastatin)

HMG-CoA reductase with NADP+ (magenta), HMG (blue), and CoA (green) (pdb id = 1DQA)

Lipitor ® (red) bound at the active site of HMG-CoA reductase (pdb id = 1HWK)

䊱 The structures of (a) (inactive) lovastatin, (active) mevinolinic acid, mevalonate, and (b) Lipitor (atorvastatin)

(c)HMG-CoA reductase with NADP, HMG, and CoA (d) Lipitor bound at the HMG-CoA reductase active site.

756 Chapter 24 Lipid Biosynthesis

HO O

H3C CH3

H3C

H3C

H+

H+

CH3

HO

H3C

H3C

HO

H3C

H3C

HO

H3C

H3C

C R O

H3C

H3C

O C R O CoASH SCoA

Squalene

Lanosterol

Squalene monooxygenase

Squalene-2,3-epoxide

2,3-Oxidosqualene:

lanosterol cyclase

7-Dehydrocholesterol

Many steps (alternative route)

Cholesterol

Cholesterol esters

Desmosterol

Acyl-CoA cholesterol acyltransferase (ACAT) Many steps

FIGURE 24.35 Cholesterol 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.

Squalene monooxygenase, an enzyme bound to the ER, converts squalene to

squalene -2,3- epoxide (Figure 24.35) This reaction employs FAD and NADPH as

coenzymes and requires O2 as well as a cytosolic protein called soluble protein

activator A second ER membrane enzyme, 2,3-oxidosqualene lanosterol cyclase,

catalyzes the second reaction, which involves a succession of 1,2 shifts of hydride

ions and methyl groups

Conversion of Lanosterol to Cholesterol Requires 20 Additional Steps

Although lanosterol may appear similar to cholesterol in structure, another 20 steps

are required to convert lanosterol to cholesterol (Figure 24.35) The enzymes

responsible for this are all associated with the ER The primary pathway involves

7-dehydrocholesterol as the penultimate intermediate An alternative pathway, also

composed of many steps, produces the intermediate desmosterol Reduction of the

double bond at C-24 yields cholesterol Cholesterol esters—a principal form of

cir-culating cholesterol—are synthesized by acyl-CoA ⬊cholesterol acyltransferases

(ACAT)on the cytoplasmic face of the ER

When most lipids circulate in the body, they do so in the form of lipoprotein

complexes.Simple, unesterified fatty acids are merely bound to serum albumin and

other proteins in blood plasma, but phospholipids, triacylglycerols, cholesterol, and

cholesterol esters are all transported in the form of lipoproteins At various sites in

the body, lipoproteins interact with specific receptors and enzymes that transfer or

modify their lipid cargoes It is now customary to classify lipoproteins according to

their densities (Table 24.1) The densities are related to the relative amounts of lipid

and protein in the complexes Because most proteins have densities of about 1.3 to

1.4 g/mL, and lipid aggregates usually possess densities of about 0.8 g/mL, the more

protein and the less lipid in a complex, the denser the lipoprotein Thus, there are

high-density lipoproteins (HDLs), low-density lipoproteins (LDLs),

intermediate-density lipoproteins (IDLs), very-low-density lipoproteins (VLDLs), and also

chylomicrons. Chylomicrons have the lowest protein-to-lipid ratio and thus are

the lowest-density lipoproteins They are also the largest

Lipoprotein Complexes Transport Triacylglycerols and Cholesterol Esters

HDL and VLDL are assembled primarily in the ER of the liver (with smaller amounts

produced in the intestine), whereas chylomicrons form in the intestine LDL is not

synthesized directly but rather is made from VLDL LDL appears to be the major

cir-culatory complex for cholesterol and cholesterol esters The primary task of

chy-lomicrons is to transport triacylglycerols Despite all this, it is extremely important to

note that each of these lipoprotein classes contains some of each type of lipid The

relative amounts of HDL and LDL are important in the disposition of cholesterol in

the body and in the development of arterial plaques (Figure 24.36) The structures of

Composition (% dry weight)

Adapted from Brown, M., and Goldstein, J., 1987 In Braunwald, E., et al., eds., Harrison’s Principles of Internal Medicine, 11th ed New York: McGraw-Hill; and Vance, D., and Vance, J., eds., 1985.

TABLE 24.1 Composition and Properties of Human Lipoproteins

FIGURE 24.36 Photograph of an arterial plaque The view is into the artery (orange), with the plaque shown

in yellow at the back.

758 Chapter 24 Lipid Biosynthesis

the various lipoproteins are approximately similar, and they consist of a core of mo-bile triacylglycerols or cholesterol esters surrounded by a single layer of phospholipid, into which is inserted a mixture of cholesterol and proteins (Figure 24.37) Note that the phospholipids are oriented with their polar head groups facing outward to inter-act with solvent water and that the phospholipids thus shield the hydrophobic lipids inside from the solvent water outside The proteins also function as recognition sites for the various lipoprotein receptors throughout the body A number of different apoproteins have been identified in lipoproteins (Table 24.2), and others may exist

as well The apoproteins have an abundance of hydrophobic amino acid residues, as

is appropriate for interactions with lipids A cholesterol ester transfer protein also

as-sociates with lipoproteins

Lipoproteins in Circulation Are Progressively Degraded

by Lipoprotein Lipase

The livers and intestines of animals are the primary sources of circulating lipids Chy-lomicrons carry triacylglycerol and cholesterol esters from the intestines to other tis-sues, and VLDLs carry lipid from liver, as shown in Figure 24.38 At various target sites, particularly in the capillaries of muscle and adipose cells, these particles are

de-graded by lipoprotein lipase, which hydrolyzes triacylglycerols Lipase action causes

progressive loss of triacylglycerol (and apoprotein) and makes the lipoproteins smaller This process gradually converts VLDL particles to IDL and then LDL parti-cles, which are either returned to the liver for reprocessing or redirected to adipose tissues and adrenal glands Every 24 hours, nearly half of all circulating LDL is re-moved from circulation in this way The LDL binds to specific LDL receptors, which

cluster in domains of the plasma membrane known as coated pits (discussed in sub-sequent paragraphs) These domains eventually invaginate to form coated vesicles (Figure 24.39), which pinch off from the plasma membrane and form endosomes

(literally “bodies inside” the cell) In the low pH environment of the endosome, the LDL particles dissociate from their receptors The endosomes then fuse with

lyso-somes, and the LDLs are degraded by lysosomal acid lipases.

HDLs have much longer life spans in the body (5 to 6 days) than other lipopro-teins Newly formed HDL contains virtually no cholesterol ester However, over

time, cholesterol esters are accumulated through the action of lecithin ⬊cholesterol acyltransferase (LCAT),a 59-kD glycoprotein associated with HDLs Another

asso-ciated protein, cholesterol ester transfer protein, transfers some of these esters to

VLDL and LDL Alternatively, HDLs function to return cholesterol and cholesterol esters to the liver This latter process apparently explains the correlation between high HDL levels and reduced risk of cardiovascular disease (High LDL levels, on

Concentration

in Plasma Apoprotein M r (mg/100 mL) Distribution A-1 28,300 90–120 Principal protein in HDL A-2 8,700 30–50 Occurs as dimer mainly in HDL B-48 240,000 5 Found only in chylomicrons B100 500,000 80–100 Principal protein in LDL

C-3 8,800 8–15 Found in chylomicrons, VLDL, IDL, HDL

Adapted from Brown, M., and Goldstein, J., 1987 In Braunwald, E., et al., eds., Harrison’s Principles of Internal Medicine, 11th

ed New York: McGraw-Hill; and Vance, D., and Vance, J., eds., 1985 Biochemistry of Lipids and Membranes, Menlo Park, CA:

TABLE 24.2 Apoproteins of Human Lipoproteins

( a )

( b )

FIGURE 24.37 A model for the structure of a typical

lipoprotein (a) A core of cholesterol and cholesteryl

esters is surrounded by a phospholipid (monolayer)

membrane Apolipoprotein A-I is modeled here as a long

amphipathic-helix, with the nonpolar face of the helix

embedded in the hydrophobic core of the lipid particle

and the polar face of the helix exposed to solvent (b) A

ribbon diagram of apolipoprotein A-I (Adapted from

Borhani, D W., Rogers, D P., Engler, J A., and Brouillette, C G., 1997.

Crystal structure of truncated human apolipoprotein A-I

sug-gests a lipid-bound conformation Proceedings of the National

Academy of Sciences 94:12291–12296.)

reticulum

Assembly of components into prelipoprotein particles in the ER, then transfer to Golgi

Secretory vesicle Golgi

Liver cell

Extracellular space

Golgi processes the particles with additional phospholipids and perhaps also cholesterol and cholesterol esters added

Synthesis of apoproteins, phosphatidylcholine, triacylglycerol, cholesterol, cholesterol esters occurs in the endoplasmic reticulum

1

2

3

VLDL

Formation of secretory vesicle containing lipoprotein particles

4

The VLDL is released into the circulation

5

FIGURE 24.38 Lipoprotein components are synthesized predominantly in the ER of liver cells Following

assem-bly of lipoprotein particles (red dots) in the ER and processing in the Golgi, lipoproteins are packaged in

secre-tory vesicles for export from the cell (via exocytosis) and released into the circulasecre-tory system.

+

LDL

LDL

LDL receptor

Vesicle loses

its coating

and forms

endosome

Recycling vesicle

LDL receptors bud off and form

a small recycling vesicle

Endosome formation

may or may not include

fusion with another

vesicle

Synthesis of LDL receptors

Synthesis of cholesterol

Oversupply of cholesterol

ACAT

Remaining vesicle fuses with lysosome

Apoprotein B is degraded

by lysosomal protease and released as amino acids Apoprotein B

Amino acids

Free cholesterol

HMG-CoA reductase

Inhibits

Activates

Free cholesterol released Lysosome

Cholesterol esters in core are hybridized

by ACAT and stored in cell

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

760 Chapter 24 Lipid Biosynthesis

the other hand, are correlated with an increased risk of coronary artery and

cardio-vascular disease.)

The Structure of the LDL Receptor Involves Five Domains

The LDL receptor in plasma membranes (Figure 24.40) consists of 839 amino acid residues and is composed of five domains, two of which contain multiple subdo-mains The N-terminal LDL-binding domain (292 residues) contains seven cysteine-rich repeats, denoted R1 to R7 The next segment (417 residues) contains three

epidermal growth factor repeats,as well as a ␤-propellor module This is followed in the sequence by a 58-residue segment of O-linked oligosaccharides, a 22-residue membrane-spanning segment, and a 50-residue segment extending into the cytosol The clustering of receptors prior to the formation of coated vesicles requires the presence of this cytosolic segment Note that the LDL particle binds specifically to the receptor at the fourth and fifth cysteine-rich repeats (R4 and R5)

Figure 24.39 shows the release of LDL particles in endosomes that pinch off from the plasma membrane when cells take up LDLs What molecular events trigger the release of LDL particles? A collaboration by three Nobel laureates has provided an answer Johann Deisenhofer, Michael Brown, and Joseph Goldstein have deter-mined the structure of the extracellular domain of the LDL receptor at pH 5.3, the typical pH inside endosomes At this low pH, the receptor polypeptide is folded back on itself, with the -propellor domain associated with R4 and R5, the two re-peats that normally bind the LDL particle (Figure 24.41) The implication is that the-propellor displaces the LDL particle in the lower pH environment of the

en-dosome What residues at the interface between the propellor and the R4 and R5 repeats act as the pH sensors? Three histidines at the propellor–R4/R5 interface— His190, His562, and His586—are the likely pH-sensing residues His190lies at the tip of

a loop on R5, whereas His562and His586are on the surface of the propellor domain (Figure 24.41) These three His residues form a cluster at the three-way junction be-tween R4, R5, and the -propellor

Defects in Lipoprotein Metabolism Can Lead to Elevated Serum Cholesterol

The mechanism of LDL metabolism and the various defects that can occur therein have been studied extensively by Michael Brown and Joseph Goldstein, who received

the Nobel Prize in Physiology or Medicine in 1985 Familial hypercholesterolemia is

the term given to a variety of inherited metabolic defects that lead to greatly elevated levels of serum cholesterol, much of it in the form of LDL particles The general

Cys-rich repeats

-propellor

EGF repeat EGF repeats

O-linked

oligosaccharide

domain

58 residues

Transmembrane

domain

22 residues

Cytosolic

domain

50 residues

C

R7

R2 R1

R3

R4 R5

R6 LDL N

FIGURE 24.40 The structure of the LDL receptor The

amino-terminal binding domain is responsible for

recognition and binding of LDL apoprotein The B-100

apolipoprotein of the LDL particle is presumed to bind

to the fourth and fifth cysteine-rich repeats (R4 and R5).

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

aggre-gation of LDL receptors during endocytosis.

(a)

R4 R5

H190

R4

R3 R7

R6

R2 R5

-propellor

FIGURE 24.41 (a) The cysteine-rich repeats R4 and R5 are the site of LDL particle binding Each repeat

con-tains two loops connected by three disulfide bonds The second loop in each repeat carries acidic residues (Asp and Glu) and forms a Ca2-binding site (b) The-propellor domain of the LDL receptor (c) The

struc-ture of the LDL receptor extracellular domain at pH 5.3 (similar to that found in endosomes) The -propellor

domain is associated with cysteine-rich domains R4 and R5 A cluster of histidines (His 190 , His 562 , and His 586 ) and a variety of hydrophobic and charged interactions mediate the interaction (pdb id  1N7D).

genetic defect responsible for familial hypercholesterolemia is the absence or

dys-function of LDL receptors in the body Only about half the normal level of LDL

re-ceptors is found in heterozygous individuals (persons carrying one normal gene and

one defective gene) Homozygotes (with two copies of the defective gene) have few,

if any, functional LDL receptors In such cases, LDLs (and cholesterol) cannot be

absorbed, and plasma levels of LDL (and cholesterol) are very high Typical

hetero-zygotes display serum cholesterol levels of 300 to 400 mg/dL, but homohetero-zygotes carry

serum cholesterol levels of 600 to 800 mg/dL or even higher There are two possible

causes of an absence of LDL receptors—either receptor synthesis does not occur at

all, or the newly synthesized protein does not successfully reach the plasma

brane due to faulty processing in the Golgi or faulty transport to the plasma

mem-brane Even when LDL receptors are made and reach the plasma membrane, they

may fail to function for two reasons They may be unable to form clusters competent

in coated pit formation because of folding or sequence anomalies in the

carboxy-terminal domain, or they may be unable to bind LDL because of sequence or

fold-ing anomalies in the LDL-bindfold-ing domain

Bile acids, which exist mainly as bile salts, are polar carboxylic acid derivatives of

cholesterol that are important in the digestion of food, especially the solubilization

of ingested fats The Naand Ksalts of glycocholic acid and taurocholic acid are the

principal bile salts (Figure 24.42) Glycocholate and taurocholate are conjugates of

HO

CH3

H3C

COO–

CH3

CH3

OH H

OH

HO

H3N CH2 COO–

H3N CH2 CH2 SO3–

O

CH3

CH3

OH H

HO

H3C

C

O

CH3

CH3

OH HO

H

HO

H3C

C N

HO

SO3– N

H

HO

CH3

H3C

OH

7-Hydroxycholesterol

7-Hydroxylase

Cholic acid

Glycine

Many steps

Taurine

Glycocholic acid Taurocholic acid

Cholesterol

FIGURE 24.42 Cholic acid, a bile salt, is synthesized from cholesterol via 7-hydroxycholesterol Conjugation

with taurine or glycine produces taurocholic acid and glycocholic acid, respectively Taurocholate and glyco-cholate are freely water soluble and are highly effective detergents.

762 Chapter 24 Lipid Biosynthesis

cholic acid with glycine and taurine, respectively Because they contain both

nonpo-lar and pononpo-lar domains, these bile salt conjugates are highly effective as detergents These substances are made in the liver, stored in the gallbladder, and secreted as needed into the intestines

The formation of bile salts represents the major pathway for cholesterol

degra-dation The first step involves hydroxylation at C-7 (Figure 24.42) 7␣-Hydroxylase,

which catalyzes the reaction, is a mixed-function oxidase involving cytochrome P-450.

Mixed-function oxidasesuse O2as substrate One oxygen atom goes to hydroxylate the substrate while the other is reduced to water (Figure 24.43) The function of cytochrome P- 450 is to activate O2for the hydroxylation reaction Such hydroxy-lations are quite common in the synthetic routes for cholesterol, bile acids, and steroid hormones and also in detoxification pathways for aromatic compounds Several of these are considered in the next section 7-Hydroxycholesterol is the precursor for cholic acid

Steroid hormones are crucial signal molecules in mammals (The details of their physiological effects are described in Chapter 32.) Their biosynthesis begins with

the desmolase reaction, which converts cholesterol to pregnenolone (Figure

24.44) Desmolase is found in the mitochondria of tissues that synthesize steroids (mainly the adrenal glands and gonads) Desmolase activity includes two hydroxy-lases and utilizes cytochrome P- 450

HUMAN BIOCHEMISTRY

Steroid 5 ␣-Reductase—A Factor in Male Baldness, Prostatic Hyperplasia,

and Prostate Cancer

An enzyme that metabolizes testosterone may be involved in the

benign conditions of male-pattern baldness (also known as

andro-genic alopecia) and benign prostatic hyperplasia (prostate gland

en-largement), as well as potentially fatal prostate cancers Steroid

5-reductases are membrane-bound enzymes that catalyze the

NADPH-dependent reduction of testosterone to

dihydrotestos-terone (DHT) (see accompanying figure) Two isoforms of 5

-reductase have been identified In humans; the type I enzyme

pre-dominates in the sebaceous glands of skin and liver, whereas type

II is most abundant in the prostate, seminal vesicles, liver, and epi-didymis DHT is a contributory factor in male baldness and pro-static hyperplasia, and it has also been shown to act as a mitogen (a stimulator of cell division) For these reasons, 5-reductase

in-hibitors are potential candidates for treatment of these human conditions

Finasteride (see figure) is a specific inhibitor of type II 5

-reductase It has been used clinically for treatment of benign pro-static hyperplasia, and it is also marketed under the trade name Propecia by Merck as a treatment for male baldness Type II 5

-reductase inhibitors may also be potential therapeutic agents for treatment of prostate cancer Somatic mutations occur in the gene for type II 5-reductase during prostate cancer progression.

Because type I 5-reductase is the predominant form of the

en-zyme in human scalp, the mechanism of finasteride’s promotion

of hair growth in men with androgenic alopecia has been uncertain However, scientists at Merck have shown that whereas type I 5-reductase predominates in sebaceous ducts of the skin,

type II 5-reductase is the only form of the enzyme present in hair

follicles Thus, finasteride’s therapeutic effects may arise from in-hibition of the type II enzyme in the hair follicle itself

OH

O

CH3

H

CH3

C NHC(CH3)3

O

CH3

H N H

H H

CH3 O

Dihydrotestosterone Finasteride

7-Hydroxycholesterol

Cholesterol

+

Cytochrome P-450 reductase (Flavin-H2)

Cytochrome P-450

reductase (Flavin)

7-Hydroxylase

(Cytochrome P-450)

Fe2+

7-Hydroxylase

(Cytochrome P-450)

Fe3+

FIGURE 24.43 The mixed-function oxidase activity of 7-hydroxylase.