Eicosanoids Are Local Hormones Animal cells can modify arachidonic acid and other polyunsaturated fatty acids, in processes often involving cyclization and oxygenation, to produce so-cal
Trang 12% to 8% of the lipids in most animal membranes, but breakdown products of PI,
in-cluding inositol-1,4,5-trisphosphate and diacylglycerol, are second messengers in a
vast array of cellular signaling processes
Dihydroxyacetone Phosphate Is a Precursor to the Plasmalogens
Certain glycerophospholipids possess alkyl or alkenyl ether groups at the 1-position
in place of an acyl ester group These glyceroether phospholipids are synthesized
from dihydroxyacetone phosphate (Figure 24.23) Acylation of dihydroxyacetone
phosphate (DHAP) is followed by an exchange reaction, in which the acyl group is
removed as a carboxylic acid and a long-chain alcohol adds to the 1-position This
C
O
CH2
H C
OH O
CH2 O
O
P O–
O–
CoA S
O
C R
C
CH2
O
O
CH2 O
O
P O–
O–
O
C
R
HO CH2CH2R1
R C O–
C
CH2 O
O
CH2 O P O–
O–
R1CH2CH2
R1CH2CH2
R1CH2CH2
O
+
HOCH
CH2 O
CH2 O P O–
O–
O C
R2
O C
CH2 O
CH2 O P O–
O–
R1CH2CH2 O
O H CDP- ethanolamine
O C
CH2
CH2 O P O
O–
O H
CH2CH2NH3 +
+ +
2 H2O
+
O
C
CH2 O
CH2 O P O
O–
O H
CH2CH2NH3 +
H C
R1
CDP
NAD+
NADH
NADP+
NADPH H +
H +
O2
CoASH
CoASH
1
2
3
4
5 6
Dihydroxyacetone phosphate
1-Acyldihydroxyacetone phosphate
1-Acyldihydroxyacetone
phosphate synthase
Dihydroxyacetone
phosphate
acyltransferase
1-Alkyldihydroxyacetone phosphate
1-Alkyldihydroxyacetone
phosphate
oxidoreductase
1-Alkylglycero-3-phosphate
1-Alkylglycerophosphate acyltransferase
1-Alkyl-2-acylglycero-3-phosphate
CDP-ethanolamine transferase 1-Alkyl-2-acylglycero-3-phosphoethanolamine
1-Alkyl-2-acylglycero-phosphoethanolamine desaturase
Plasmalogen
FIGURE 24.23 Biosynthesis 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 (as shown here for
phospho-ethanolamine), 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.
Trang 2744 Chapter 24 Lipid Biosynthesis
long-chain alcohol is derived from the corresponding CoA by means of an
acyl-CoA reductase reaction involving oxidation of two molecules of NADH The 2-keto
group of the DHAP backbone is then reduced to an alcohol, followed by acylation The resulting 1-alkyl-2-acylglycero-3-phosphate can react in a manner similar to phosphatidic acid to produce ether analogs of phosphatidylcholine,
phosphatidyl-ethanolamine, and so forth (Figure 24.23) In addition, specific desaturase enzymes
associated with the ER can desaturate the alkyl ether chains of these lipids as shown The products, which contain ,-unsaturated ether-linked chains at the C-1
posi-tion, are plasmalogens; they are abundant in cardiac tissue and in the central
nervous system The desaturases catalyzing these reactions are distinct from but sim-ilar to those that introduce unsaturations in fatty acyl-CoAs
Platelet-Activating Factor Is Formed by Acetylation
of 1-Alkyl-2-Lysophosphatidylcholine
A particularly interesting ether phospholipid with unusual physiological
prop-erties, 1-alkyl-2-acetylglycerophosphocholine, also known as platelet-activating
factor, possesses an alkyl ether at C-1 and an acetyl group at C-2 (Figure 24.24) The very short chain at C-2 makes this molecule much more water soluble than typical glycerolipids Platelet-activating factor displays a dramatic ability to dilate blood vessels (and thus reduce blood pressure in hypertensive animals) and to aggregate platelets
Sphingolipid Biosynthesis Begins with Condensation of Serine and Palmitoyl-CoA
Sphingolipids, ubiquitous components of eukaryotic cell membranes, are present at high levels in neural tissues The myelin sheath that insulates nerve axons is particu-larly rich in sphingomyelin and other related lipids Prokaryotic organisms normally
do not contain sphingolipids Sphingolipids are built upon sphingosine backbones rather than glycerol The initial reaction, which involves condensation of serine and
palmitoyl-CoA with release of bicarbonate, is catalyzed by 3-ketosphinganine synthase,
HO C
CH2 O
CH2 O
O
P O O–
RCH2CH2
H
CH2CH2N(CH+ 3)3
O
CH3C SCoA
O
CH3C O–
O C
CH2 O
CH2 O
O
P O O–
RCH2CH2
H
CH2CH2N(CH+ 3)3 O
CH3C
1-Alkyl-2-lysophosphatidylcholine
Acetyl-CoA: 1-alkyl-2-lysoglycero-phosphocholine transferase Acetylhydrolase
1-Alkyl-2-acetylglycerophosphocholine (platelet-activating factor, PAF)
CoASH
H2O
FIGURE 24.24 Platelet-activating factor, formed from
1-alkyl-2-lysophosphatidylcholine by acetylation at C-2,
is degraded by the action of acetylhydrolase.
Trang 3a PLP-dependent enzyme (Figure 24.25) Reduction of the ketone product to form
sphinganine is catalyzed by 3-keto-sphinganine reductase, with NADPH as a reactant.
In the next step, sphinganine is acylated to form N-acyl sphinganine, which is then
desaturated to form ceramide Sphingosine itself does not appear to be an
interme-diate in this pathway in mammals
CH3(CH2)14
O
C S CoA
–OOC C CH2OH +NH3 H
CH3(CH2)14
O
C C CH2OH +NH3 H
CH3(CH2)14 C C CH2OH
+NH3
H
H
CH3(CH2)12
CH3 (CH2)n
OH
OH
O
NH H
C H
H
C
C H
3-Ketosphinganine
synthase
2S-3-Ketosphinganine
N-acyl-sphinganine
Ceramide
X
XH2
2S,3R-Sphinganine
+
3-Ketosphinganine reductase
HCO3–
NADP+
NADPH H+
CoASH
H2O
SCoA
CoASH
FIGURE 24.25 Biosynthesis 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, acyla-tion, and desaturation (via reduction of an electron acceptor, X) form ceramide, the precursor of other sphingolipids.
Trang 4746 Chapter 24 Lipid Biosynthesis
Ceramide Is the Precursor for Other Sphingolipids and Cerebrosides Ceramide is the building block for all other sphingolipids Sphingomyelin, for
example, is produced by transfer of phosphocholine from phosphatidylcholine
(Figure 24.26) Glycosylation of ceramide by sugar nucleotides yields cerebrosides,
such as galactosylceramide, which makes up about 15% of the lipids of myelin sheath
CH2OH
O O HO
OH
OH
H N O C
H C C H (CH2)12
CH2 CH
CHOH
R1
UDP-Gal
UDP
CH2OH
O H
H
H
OH H
OH
O
N H O
HC
C OH
C
CH2
R2
O
CH2OH O HO
H
H H OH
H
OH H
CH2OH O H
H
H H OH
H
OH
O
N H O
HC
C OH
C
CH2
R2
O
CH2OH O
H
H H OH
H
OH H
CMP- sialic acid
O
CH2OH O H H OH
H H
C O
CH3 HO
O H
H
H H OH
H
OH
O
N H O
HC
C OH
C
CH2
R2
O
CH2OH O
H
H H O
H
OH H
O
CH2OH O H H OH
H H
C O
CH3 HO
O
H H
COH H H HN
OH H
COO–
C O
CH3
H HCOH
CH2OH
CH2OH
UDP- Glu
UDP UDP- Gal UDP
CH3
H N O C
H C C H (CH2)12
CH2
CH2OH CH
CHOH
R1
H N O
O
O
O P
– O
C
H C C H (CH2)12
CH2
CH2
CH3
CH3
+
H3C
C
CHOH
R1
1,2-Diacylglycerol
Phosphatidyl-choline
-D -Galactosylceramide
UDP- galacto-syltransferase
-D -Galactosyl-(1 4)--D -glucosylceramide
UDP- N-Acetylgalactosamine
UDP
N-Acetylgalactosaminyltransferase
-D-N-Acetylgalactosamine-(1
4)--D -galactosyl-(1 4)--D -glucosylceramide
CMP
Sialytransferase
Ganglioside GM
Ceramide
Sphingomyelin
FIGURE 24.26 Glycosylceramides (such as
galactosyl-ceramide), gangliosides, and sphingomyelins are
synthe-sized from ceramide in animals.
Trang 5structures Cerebrosides that contain one or more sialic acid (N-acetylneuraminic
acid) moieties are called gangliosides Several dozen gangliosides have been
charac-terized, and the general form of the biosynthetic pathway is illustrated for the
case of ganglioside GM2 (Figure 24.26) Sugar units are added to the developing
ganglioside from nucleotide derivatives, including UDP–N-acetylglucosamine,
UDP–galactose, and UDP–glucose
Are Their Functions?
Eicosanoids,so named because they are all derived from 20-carbon fatty acids,
are ubiquitous breakdown products of phospholipids In response to appropriate
stimuli, cells activate the breakdown of selected phospholipids (Figure 24.27)
Phospholipase A2(see Chapter 8) selectively cleaves fatty acids from the C-2
po-sition of phospholipids Often these are unsaturated fatty acids, among which is
arachidonic acid Arachidonic acid may also be released from phospholipids by
the combined actions of phospholipase C (which yields diacylglycerols) and
dia-cylglycerol lipase (which releases fatty acids)
Eicosanoids Are Local Hormones
Animal cells can modify arachidonic acid and other polyunsaturated fatty acids, in
processes often involving cyclization and oxygenation, to produce so-called local
hor-mones that (1) exert their effects at very low concentrations and (2) usually act near
their sites of synthesis These substances include the prostaglandins (PG) (Figure
24.27) as well as thromboxanes (Tx), leukotrienes, and other hydroxyeicosanoic acids.
Thromboxanes, discovered in blood platelets (thrombocytes), are cyclic ethers (TxB2is
actually a hemiacetal; see Figure 24.27) with a hydroxyl group at C-15
Prostaglandins Are Formed from Arachidonate by Oxidation
and Cyclization
All prostaglandins are cyclopentanoic acids derived from arachidonic acid The
biosynthesis of prostaglandins is initiated by an enzyme associated with the ER, called
prostaglandin endoperoxide H synthase (PGHS), also known as cyclooxygenase
(COX).The enzyme catalyzes simultaneous oxidation and cyclization of arachidonic
acid The enzyme is viewed as having two distinct activities, COX and peroxidase
(POX), as shown in Figure 24.28
A DEEPER LOOK
The Discovery of Prostaglandins
The name prostaglandin was given to this class of compounds by Ulf
von Euler, their discoverer, in Sweden in the 1930s He extracted
fluids containing these components from human semen Because
he thought they originated in the prostate gland, he named them
prostaglandins Actually, they were synthesized in the seminal
vesi-cles, and it is now known that similar substances are synthesized in
most animal tissues (both male and female) Von Euler observed
that injection of these substances into animals caused smooth
mus-cle contraction and dramatic lowering of blood pressure
Von Euler (and others) soon found that it is difficult to analyze
and characterize these obviously interesting compounds because
they are present at extremely low levels Prostaglandin E2, or
PGE2, is present in human serum at a level of less than 1014M!
In addition, they often have half-lives of only 30 seconds to a few
minutes, not lasting long enough to be easily identified Moreover, most animal tissues upon dissection and homogenization rapidly synthesize and degrade a variety of these substances, so the amounts obtained in isolation procedures are extremely sensitive
to the methods used and highly variable even when procedures are carefully controlled Sune Bergström, Bengt Samuelsson, and their colleagues described the first structural determinations of prostaglandins in the late 1950s In the early 1960s, dramatic ad-vances in laboratory techniques, such as NMR spectroscopy and mass spectrometry, made further characterization possible Von Euler received the Nobel Prize for Physiology or Medicine in 1970, and Bergström, Samuelsson, and John Vane shared the Nobel for Physiology or Medicine in 1982
Trang 6748 Chapter 24 Lipid Biosynthesis
A Variety of Stimuli Trigger Arachidonate Release and Eicosanoid Synthesis
The release of arachidonate and the synthesis or interconversion of eicosanoids can
be initiated by a variety of stimuli, including histamine, hormones such as epineph-rine and bradykinin, proteases such as thrombin, and even serum albumin An im-portant mechanism of arachidonate release and eicosanoid synthesis involves tissue injury and inflammation When tissue damage or injury occurs, special inflammatory
OH
O
COO–
HO
OH
OH
COO–
HO
–OOC
O
COO–
O
OH HO
H
COO–
OH
O
O
COO–
OH
HO
O
HO H
COO–
H S CH2
CH C O
N H
CH2COO–
NH C O
CH2CH2 CH
COO–
H3+N
2 O2
PGE 2
PGF 2a
PGI 2
TxB 2
PGH 2
PGD 2
Leukotriene C
Arachidonate
Activation of PLC and diacylglycerol lipase
Activation of PLA2
Receptor
Hormone (or other stimulus)
Phospholipids
FIGURE 24.27 Arachidonic 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 similar-ities 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 prosta-glandins possessing ,-unsaturated ketones.The number following the letters refers to the number of carbon–
carbon double bonds Thus, PGE 2 contains two double bonds.
Trang 7cells, monocytes and neutrophils, invade the injured tissue and interact with the
resi-dent cells (such as smooth muscle cells and fibroblasts) This interaction typically leads
to arachidonate release and eicosanoid synthesis Examples of tissue injury in which
eicosanoid synthesis has been characterized include heart attack (myocardial
infarc-tion), rheumatoid arthritis, and ulcerative colitis
“Take Two Aspirin and…” Inhibit Your Prostaglandin Synthesis
In 1971, biochemist John Vane was the first to show that aspirin (acetylsalicylate;
Fig-ure 24.29) exerts most of its effects by inhibiting the biosynthesis of prostaglandins
Its site of action is PGHS COX activity is destroyed when aspirin O -acetylates Ser530
COOH COX
POX
COOH
.
O
COOH
O OH H
H H
H
COOH
H H H
H
O
O
O
O
H
O
O O
5, 8,11,14-Eicosatetraenoic acid (arachidonic acid)
Peroxide radical
PGG 2
PGH 2
O O
FIGURE 24.28 Prostaglandin endoperoxide H synthase (PGHS), the enzyme that converts arachidonic acid to prostaglandin PGH 2 , possesses two distinct activities: cyclooxygenase (COX) and a glutathione-dependent hydroperoxidase (POX) The mechanism of the reaction begins with hydrogen atom abstraction by a tyrosine radical on the enzyme, followed by rearrangement to cyclize and incorporate two oxygen molecules Reduc-tion of the peroxide at C15 completes the reacReduc-tion COX
is the site of action of aspirin and other analgesic agents.
O C CH3
O Ser
COO–
O
C CH3
CH CH
CH3
CH2
CH3
O O
COO–
OH Ser
H3C
H3C
(b) (a)
Salicylate
Active cyclooxygenase Acetaminophen
Ibuprofen
Inactive cyclooxygenase Acetylsalicylate (aspirin)
FIGURE 24.29 (a) The structures of several common analgesic agents Acetaminophen is marketed under the trade
name Tylenol Ibuprofen is sold as Motrin, Nuprin, and Advil (b) Acetylsalicylate (aspirin) inhibits the COX activity of
endoperoxide synthase via acetylation (covalent modification) of Ser 530
Trang 8750 Chapter 24 Lipid Biosynthesis
on the enzyme From this you may begin to infer something about how prosta-glandins (and aspirin) function Prostaprosta-glandins are known to enhance inflammation
in animal tissues Aspirin exerts its powerful anti-inflammatory effect by inhibiting this first step in their synthesis Aspirin does not have any measurable effect on the peroxidase activity of the synthase Other nonsteroidal anti-inflammatory agents,
such as ibuprofen (Figure 24.29) and phenylbutazone, inhibit COX by competing at
the active site with arachidonate or with the peroxyacid intermediate (PGG2, as in Figure 24.28) See A Deeper Look above
The most prevalent steroid in animal cells is cholesterol (Figure 24.30) Plants
con-tain no cholesterol, but they do concon-tain other steroids very similar to cholesterol in
structure (see page 236) Cholesterol serves as a crucial component of cell mem-branes and as a precursor to bile acids (such as cholate, glycocholate, taurocholate) and steroid hormones (such as testosterone, estradiol, progesterone) Also, vitamin
D3is derived from 7-dehydrocholesterol, the immediate precursor of cholesterol Liver
is the primary site of cholesterol biosynthesis
A DEEPER LOOK
The Molecular Basis for the Action of Nonsteroidal Anti-inflammatory Drugs
Prostaglandins are potent mediators of inflammation The first and
committed step in the production of prostaglandins from
arachi-donic acid is the bis-oxygenation of arachidonate to prostaglandin
PGG2 This is followed by reduction to PGH2in a peroxidase
reac-tion Both these reactions are catalyzed by PGHS or COX This
en-zyme is inhibited by the family of drugs known as nonsteroidal
anti-inflammatory drugs, or NSAIDs Aspirin, ibuprofen, flurbiprofen,
and acetaminophen (trade name Tylenol) are all NSAIDs
There are two isoforms of COX in animals: COX-1, which car-ries out normal, physiological production of prostaglandins, and COX-2, which is induced by cytokines, mitogens, and endotoxins
in inflammatory cells and is responsible for the production of prostaglandins in inflammation
The enzyme structure shown in panel a is that of residues 33 to
583 of COX-1 from sheep, inactivated by ibuprofen (cyan) These
551 residues comprise three distinct domains The first of these,
(a)pdb id 1EQG (b) Superposition of pdb id 1EQG and 1CX2
Trang 9Mevalonate Is Synthesized from Acetyl-CoA Via HMG-CoA Synthase
The cholesterol biosynthetic pathway begins in the cytosol with the synthesis of
mevalonate from acetyl-CoA (Figure 24.31) The first step is the -ketothiolase–
catalyzed Claisen condensation of two molecules of acetyl-CoA to form
acetoacetylCoA In the next reaction, acetylCoA and acetoacetylCoA join to form 3hydroxy
-3-methylglutaryl -CoA, which is abbreviated HMG -CoA The reaction, a second Claisen
condensation, is catalyzed by HMG-CoA synthase The third step in the pathway is
residues 33 to 72, is a small, compact module that is similar to
epi-dermal growth factor The second domain, composed of residues
73 to 116, forms a right-handed spiral of four -helical segments.
These-helical segments form a membrane-binding motif The
helical segments are amphipathic, with most of the hydrophobic
residues facing away from the protein, where they can interact
with a lipid bilayer The third domain of the COX enzyme, the
cat-alytic domain, is a globular structure that contains both the COX
and the peroxidase active sites
The COX active site lies at the end of a long, narrow,
hydro-phobic tunnel or channel Three of the -helices of the
membrane-binding domain lie at the entrance to this tunnel The walls of
the tunnel are defined by four -helices, formed by residues
106 to 123, 325 to 353, 379 to 384, and 520 to 535
The COX-1 structure shown in panel a has a molecule of
ibupro-fen bound in the tunnel Deep in the tunnel, at the far end, lies
Tyr385, a catalytically important residue Heme-dependent
peroxi-dase activity is implicated in the formation of a proposed Tyr385
rad-ical, which is required for COX activity Aspirin and other NSAIDs
block the synthesis of prostaglandins by filling and blocking the
tun-nel, preventing the migration of arachidonic acid to Tyr385in the ac-tive site at the back of the tunnel
Why do the new “COX-2 inhibitors” bind to (and inhibit) COX-2 but not COX-1? A single amino acid substitution makes all the dif-ference Panel b shows an overlay of COX-1 (1EQG) and COX-2 (1CX2) structures COX-2 has a valine (blue) at position 523, which leaves room for binding of a Celebrex-like inhibitor (orange) On the other hand, COX-1 has bulkier isoleucine (red) at position 523, which prevents binding of the inhibitor
COX-2 inhibitors were introduced as pain medications in 1997, and by 2004 nearly half of the 100 million prescriptions written an-nually for NSAIDs in the United States were COX-2 inhibitors However, several COX-2 inhibitors were taken off the U.S market
in late 2004 and early 2005, when their use was linked to heart at-tacks and strokes in a small percentage of users Since that time, prescriptions for COX-2 inhibitors have dropped by 65% Inter-estingly, although COX-2 inhibitors were originally intended to al-leviate pain without the risk of adverse gastrointestinal effects, less than 5% of patients that used COX-2 prescriptions at the peak of their popularity were at high risk for these adverse effects
COOH COOH
O
O
CH2Br CH3
CH3
H3N
CHF2
NH2
CF3 O
O
O
S O O
N N
N N
Ibuprofen
* Abby Garrett took this.
(c)
H
HO
1
2
3
4 5
CH19 3
10 9 8
6 7
11 13
14
12 16 17 15
H3C
18
C
H3C21
20
CH3
H
25
26
27
2 1
8 9 10
11
13
16 17
CH3
18
H C
H3C21
20
CH3
H
25
26
27
CH3
19
12
FIGURE 24.30 The structure of cholesterol, drawn (a) in the traditional planar motif and (b) in a form that more
accurately describes the conformation of the ring system.
Trang 10752 Chapter 24 Lipid Biosynthesis
the rate-limiting step in cholesterol biosynthesis Here, HMG-CoA undergoes two
NADPH-dependent reductions to produce 3R -mevalonate (Figure 24.32) The
reac-tion is catalyzed by HMG-CoA reductase, a 97-kD glycoprotein that spans the ER
membrane with its active site facing the cytosol As the rate-limiting step, HMG-CoA reductase is the principal site of regulation in cholesterol synthesis
Three different regulatory mechanisms are involved:
1 Phosphorylation by cAMP-dependent protein kinases inactivates the reductase This inactivation can be reversed by two specific phosphatases (Figure 24.33)
2 Degradation of HMG-CoA reductase This enzyme has a half-life of only
3 hours, and the half-life itself depends on cholesterol levels: High [cholesterol] means a short half-life for HMG-CoA reductase
3 Gene expression Cholesterol levels control the amount of mRNA If terol] is high, levels of mRNA coding for the reductase are reduced If [choles-terol] is low, more mRNA is made (Regulation of gene expression is discussed
in Chapter 29.)
A Thiolase Brainteaser Asks Why Thiolase Can’t Be Used
in Fatty Acid Synthesis
If acetate units can be condensed by the thiolase reaction to yield acetoacetate in the first step of cholesterol synthesis, why couldn’t this same reaction also be used in fatty acid synthesis, avoiding all the complexity of the fatty acyl synthase? The answer is
O
–OOC
CH3 C SCoA
O
CH3 C SCoA
O
CH3 C
O
CH2 C SCoA
O
CH2 C SCoA
CH3 C OH
CH2
CH3 C OH
CH2
H H
2 H+
2
O
CH3 C SCoA
Acetyl-CoA
OH
NADP+
NADPH
CoASH
CoASH
CoASH
Acetyl-CoA
Acetyl-CoA
Acetoacetyl-CoA
3-Hydroxy-3-methylglutaryl-CoA
(HMG-CoA)
HMG-CoA reductase
3R -Mevalonate
Thiolase
HMG-CoA synthase
FIGURE 24.31 The biosynthesis of 3R-mevalonate from
acetyl-CoA.
–OOC
O
CH2 C S
CH3 C OH
CH2
(a)
3-Hydroxy-3- methylglutaryl-CoA (HMG-methylglutaryl-CoA)
CH3 C
OH
CH2
H H
3R -Mevalonate
H H
H+
N
C
NH2
R First
Second
–OOC
O
CH2 C S
CH3 C
OH
CH2
Enzyme-bound intermediate
H H
N
C
NH2
R O H
O
H
OH NADPH NADPH
CoASH
CoA
CoA
(b)
HMG-CoA Reductase (pdb id = 1DQA)
ANIMATED FIGURE 24.32 (a) A reaction mechanism for HMG-CoA
reductase Two successive NADPH-dependent reductions convert the thioester, HMG-CoA,
to a primary alcohol (b) HMG-CoA reductase structure See this figure animated at
www.cengage.com/login.