Voet D., Voet Ju.G. Biochemistry

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The X-ray structure of the rabbit reticulocyte 15-LO, a

homolog of 5-LO, in complex with the competitive in-

hibitor RS75091

was determined by Michelle Browner. This 663-residue

monomeric protein consists of an N-terminal 8-stranded 

barrel domain and a C-terminal catalytic domain (Fig.25-77).

Its active site Fe atom is coordinated by four invariant His

residues and by a C-terminal carboxylate oxygen in a lig-

anding arrangement that is best described as a distorted oc-

tahedron with one of its six vertices unoccupied. The Fe,

which is well below the protein surface, faces an internal

cavity occupied by RS75091. This identifies the substrate

binding cavity, which is lined with mostly hydrophobic

residues and follows an irregular pathway past the Fe atom

to the protein surface. Intriguingly, 15-LO (as does soybean

lipoxygenase-1) contains two rarely observed  helices

(Fig. 8-14c), each of which contains two of the Fe-liganding

His residues. Each of these  helices is embedded in a

longer helix rather than being at the end of an  helix as is

the case for all previously observed  helices.

The sizes of the substrate-binding cavities of the 5- and

12-LOs have been predicted through their homology mod-

eling (Section 9-3B) with 15-LO. 5-LO and 12-LO have

smaller amino acids substituted for those in 15-LO, such

that, for example, 5-LO is predicted to have a cavity with

⬃20% greater volume than that of 15-LO. The mutagene-

sis of 5-LO by Harmut Kuhn so as to decrease the size of its

cavity yielded an enzyme with the specificity of 15-LO, thus

supporting the proposal that it is the size of the cavity that

determines lipoxygenase specificity.

b. Peptidoleukotrienes

LTA

is converted to peptidoleukotrienes by reaction with

LTC

synthase, a glutathione-S-transferase that catalyzes

the addition of the glutathione sulfhydryl group to the

LTA

epoxide, forming the first of the peptidoleukotrienes,

leukotriene C

(LTC

, Fig. 25-78). -Glutamyltransferase

removes glutamic acid, converting LTC

to leukotriene

(LTD

). LTD

is converted to leukotriene E

(LTE

)

by a dipeptidase that removes glycine. LTA

can also be

hydrolyzed to leukotriene B

(LTB

), a potent chemotac-

tic agent (a substance that attracts motile cells) involved

in attracting certain types of white blood cells to fight

infection.

Various inflammatory and hypersensitivity disorders

(such as asthma) are associated with elevated levels of

leukotrienes. The development of drugs that inhibit

leukotriene synthesis has therefore been an active field of

RS75091

COOH

research. 5-LO activity requires the presence of 5-lipoxyge-

nase-activating protein (FLAP), a homotrimeric integral

membrane protein of 161-residue subunits that is located

in both the nuclear and ER membranes. FLAP, which has

no enzymatic activity, binds the arachidonic acid substrate

of 5-LO and facilitates enzyme–substrate binding as well as

5-LO’s interaction with the membrane. Several inhibitors

of leukotriene synthesis, such as MK-591,

bind to FLAP so as to inhibit both of its functions.

MK-591

Section 25-7. Eicosanoid Metabolism: Prostaglandins, Prostacyclins, Thromboxanes, Leukotrienes, and Lipoxins 1001

Figure 25-77 X-ray structure of rabbit reticulocyte

15-lipoxygenase (15-LO) in complex with its competitive

inhibitor RS75091. The N-terminal  barrel domain is gold and

the C-terminal catalytic domain is light blue with its two

Fe-liganding  helical segments magenta. The Fe is represented

by an orange sphere and the RS75091 is drawn in space-filling

form with C green and O red. [Based on an X-ray structure by

Michelle Browner, Roche Bioscience, Palo Alto, California.

PDBid 1LOX.]

JWCL281_c25_940-1018.qxd 6/8/10 9:00 AM Page 1001

The X-ray structure of human FLAP in complex with

MK-591 (Fig. 25-79), determined by Joseph Becker, reveals

that each subunit forms an up–down–up–down four-helix

bundle whose N- and C-termini are on the luminal side of

the membrane, and that its three identical subunits have

extensive intersubunit contacts, thereby forming a 12-helix

bundle. MK-591 binds in lipid-exposed grooves between

pairs of subunits. Moreover, the trimer forms an elongated

pocket along its 3-fold axis that is open to the lumen. This,

together with biochemical data, suggests that one 5-LO

molecule binds to the cytosolic surface of a FLAP trimer

where, through conformational changes in FLAP, it accepts

arachidonic acid molecules that FLAP has extracted from

the membrane. Inhibitors such as MK-591 presumably

block this extraction process.

c. Diets Rich in Marine Lipids May Decrease

Cholesterol, Prostaglandin, and Leukotriene Levels

Greenland Eskimos have a very low incidence of coro-

nary heart disease and thrombosis despite their high di-

etary intake of cholesterol and fat. Their consumption of

marine animals provides them with a higher proportion of

unsaturated fats than the typical American diet. A major

unsaturated component of marine lipids is 5,8,11,14,17-

1002 Chapter 25. Lipid Metabolism

Figure 25-78 Formation of the leukotrienes from LTA

Figure 25-79 X-ray structure of human 5-lipoxygenase-

activating protein (FLAP) in complex with MK-591. The protein

is drawn in ribbon form and viewed from within the membrane

with its approximate molecular 3-fold axis vertical.The subunit

closest to the viewer of this homotrimeric protein is colored in

rainbow order from its N-terminus (blue) to its C-terminus (red).

The other subunits are pale blue and pale orange.The bound

MK-591 is drawn in stick form with C magenta, N blue, O red, S

yellow, and C green.The inferred position of the membrane is

indicated by the horizontal black lines. [Based on an X-ray

structure by Joseph Becker, Merck Research Laboratories,

Rahway, New Jersey. PDBid 2Q7M.]

Leukotriene A

(LTA

)

COOH

Leukotriene C

(LTC

)

Leukotriene D

(LTD

)

Leukotriene E

(LTE

)

Glycine

Glutamic acid

COOH

Leukotriene B

(LTB

)

COOH

NH C

NH CH

COOH

CH COOHHOOC

leukotriene A

hydrolase

LTC

synthase

(a glutathione-S-transferase)

Glutathione

-glutamyltransferase

COOH

NH CH

COOH

dipeptidase

JWCL281_c25_940-1018.qxd 4/20/10 1:59 PM Page 1002

eicosapentaenoic acid (EPA; Fig. 25-67), an ␻–3 fatty acid,

rather than the arachidonic acid precursor linoleic acid, an

␻–6 fatty acid. EPA inhibits formation of TxA

(Fig. 25-70)

and is a precursor of the series-5 leukotrienes, compounds

with substantially lower physiological activities than their

arachidonate-derived (series-4) counterparts. This suggests

that a diet containing marine lipids should decrease the ex-

tent of prostaglandin- and leukotriene-mediated inflam-

matory responses. Indeed, dietary enrichment with EPA in-

hibits the in vitro chemotactic and aggregating activities of

neutrophils (a type of white blood cell). Moreover, an

EPA-rich diet decreases the cholesterol and triacylglycerol

levels in the plasma of hypertriacylglycerolemic patients.

d. Lipoxins and Aspirin-Induced epi-Lipoxins Have

Anti-Inflammatory Properties

Eicosanoids are usually associated with the inflammatory

response.However,some eicosanoids have anti-inflammatory

properties.The lipoxins (LXs), products of the 12- and 15-LO

pathways (sometimes also involving 5-LO), are so named be-

cause they are synthesized through lipoxygenase interactions.

Their activities appear to inhibit those of leukotrienes and

hence they are anti-inflammatory. There are many ways for

LXs to be synthesized by combinations of the actions of 5-,

12-, and 15-LOs. Here we discuss only one such route (Fig.

25-80, left). Lipoxin A

(LXA

) synthesis from arachidonic

acid begins in endothelial and epithelial cells by the 15-LO-

catalyzed synthesis of (15S)-hydroperoxyeicosatetraenoic

acid [(15S)-HPETE], which is reduced by glutathione

peroxidase to (15S)-hydroxyeicosatetraenoic acid [(15S)-

HETE]. The (15S)-HETE then makes its way to leukocytes

where it is converted to LXA

by 5-LO and a hydrolase.

Charles Serhan discovered an additional pathway for

the anti-inflammatory action of aspirin that also involves

lipoxin production.As we have previously seen (Fig. 25-74),

aspirin covalently inhibits the cyclooxygenase activity of

Section 25-7. Eicosanoid Metabolism: Prostaglandins, Prostacyclins, Thromboxanes, Leukotrienes, and Lipoxins 1003

Figure 25-80 Lipoxin biosynthesis. The biosynthesis of the

lipoxin LXA

(left) and the aspirin-triggered epi-lipoxin (ATL)

15-epi-LXA

(right). In endothelial and epithelial cells,

arachidonic acid is converted by 15-LO and glutathione

15-LXA

COOH

OHHO

hydrolase

15-epi-LXA

(15S)-HETE

Leukocytes

Endothelial and

epithelial cells

(15R)-HETE

COOH

OHHO

COOH

hydrolase

5-LO 5-LO

15-LO

+ glutathoine peroxidase

aspirin-acetylated COX-2

COOH

Arachidonic acid

COOH

≥

peroxidase to (15S)-HETE or by aspirin-acetylated COX-2 to

(15R)-HETE.After transfer to leukocytes, 5-LO and a hydrolase

convert these intermediate products to LXA

and 15-epi-LXA

JWCL281_c25_940-1018.qxd 7/21/10 6:21 PM Page 1003

PGHS (COX). However, aspirin-acetylated COX-2 retains

a residual 15-LO activity (Steps 3 and 4 in Fig. 25-71)

through which it initiates a pathway that converts arachi-

donic acid to the anti-inflammatory agents called aspirin-

triggered epi-lipoxins (ATLs; Fig. 25-80, right). This path-

way begins in endothelial and epithelial cells with the

aspirin-acetylated COX-2-catalyzed conversion of arachi-

donic acid to (15R)-hydroxyeicosatetraenoic acid [(15R)-

HETE], the epimer of (15S)-HETE. In leukocytes, 5-LO

and a hydrolase then convert (15R)-HETE to the anti-

inflammatory agent 15-epi-lipoxin A

(15-epi-LXA

These are indeed exciting times in the study of eicosanoid

metabolism and its physiological manifestations. As the

mechanisms of action of the prostaglandins, prostacyclins,

thromboxanes, leukotrienes, and lipoxins are becoming bet-

ter understood, they are providing the insights required for

the development of new and improved therapeutic agents.

8 PHOSPHOLIPID AND

GLYCOLIPID METABOLISM

The “complex lipids” are dual-tailed amphipathic molecules

composed of either 1,2-diacyl-sn-glycerol or N-acylsphingo-

sine (ceramide) linked to a polar head group that is either a

carbohydrate or a phosphate ester (Fig. 25-81; Sections 12-

1C and 12-1D; sn stands for stereospecific numbering, which

assigns the 1 position to the group occupying the pro-S posi-

tion of a prochiral center). Hence, there are two categories

of phospholipids, glycerophospholipids and sphingophos-

pholipids, and two categories of glycolipids, glyceroglyco-

lipids and sphingoglycolipids (also called glycosphingolipids;

GSLs). In this section we describe the biosynthesis of the

complex lipids from their simpler components. We shall see

that the great variety of these substances is matched by the

numerous enzymes required for their specific syntheses.

Note also that these substances are synthesized in mem-

branes, mostly on the cytosolic face of the endoplasmic retic-

ulum, and from there are transported to their final cellular

destinations as indicated in Sections 12-4B–D.

A. Glycerophospholipids

Glycerophospholipids have significant asymmetry in their

C1- and C2-linked fatty acyl groups: C1 substituents are

mostly saturated fatty acids, whereas those at C2 are by and

large unsaturated fatty acids. We shall examine the major

pathways of biosynthesis and metabolism of the glyc-

erophospholipids with an eye toward understanding the

origin of this asymmetry.

a. Biosynthesis of Diacylglycerophospholipids

The triacyglycerol precursors 1,2-diacyl-sn-glycerol and

phosphatidic acid are also the precursors of certain glyc-

erophospholipids (Figs. 25-42 and 25-81). Activated phos-

phate esters of the polar head groups (Table 12-2) react

with the C3 OH group of 1,2-diacyl-sn-glycerol to form the

phospholipid’s phosphodiester bond. In some cases the

phosphoryl group of phosphatidic acid is activated and re-

acts with the unactivated polar head group.

The mechanism of activated phosphate ester formation

is the same for both the polar head groups ethanolamine

and choline (Fig. 25-82):

1. ATP first phosphorylates the OH group of choline or

ethanolamine.

2. The phosphoryl group of the resulting phospho-

ethanolamine or phosphocholine then attacks CTP, dis-

placing PP

, to form the corresponding CDP derivatives,

which are activated phosphate esters of the polar head

group.

3. The C3 OH group of 1,2-diacyl-sn-glycerol attacks

the phosphoryl group of the activated CDP–ethanolamine

or CDP–choline, displacing CMP to yield the correspon-

ding glycerophospholipid.

The liver also converts phosphatidylethanolamine to phos-

phatidylcholine by trimethylating its amino group, using S-

adenosylmethionine (Section 26-3Ea) as the methyl donor.

Phosphatidylserine is synthesized from phosphati-

dylethanolamine by a head group exchange reaction cat-

alyzed by phosphatidylethanolamine:serine transferase in

which serine’s OH group attacks the donor’s phosphoryl

group (Fig. 25-83). The original head group is then elimi-

nated, forming phosphatidylserine.

In the synthesis of phosphatidylinositol and phos-

phatidylglycerol, the hydrophobic tail is activated rather

than the polar head group. Phosphatidic acid, the precursor

of 1,2-diacyl-sn-glycerol (Fig. 25-42), attacks the -

phosphoryl group of CTP to form the activated CDP–

1004 Chapter 25. Lipid Metabolism

Figure 25-81 The glycerolipids and sphingolipids. The structures of the common head groups,

X, are presented in Table 12-2.

(CH

)

Glycerolipid

Sphingolipid

= H

= Carbohydrate

= Phosphate ester

1,2-Diacylglycerol

Glyceroglycolipid

Glycerophospholipid

-Acylsphingosine (ceramide)

Sphingoglycolipid (glycosphingolipid)

Sphingophospholipid

JWCL281_c25_940-1018.qxd 6/8/10 9:00 AM Page 1004

diacylglycerol and PP

(Fig. 25-84). Phosphatidylinositol re-

sults from the attack of inositol on CDP–diacylglycerol.

Phosphatidylglycerol is formed in two reactions: (1) attack

of the C1 ¬OH group of sn-glycerol-3-phosphate on

CDP–diacylglycerol, yielding phosphatidylglycerol phos-

phate; and (2) hydrolysis of the phosphoryl group to form

phosphatidylglycerol.

Cardiolipin, an important phospholipid first isolated

from heart tissue, is synthesized from two molecules of

phosphatidylglycerol (Fig. 25-85). The reaction occurs by

the attack of the C1 OH group of one of the phosphatidyl-

glycerol molecules on the phosphoryl group of the other,

displacing a molecule of glycerol.

Enzymes that synthesize phosphatidic acid have a gen-

eral preference for saturated fatty acids at C1 and for un-

saturated fatty acids at C2.Yet, this general preference can-

not account, for example, for the observations that ⬃80%

of brain phosphatidylinositol has a stearoyl group (18:0) at

C1 and an arachidonoyl group (20:4) at C2, and that ⬃40%

of lung phosphatidylcholine has palmitoyl groups (16:0) at

both positions (this latter substance is the major compo-

nent of the surfactant that prevents the lung from collaps-

ing when air is expelled; its deficiency is responsible for res-

piratory distress syndrome in premature infants). William

Lands showed that such side chain specificity results from

“remodeling” reactions in which specific acyl groups of in-

dividual glycerophospholipids are exchanged by specific

phospholipases and acyltransferases.

b. Biosynthesis of Plasmalogens and

Alkylacylglycerophospholipids

Eukaryotic membranes contain significant amounts of

two other types of glycerophospholipids:

1. Plasmalogens, which contain a hydrocarbon chain

linked to glycerol C1 via a vinyl ether linkage:

C O CH

CH CH

–

P OX

A plasmalogen

Section 25-8. Phospholipid and Glycolipid Metabolism 1005

Figure 25-82 The biosynthesis of phosphatidylethanolamine

and phosphatidylcholine. In mammals, CDP–ethanolamine and

CDP–choline are the precursors of the head groups.

Figure 25-83 Phosphatidylserine synthesis. Serine replaces

ethanolamine in phosphatidylethanolamine by a head group

exchange reaction.

R = H

R = CH

–

Phosphatidylethanolamine

Phosphatidylcholine (lecithin)

R = H

R = CH

–

CDP–ethanolamine

CDP–choline

–

Cytidine

–

Phosphoethanolamine

Phosphocholine

R = H

R = CH

NR

Ethanolamine

Choline

ATP

ADP

ethanolamine kinase

choline kinase

CTP

CTP:phosphoethanolamine

cytidyltransferase

or CTP:phosphocholine

cytidyltransferase

1,2-Diacylglycerol

CMP

CDP–ethanolamine:1,2-diacylglycerol

phosphoethanolamine transferase

CDP–choline:1,2-diacylglycerol

phosphocholine transferase

R = H

R = CH

NR

C O CH

–

P OCH

Phosphatidylethanolamine

HO CH

CH COO

–

Serine

HO CH

–

P O CH

CHR

CH COO

–

Phosphatidylserine

phosphatidylethanolamine:

serine transferase

JWCL281_c25_940-1018.qxd 4/20/10 1:59 PM Page 1005

1006 Chapter 25. Lipid Metabolism

Figure 25-84 The biosynthesis of phosphatidylinositol and phosphatidylglycerol. In mammals,

this process involves a CDP–diacylglycerol intermediate.

Figure 25-85 The formation of cardiolipin.

–

Phosphatidic acid

CTP

–

CDP–diacylglycerol

–

O Cytidine

CMP

Glycerol-3-phosphate Inositol

–

Phosphatidylglycerol phosphate

O PO

–

Phosphatidylglycerol

CHOH

–

Phosphatidylinositol

OH HO

2 R

C O C

–

P OCH

CHOH

Phosphatidylglycerol

–

OCH

CHCH

glycerol

C O CH

–

Cardiolipin

JWCL281_c25_940-1018.qxd 4/20/10 1:59 PM Page 1006

2. Alkylacylglycerophospholipids, in which the alkyl

substituent at glycerol C1 is attached via an ether linkage:

About 20% of mammalian glycerophospholipids are plas-

malogens. The exact percentage varies both from species to

species and from tissue to tissue within a given organism.

While plasmalogens comprise only 0.8% of the phospho-

lipids in human liver,they account for 23% of those in human

nervous tissue. The alkylacylglycerophospholipids are less

abundant than the plasmalogens; for instance, 59% of the

ethanolamine glycerophospholipids of human heart are plas-

malogens, whereas only 3.6% are alkylacylglycerophospho-

lipids. However, in bovine erythrocytes, 75% of the

ethanolamine glycerophospholipids are of the alkylacyl type.

C O CH

–

P O

An alkylacyl-

glycerophospholipid

The pathway forming ethanolamine plasmalogens and

alkylacylglycerophospholipids involves several reactions

(Fig. 25-86):

1. Exchange of the acyl group of 1-acyldihydroxyace-

tone phosphate for an alcohol.

2. Reduction of the ketone to 1-alkyl-sn-glycerol-3-

phosphate.

3. Acylation of the resulting C2 OH group by acyl-CoA.

4. Hydrolysis of the phosphoryl group to yield an

alkylacylglycerol.

5. Attack by the new OH group of alkylacylglycerol on

CDP–ethanolamine to yield 1-alkyl-2-acyl-sn-glycerophos-

phoethanolamine.

6. Introduction of a double bond into the alkyl group to

form the plasmalogen by a desaturase having the same co-

factor requirements as the fatty acid desaturases (Section

25-4E).

Recall that the precursor–product relationship between

the alkylacylglycerophospholipid and the plasmalogen was

Section 25-8. Phospholipid and Glycolipid Metabolism 1007

Figure 25-86 The biosynthesis of ethanolamine plasmalogen via

a pathway in which 1-alkyl-2-acyl-sn-glycerophosphoethanolamine

is an intermediate. The participating enzymes are (1) alkyl-DHAP

synthase, (2) 1-alkyl-sn-glycerol-3-phosphate dehydrogenase, (3)

acyl-CoA:1-alkyl-sn-glycerol-3-phosphate acyltransferase, (4) 1-alkyl-

2-acyl-sn-glycerol-3-phosphate phosphatase, (5) CDP–ethanolamine:

1-alkyl-2-acyl-sn-glycerophosphoethanolamine transferase, and

(6) 1-alkyl-2-acyl-sn-glycerophosphoethanolamine desaturase.

1-Acyldihydroxyacetone phosphate

OPO

2–

C OCR



CR SCoA

NADPH

+ H

NADP

OHCR

R CH

1-Alkyl-2-acyl-sn-glycerol-3-phosphate

CHO

OPO

2–

CR

1-Alkyl-sn-glycerol-3-phosphate

CHHO

OPO

2–

1-Alkyl-2-acyl-sn-glycerol

CHO

CR

CMP

CoASH

CDP–ethanolamine

1-Alkyl-2-acyl-sn-glycerophosphoethanolamine

CHO

CR

O OP

–

Ethanolamine plasmalogen

CHO

CR

OOP

–

1-Alkyldihydroxyacetone phosphate

OPO

2–

6 2H

+ NADH + H

cytochrome b

JWCL281_c25_940-1018.qxd 4/20/10 1:59 PM Page 1007

established through studies using [

C]ethanolamine (Sec-

tion 16-3Be).

The alkylacylglycerophospholipid with an acetyl group

at R

and a choline polar head group (X), 1-O-hexadecyl-

2-acetyl-sn-glycero-3-phosphocholine, is known as

platelet-activating factor (PAF). This molecule has diverse

functions and acts at very low concentrations (10

10

M) to

lower blood pressure and to cause blood platelets to ag-

gregate.

B. Sphingophospholipids

Only one major phospholipid contains ceramide

(N-acylsphingosine) as its hydrophobic tail: sphingomyelin

(N-acylsphingosine phosphocholine; Section 12-1D), an

important structural lipid of nerve cell membranes. The

molecule was once thought to be synthesized from

N-acylsphingosine and CDP–choline. However, it is now

known that the main route of sphingomyelin synthesis oc-

curs through donation of the phosphocholine group of

phosphatidylcholine to N-acylsphingosine (Fig. 25-87).

These pathways were differentiated by establishing the

precursor–product relationships between CDP–choline,

phosphatidylcholine, and sphingomyelin (Section 16-3Be).

Mouse liver microsomes were isolated and incubated for a

short time with [

H]choline. Radioactivity appeared in

sphingomyelin only after first appearing in both

CDP–choline and phosphatidylcholine, ruling out the

direct transfer of phosphocholine from CDP–choline to

N-acylsphingosine.

The most prevalent acyl groups of sphingomyelin are

palmitoyl (16:0) and stearoyl (18:0) groups. Longer chain

fatty acids such as nervonic acid (24:1) and behenic acid

(22:0) occur with lesser frequency in sphingomyelins.

C. Sphingoglycolipids

Most sphingolipids are sphingoglycolipids, that is, their polar

head groups consist of carbohydrate units (Section 12-1D).

The principal classes of sphingoglycolipids, as indicated in

Fig. 25-88, are cerebrosides (ceramide monosaccharides),

sulfatides (ceramide monosaccharide sulfates), globosides

(neutral ceramide oligosaccharides), and gangliosides

(acidic, sialic acid–containing ceramide oligosaccharides).

The carbohydrate unit is glycosidically attached to the N-

acylsphingosine at its C1 OH group (Fig. 25-81).

The lipids providing the carbohydrate that covers the

external surfaces of eukaryotic cells are sphingoglycolipids.

Along with glycoproteins (Section 23-3), they are biosyn-

thesized on the luminal surfaces of the endoplasmic reticu-

lum and the Golgi apparatus and reach the plasma mem-

brane through vesicle flow (Sections 12-4C and 12-4D),

where membrane fusion results in their facing the external

surface of the lipid bilayer (Fig. 12-60). Degradation of

sphingoglycolipids occurs in the lysosomes after endocyto-

sis from the plasma membrane.

In the following subsections, we discuss the biosynthesis

and breakdown of N-acylsphingosine and sphingoglyco-

lipids and consider the diseases caused by deficiencies in

their degradative enzymes.

a. Biosynthesis of Ceramide (N-Acylsphingosine)

Biosynthesis of N-acylsphingosine occurs in four reactions

from the precursors palmitoyl-CoA and serine (Fig. 25-89):

1. 3-Ketosphinganine synthase (serine palmitoyltrans-

ferase), a pyridoxal phosphate–dependent enzyme, cat-

alyzes the condensation of palmitoyl-CoA with serine yield-

ing 3-ketosphinganine (pyridoxal phosphate–dependent

reactions are discussed in Section 26-1A).

1008 Chapter 25. Lipid Metabolism

Figure 25-87 The synthesis of sphingomyelin from N-acylsphingosine and phosphatidylcholine.

Ceramide (N-acylsphingosine)

RCNHC

(CH

)

Phosphatidylcholine

Diacylglycerol

COC

O POCH

N(CH

)

Sphingomyelin

R C NH C

O POCH

N(CH

)

–

OH H H

(CH

)

JWCL281_c25_940-1018.qxd 6/8/10 9:00 AM Page 1008

2. 3-Ketosphinganine reductase catalyzes the NADPH-

dependent reduction of 3-ketosphinganine’s keto group to

form sphinganine (dihydrosphingosine).

3. Dihydroceramide is formed by transfer of an acyl

group from an acyl-CoA to the sphinganine’s 2-amino

group, forming an amide bond.

4. Dihydroceramide dehydrogenase converts dihydro-

ceramide to ceramide by an FAD-dependent oxidation

reaction.

b. Biosynthesis of Cerebrosides (Glycosylceramides)

Galactocerebroside (1--galactosylceramide) and glu-

cocerebroside (1--glucosylceramide) are the two most

common cerebrosides. In fact, the term cerebroside is often

Section 25-8. Phospholipid and Glycolipid Metabolism 1009

Figure 25-88 Diagrammatic representation of the principal

classes of sphingoglycolipids. The G

ganglioside structures are

presented in greater detail in Fig. 12-7.

Figure 25-89 The biosynthesis of ceramide

(N-acylsphingosine).

OSO

–

Cerebrosides

Sulfatide

Globosides

Gangliosides

Glucocerebroside

Galactocerebroside

Lactosyl ceramide

Trihexosyl ceramide

Globoside

NANA

= glucose

= N-acetylgalactosamine

= ceramide

= galactose

NANA

= N-acetylneuraminic acid (sialic acid)

S +CH

(CH

)

(CH

)

Palmitoyl-CoA

–

Serine

3-ketosphinganine reductase

3-ketosphinganine synthase

–

+NADPH

NADP

CoA

CoASH

3-Ketosphinganine

(3-ketodihydrosphingosine)

(CH

)

Sphinganine

(dihydrosphingosine)

(CH

)

Dihydroceramide

(N-acylsphinganine)

Ceramide

(N-acylsphingosine)

acyl-CoA transferase

SCoAR

CCCH

(CH

)

CoASH

dihydroceramide dehydrogenase

FAD

FADH

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used synonymously with galactocerebroside. Both are syn-

thesized from ceramide by addition of a glycosyl unit from

the corresponding UDP–hexose (Fig. 25-90). Galactocere-

broside is a common component of brain lipids. Glucocere-

broside, although relatively uncommon, is the precursor of

globosides and gangliosides.

c. Biosynthesis of Sulfatides

Sulfatides (galactocerebroside-3-sulfate) account for

15% of the lipids of white matter in the brain. They are

formed by transfer of an “activated” sulfate group from 3-

phosphoadenosine-5-phosphosulfate (PAPS) to the C3

OH group of galactose in galactocerebroside (Fig. 25-91).

d. Biosynthesis of Globosides and Gangliosides

Biosynthesis of both globosides (neutral ceramide

oligosaccharides) and gangliosides (acidic, sialic acid–

containing ceramide oligosaccharides) is catalyzed by a

series of glycosyltransferases. While the reactions are

chemically similar, each is catalyzed by a specific enzyme.

The pathways begin with transfer of a galactosyl unit from

UDP–Gal to glucocerebroside to form a (1 S 4) linkage

(Fig. 25-92). Since this bond is the same as that linking glu-

cose and galactose in lactose, this glycolipid is often re-

ferred to as lactosyl ceramide. Lactosyl ceramide is the pre-

cursor of both globosides and gangliosides. To form a

globoside, one galactosyl and one N-acetylgalactosaminyl

unit are sequentially added to lactosyl ceramide from

UDP–Gal and UDP–GalNAc, respectively. The G

gan-

gliosides are formed by addition of N-acetylneuraminic

acid (NANA, sialic acid)

from CMP–NANA to lactosyl ceramide in (2 S 3) linkage

yielding G

. The sequential additions to G

of the

N-acetylgalactosamine and galactose units from

UDP–GalNAc and UDP–Gal yield gangliosides G

and

. Other gangliosides are formed by adding a second

COO

–

H C

C N

N-Acetylneuraminic acid

(NANA, sialic acid)

1010 Chapter 25. Lipid Metabolism

Figure 25-90 The biosynthesis of cerebrosides.

Figure 25-91 The biosynthesis of sulfatides.

(CH

)

CHNH

Glucocerebroside (1-

-D-glucosylceramide)

HOH

UDP–glucose

UDP

UDP glucose:ceramide

glycosyltransferase

(glucosylceramide synthase)

UDP galactose:ceramide

glycosyltransferase

(CH

)

CHNH

Galactocerebroside (1-

-D-galactosylceramide)

HOH

Ceramide

UDP–galactose

UDP

–

3-Phosphoadenosine-5-

phosphosulfate (PAPS)

3-Phosphoadenosine-5-

phosphate

Adenine

2

PO OH

–

Galactocerebroside

OSO



HOH

(CH

)

Sulfatide (galactocerebroside-3-sulfate)

CC CH

OH H

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