Garrett R.H., Grisham C.M. - Biochemistry (1999)(2nd ed.)(en)

FIGURE 25.8

25.1 ● The Fatty Acid Biosynthesis and Degradation Pathways Are Different

811

six-carbon -ketoacyl-ACP and CO2. Subsequent reduction to a -alcohol, dehydration, and another reduction yield a six-carbon saturated acyl-ACP. This cycle continues with the net addition of a two-carbon unit in each turn until the chain is 16 carbons long (Figure 25.7). The -ketoacyl-ACP synthase cannot accommodate larger substrates, so the reaction cycle ends with a 16-carbon chain. Hydrolysis of the C16-acyl-ACP yields a palmitic acid and the free ACP.

In the end, seven malonyl-CoA molecules and one acetyl-CoA yield a palmitate (shown here as palmitoyl-CoA):

Acetyl-CoA 7 malonyl-CoA 14 NADPH 14 H 88n

palmitoyl-CoA 7 HCO3 14 NADP 7 CoASH The formation of seven malonyl-CoA molecules requires

7 Acetyl-CoA 7 HCO3 7 ATP4 88n

7 malonyl-CoA 7 ADP3 7 Pi2 7 H

Thus, the overall reaction of acetyl-CoA to yield palmitic acid is

8 Acetyl-CoA 7 ATP4 14 NADPH 7H 88n

palmitoyl-CoA 14 NADP 7 CoASH 7 ADP3 7Pi2

Note: These equations are stoichiometric and are charge balanced. See Problem 1 at the end of the chapter for practice in balancing these equations.

Fatty Acid Synthesis in Eukaryotes Occurs on a

Multienzyme Complex

In contrast to bacterial and plant systems, the reactions of fatty acid synthesis beyond the acetyl-CoA carboxylase in animal systems are carried out by a special multienzyme complex called fatty acid synthase (FAS). In yeast, this 2.4 106 D complex contains two different peptide chains, an subunit of 213 kD and a subunit of 203 kD, arranged in an 6 6 dodecamer. The separate enzyme activities associated with each chain are shown in Figure 25.8. In animal systems, FAS is a dimer of identical 250-kD multifunctional polypeptides. Studies of the action of proteolytic enzymes on this polypeptide have led to a model involving three separate domains joined by flexible connecting sequences (Figure 25.9). The first domain is responsible for the binding of acetyl and malonyl building blocks and for the condensation of these units. This domain includes the acetyl transferase, the malonyl transferase, and the acyl-malonyl-ACP condensing enzyme (the -ketoacyl synthase). The second domain is primarily responsible for the reduction of the intermediate synthesized in domain 1, and contains the acyl carrier protein, the -ketoacyl reductase, the dehydratase, and the enoyl-ACP reductase. The third domain contains the thioesterase that liberates the product palmitate when the growing acyl chain reaches its limit length of 16 carbons. The close association of activities in this complex permits efficient exposure of intermediates to one active site and then the next. The presence of all these activities on a single polypeptide ensures that the cell will simultaneously synthesize all the enzymes needed for fatty acid synthesis.

The Mechanism of Fatty Acid Synthase

The first domain of one subunit of the fatty acid synthase interacts with the second and third domains of the other subunit; that is, the subunits are arranged in a head-to-tail fashion (Figure 25.9). The first step in the fatty acid synthase reaction is the formation of an acetyl-O-enzyme intermediate between the acetyl group of an acetyl-CoA and an active-site serine of the acetyl trans-

	α –Subunit
	Condensing enzyme
KSase	(Ketoacyl-ACP
	synthase)
KRase	β -Ketoacyl reductase
	Acyl carrier protein
	β –Subunit
ATase	Acetyl transferase
MTase	Malonyl transferase
DH	β -Hydroxyacyl
	dehydratase
ERase	Enoyl reductase

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

FIGURE 25.10

(Adapted from Wakil, S. J., Stoops,

FIGURE 25.9

812 Chapter 25 ● Lipid Biosynthesis

● Fatty 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.

J. K., and Joshi, V. C., 1983. Annual Review of

Biochemistry 52:556.)

Domain 1: Acyl and malonyl binding and condensation

β -Ketoacyl synthase

Acetyl transferase

Malonyl transferase

Substrate entry

Acetyl–CoA

Malonyl–CoA	TEase
Cys		ACP
	SH	KR DH
KSase	HS	ER

ATase

Chain elongation

MTase

MTase

Domain 2: Reduction of		Chain		ATase
		elongation
domain 1 intermediate				KSase
	ER	SH
Enoyl–ACP reductase
	KR
β -Ketoacyl reductase		HS
	ACP		Cys
DH
Dehydratase				Acetyl–CoA
		TEase
				Malonyl–CoA
Thioesterase				Substrate entry
	Domain 3: Liberation of
	palmitate product

ferase (Figure 25.10). In a similar manner, a malonyl-O-enzyme intermediate is formed between malonyl-CoA and a serine residue of the malonyl transferase. The acetyl group on the acetyl transferase is then transferred to the OSH group of the acyl carrier protein, as shown in Figure 25.11. The next step is the transfer of the acetyl group to the -ketoacyl-ACP synthase, or condensing enzyme. This frees the acyl carrier protein to acquire the malonyl group from the malonyl transferase. The next step is the condensation reaction, in which decarboxylation facilitates the concerted attack of the remaining two-carbon unit of the acyl carrier protein at the carbonyl carbon of the acetate group on the condensing enzyme. Note that decarboxylation forms a transient, highly nucleophilic carbanion which can attack the acetate group.

The next three steps—reduction of the carbonyl to an alcohol, dehydration to yield a trans- , double bond, and reduction to yield a saturated chain— are identical to those occurring in bacteria and plants (Figure 25.7) and

O

O –

O

E

CH3

C

S CoA

CH3

C

S

CoA

CH3

C

O

Ser

H

O

O

Ser

Ser

E

E

● Acetyl 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.

25.1 ● The Fatty Acid Biosynthesis and Degradation Pathways Are Different

813

AT

KSase

MT

AT

KSase

MT

AT

KSase

MT

OH

SH

OH

O

SH

O

OH

SH

O

O

O

1

O

C

C

O

2

C

O

H3C

O

CH3

CH2

CH2

C

CH3C

SCoA

O2CCH2C

SCoA

CO–2

CO–2

SH

SH

S

ACP

ACP

ACP

3

AT KSase

MT

AT

KSase

MT

AT KSase

MT

AT

KSase

MT

HS

HS

CH3

CH3

CO2

HO

OH

HO

OH

OH

S

OH

OH

S

O

CH2

6

C

O

5

4

–

O

C

O

O

C

C

O

CH2

CH2

C

CH2

CH3

CH3

CH2

C

O

C

O

O

C

CO–2

O

S

S

S

SH

ACP

ACP

ACP

ACP

FIGURE 25.11 ● The mechanism of the fatty acyl synthase reaction in eukaryotes.

(1) Acetyl and malonyl groups are loaded onto acetyl transferase and malonyl transferase, respectively. (2) The acetate unit that forms the base of the nascent chain is transferred first to the acyl carrier protein domain and (3) then to the -ketoacyl synthase. (4) Attack by ACP on the carbonyl carbon of a malonyl unit on malonyl transferase forms malonylACP. (5) Decarboxylation leaves a reactive, transient carbanion that can attack the carbonyl carbon of the acetyl group on the -ketoacyl synthase. (6) Reduction of the keto group, dehydration, and saturation of the resulting double bond follow, leaving an acyl group on ACP, and steps 3 through 6 repeat to lengthen the nascent chain.

resemble the reverse of the reactions of fatty acid oxidation (and the conversion of succinate to oxaloacetate in the TCA cycle). This synthetic cycle now repeats until the growing chain is 16 carbons long. It is then released by the thioesterase domain on the synthase. The amino acid sequence of the thioesterase domain is homologous with serine proteases; the enzyme has an active-site serine that carries out nucleophilic attack on the carbonyl carbon of the fatty acyl thioester to be cleaved.

Further Processing of C16 Fatty Acids

Additional Elongation

As seen already, palmitate is the primary product of the fatty acid synthase. Cells synthesize many other fatty acids. Shorter chains are easily made if the chain is released before reaching 16 carbons in length. Longer chains are made through special elongation reactions, which occur both in the mitochondria and at the surface of the endoplasmic reticulum. The ER reactions are actually quite similar to those we have just discussed: addition of two-carbon units

FIGURE 25.12

814 Chapter 25 ● Lipid Biosynthesis

at the carboxyl end of the chain by means of oxidative decarboxylations involving malonyl-CoA. As was the case for the fatty acid synthase, this decarboxylation provides the thermodynamic driving force for the condensation reaction. The mitochondrial reactions involve addition (and subsequent reduction) of acetyl units. These reactions (Figure 25.12) are essentially a reversal of fatty acid oxidation, with the exception that NADPH is utilized in the saturation of the double bond, instead of FADH2.

Introduction of a Single cis Double Bond

Both prokaryotes and eukaryotes are capable of introducing a single cis double bond in a newly synthesized fatty acid. Bacteria such as E. coli carry out this process in an O2-independent pathway, whereas eukaryotes have adopted an O2-dependent pathway. There is a fundamental chemical difference between the two. The O2-dependent reaction can occur anywhere in the fatty acid chain,

			O
						SCoA
	CH3		C
O						HSCoA

R CH2 C SCoA

Thiolase

Acyl-CoA

H2O

H O

R CH2 C C C SCoA

Enoyl-CoA hydratase

H

, β -trans-Enoyl-CoA

NADPH + H+

NADP+

O

R CH2 CH2 CH2 C SCoA

Acyl-CoA (2 carbons longer)

O O

R CH2 C CH2 C SCoA

β -Ketoacyl-CoA

NADH + H+	L-β -hydroxyacyl-CoA
	dehydrogenase

NAD+

H O

R CH2 C CH2 C SCoA

OH

L-β -Hydroxyacyl-CoA

● Elongation 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.

FIGURE 25.13

25.1 ● The Fatty Acid Biosynthesis and Degradation Pathways Are Different

815

with no (additional) need to activate the desired bond toward dehydrogenation. However, in the absence of O2, some other means must be found to activate the bond in question. Thus, in the bacterial reaction, dehydrogenation occurs while the bond of interest is still near the -carbonyl or -hydroxy group and the thioester group at the end of the chain.

In E. coli, the biosynthesis of a monounsaturated fatty acid begins with four normal cycles of elongation to form a 10-carbon intermediate, -hydroxy- decanoyl-ACP (Figure 25.13). At this point, -hydroxydecanoyl thioester dehydrase forms a double bond , to the thioester and in the cis configuration. This is followed by three rounds of the normal elongation reactions to form palmitoleoyl-ACP. Elongation may terminate at this point or may be followed by additional biosynthetic events. The principal unsaturated fatty acid in E. coli, cis-vaccenic acid, is formed by an additional elongation step, using palmitoleoylACP as a substrate.

Unsaturation Reactions Occur in Eukaryotes in the

Middle of an Aliphatic Chain

The addition of double bonds to fatty acids in eukaryotes does not occur until the fatty acyl chain has reached its full length (usually 16 to 18 carbons). Dehydrogenation of stearoyl-CoA occurs in the middle of the chain despite the absence of any useful functional group on the chain to facilitate activation:

CH3O(CH2)16COOSCoA 88n CH3O(CH2)7CHPCH(CH2)7COOSCoA

This impressive reaction is catalyzed by stearoyl-CoA desaturase, a 53-kD enzyme containing a nonheme iron center. NADH and oxygen (O2) are required, as are two other proteins: cytochrome b5 reductase (a 43-kD flavoprotein) and cytochrome b5 (16.7 kD). All three proteins are associated with the endoplasmic reticulum membrane. Cytochrome b5 reductase transfers a pair of electrons from NADH through FAD to cytochrome b5 (Figure 25.14). Oxidation of reduced cytochrome b5 is coupled to reduction of nonheme Fe3 to Fe2 in the desaturase. The Fe3 accepts a pair of electrons (one at a time in a cycle) from cytochrome b5 and creates a cis double bond at the 9,10-posi- tion of the stearoyl-CoA substrate. O2 is the terminal electron acceptor in this fatty acyl desaturation cycle. Note that two water molecules are made, which means that four electrons are transferred overall. Two of these come through the reaction sequence from NADH, and two come from the fatty acyl substrate that is being dehydrogenated.

Acetyl–ACP + 4 Malonyl-ACP

Four rounds of

fatty acyl synthase

O

H

CH3(CH2)5

CH2

C

CH2

C

ACP

OH

β

-Hydroxydecanoyl–ACP

β -Hydroxydecanoyl

H2O

thioester dehydrase

O

H

H

CH3(CH2)5 C

C

CH2

C

ACP

γ

β

Three rounds of fatty acyl synthase

Palmitoleoyl–ACP

(16:1∆ 9–ACP)

Elongation at ER

cis-Vaccenoyl-ACP 18:1∆ 11–ACP

● Double 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.

2 H2O

	2	H+
NADH
+ H+	Cytochrome b5	2 Cytochrome b5	Desaturase
	reductase	(Fe2+) (Reduced)	(Fe3+)
	(FAD)
NAD+	Cytochrome b5	2 Cytochrome b5	Desaturase
	reductase	(Fe3+) (Oxidized)	(Fe	2+	)

(FADH2)

FIGURE 25.14 ● The 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.

+

H

H

O

CH3

(CH2)7

C

C

(CH2)7C

SCoA

Oleoyl-CoA

O

CH3

(CH2)16

C

S CoA

Stearoyl-CoA

+ O2

+ 2 H+

816 Chapter 25 ● Lipid Biosynthesis

The Unsaturation Reaction May Be Followed by Chain Elongation

Additional chain elongation can occur following this single desaturation reaction. The oleoyl-CoA produced can be elongated by two carbons to form a 20:1 cis- 11 fatty acyl-CoA. If the starting fatty acid is palmitate, reactions similar to the preceding scheme yield palmitoleoyl-CoA (16:1 cis- 9), which subsequently can be elongated to yield cis-vaccenic acid (18:1 cis- 11). Similarly, C16 and C18 fatty acids can be elongated to yield C22 and C24 fatty acids, such as are often found in sphingolipids.

Biosynthesis of Polyunsaturated Fatty Acids

Organisms differ with respect to formation, processing, and utilization of polyunsaturated fatty acids. E. coli, for example, does not have any polyunsaturated fatty acids. Eukaryotes do synthesize a variety of polyunsaturated fatty acids, certain organisms more than others. For example, plants manufacture double bonds between the 9 and the methyl end of the chain, but mammals cannot. Plants readily desaturate oleic acid at the 12-position (to give linoleic acid) or at both the 12and 15-positions (producing linolenic acid). Mammals require polyunsaturated fatty acids, but must acquire them in their diet. As such, they are referred to as essential fatty acids. On the other hand, mammals can introduce double bonds between the double bond at the 8- or 9-posi- tion and the carboxyl group. Enzyme complexes in the endoplasmic reticulum desaturate the 5-position, provided a double bond exists at the 8-position, and form a double bond at the 6-position if one already exists at the 9-position. Thus, oleate can be unsaturated at the 6,7-position to give an 18:2 cis- 6, 9 fatty acid.

Arachidonic Acid Is Synthesized from Linoleic Acid by Mammals

Mammals can add additional double bonds to unsaturated fatty acids in their diets. Their ability to make arachidonic acid from linoleic acid is one example (Figure 25.15). This fatty acid is the precursor for prostaglandins and other biologically active derivatives such as leukotrienes. Synthesis involves formation of a linoleoyl ester of CoA from dietary linoleic acid, followed by introduction of a double bond at the 6-position. The triply unsaturated product is then elongated (by malonyl-CoA with a decarboxylation step) to yield a 20-carbon fatty acid with double bonds at the 8-, 11-, and 14-positions. A second desaturation reaction at the 5-position followed by an acyl-CoA synthetase reaction (Chapter 24) liberates the product, a 20-carbon fatty acid with double bonds at the 5-, 8-, 11-, and 14-positions.

Regulatory Control of Fatty Acid Metabolism—An Interplay of

Allosteric Modifiers and Phosphorylation–Dephosphorylation Cycles

The control and regulation of fatty acid synthesis is intimately related to regulation of fatty acid breakdown, glycolysis, and the TCA cycle. Acetyl-CoA is an important intermediate metabolite in all these processes. In these terms, it is easy to appreciate the interlocking relationships in Figure 25.16. Malonyl-CoA can act to prevent fatty acyl-CoA derivatives from entering the mitochondria by inhibiting the carnitine acyltransferase that is responsible for this transport. In this way, when fatty acid synthesis is turned on (as signaled by higher levels of malonyl-CoA), -oxidation is inhibited. As we pointed out earlier, citrate is an important allosteric activator of acetyl-CoA carboxylase, and fatty acyl-CoAs

25.1 ● The Fatty Acid Biosynthesis and Degradation Pathways Are Different

817

	12	9
	Linoleic acid (18:2∆ 9,12)
	Acyl-CoA	CoA +	ATP
		AMP +	P P
	synthetase

Linoleoyl–CoA (18:2∆ 9,12–CoA)

Desaturation

2 H

COO–

O

C S CoA

12	9	6
			C	S	CoA
Linolenoyl–CoA (18:3∆ 6,9,12–CoA)
			O
	Malonyl_CoA
		+	Elongation
	CO		CoA
		2
14	11	8
(20:3∆ 8,11,14–CoA)				C	S	CoA
				O
	Desaturation
	2 H			O
14	11	8	5	C	S	CoA
Arachidonoyl–CoA (20:4∆ 5,8,11,14–CoA)
	H2O
	CoA			O
14	11	8	5	C	_
					O

Arachidonic acid

FIGURE 25.15 ● Arachidonic 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.

are inhibitors. The degree of inhibition is proportional to the chain length of the fatty acyl-CoA; longer chains show a higher affinity for the allosteric inhibition site on acetyl-CoA carboxylase. Palmitoyl-CoA, stearoyl-CoA, and arachidyl-CoA are the most potent inhibitors of the carboxylase.

Hormonal Signals Regulate ACC and Fatty Acid Biosynthesis

As described earlier, citrate activation and palmitoyl-CoA inhibition of acetylCoA carboxylase are strongly dependent on the phosphorylation state of the enzyme. This provides a crucial connection to hormonal regulation. Many of the enzymes that act to phosphorylate acetyl-CoA carboxylase (Figure 25.4) are controlled by hormonal signals. Glucagon is a good example (Figure 25.17). As noted in Chapter 23, glucagon binding to membrane receptors activates an intracellular cascade involving activation of adenylyl cyclase. Cyclic AMP produced by the cyclase activates a protein kinase, which then phosphorylates acetyl-CoA carboxylase. Unless citrate levels are high, phosphorylation causes inhibition of fatty acid biosynthesis. The carboxylase (and fatty acid synthesis)

FIGURE 25.16

818 Chapter 25 ● Lipid Biosynthesis

	Glucose
		first
	ADP	priming
		reaction
	Glucose-6-phosphate
	(G6P)
	Fructose-6-phosphate
	(F6P)		Glycolysis
		second
	ADP	priming
		reaction
	Fructose-1,6-bisphosphate
	(FBP)
		Dihydroxyacetate phosphate
			(DHAP)
	Glyceraldehyde-3-phosphate	Glyceraldehyde-3-phosphate
P	(G3P)		(G3P)	P
NAD+				NAD+
NADH				NADH
	1,3-bisphosphoglycerate	1,3-bisphosphoglycerate
	(BPG)		(BPG)
ADP	first		first	ADP
	ATP-forming	ATP-forming
ATP	reaction	reaction		ATP
	3-phosphoglycerate (3PG)	3-phosphoglycerate (3PG)
	2-phosphoglycerate (2PG)	2-phosphoglycerate (2PG)
	H2O		H2O
	Phosphoenolpyruvate (PEP)	Phosphoenolpyruvate (PEP)
ADP	second	second		ADP
	ATP-forming	ATP-forming
ATP	reaction	reaction		ATP

	2 Pyruvate
	Acetyl-CoA
	Oxaloacetate	Citrate
β -oxidation	Citric acid
	cycle
	Fatty acyl-CoA
	Carnitine
acyltransferase

Malate Oxaloacetate

Citrate

Acetyl-CoA

Acetyl-CoA + carboxylase

Malonyl-CoA

Fatty acyl-CoA

Fatty acid

Carnitine

Triacylglycerol

● Regulation 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.

can be reactivated by a specific phosphatase, which dephosphorylates the carboxylase. Also indicated in Figure 25.17 is the simultaneous activation by glucagon of triacylglycerol lipases, which hydrolyze triacylglycerols, releasing fatty acids for -oxidation. Both the inactivation of acetyl-CoA carboxylase and the activation of triacylglycerol lipase are counteracted by insulin, whose receptor acts to stimulate a phosphodiesterase that converts cAMP to AMP.

25.2 ● Biosynthesis of Complex Lipids

819

Glucagon

Insulin

	Glucagon	Adenylyl
	receptor
		cyclase

G-protein

ATP

cAMP

Protein kinase (inactive)

Insulin receptor

Phosphodiesterase

AMP

Protein kinase (active)

	Dephospho-acetyl-CoA carboxylase					Triacylglycerol
						lipase (inactive)
	(Active at low [citrate])
	HPO42_			ATP		ATP	HPO42_
	Phosphatases						Phosphatases
		H2O		ADP		ADP	H2O
	Phospho-acetyl-CoA carboxylase					Triacylglycerol		P
	(Active only at high [citrate])
						lipase (active)
	P	P	P	P	P
	P				P

Triacylglycerols

Fatty acids and glycerol

FIGURE 25.17 ● Hormonal signals regulate fatty acid synthesis, primarily through actions on acetyl-CoA carboxylase. Availability of fatty acids also depends upon hormonal activation of triacylglycerol lipase.

25.2 ● Biosynthesis of Complex Lipids

Complex lipids consist of backbone structures to which fatty acids are covalently bound. Principal classes include the glycerolipids, for which glycerol is the backbone, and sphingolipids, which are built on a sphingosine backbone. The two major classes of glycerolipids are glycerophospholipids and triacylglycerols. The phospholipids, which include both glycerophospholipids and sphingomyelins, are crucial components of membrane structure. They are also precursors of hormones such as the eicosanoids (e.g., prostaglandins) and signal molecules, such as the breakdown products of phosphatidylinositol.

Different organisms possess greatly different complements of lipids and therefore invoke somewhat different lipid biosynthetic pathways. For example,

FIGURE 25.18

820 Chapter 25 ● Lipid Biosynthesis

sphingolipids and triacylglycerols are produced only in eukaryotes. In contrast, bacteria usually have rather simple lipid compositions. Phosphatidylethanolamine accounts for at least 75% of the phospholipids in E. coli, with phosphatidylglycerol and cardiolipin accounting for most of the rest. E. coli membranes possess no phosphatidylcholine, phosphatidylinositol, sphingolipids, or cholesterol. On the other hand, some bacteria (such as Pseudomonas) can synthesize phosphatidylcholine, for example. In this section and the one following, we consider some of the pathways for the synthesis of glycerolipids, sphingolipids, and the eicosanoids, which are derived from phospholipids.

CH2OH

HO

C

H

CH2OH

Glycerol

ATP

Glycerokinase

ADP

CH2OH

NADH + H+

NAD+

CH2OH

O

O

C

O

HO

C

H

O

O–

O–

CH2

P

CH2

O

P

Glycerol-3-P

O–

dehydrogenase

O–

Dihydroxyacetone-P

Glycerol-3-P

O

O

O

CoA

Dihydroxyacetone-P

R1

C

Glycerol-3-P

R1

C

CoA

or

R1

C

ACP

acyltransferase

acyltransferase

CoA

CoA

or

ACP

O

O

R1

C

O

CH2

O

NADPH + H+

NADP+

R1

C

O

CH2

O

C

O

O

HO

C

H

O–

CH2

P

O–

CH2

O

P

Acyldihydroxyacetone-P

O–

reductase

O–

1-Acyldihydroxyacetone-P

1-Acylglycerol-3-P

O

O

1-Acylglycerol-3-P

R2

C

CoA

or

R2

C

ACP

acyltransferase

CoA

or

ACP

O

R1

C

O

CH2

O

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

R2 C O C H O

CH2 O P O–

O–

Phosphatidic acid