Saturated Fatty Acids

The processes of fatty acid biosynthesis are well studied and are known to be catalysed by the enzyme fatty acid synthase. In animals, this is a multifunctional protein containing all of the catalytic activities required, whilst bacteria and plants utilize an assembly of separable enzymes. Acetyl-CoA and malonyl-CoA themselves are not involved in the condensation step: they are converted into enzyme-bound thioesters, the malonyl ester by means of an acyl carrier protein (ACP) (Figure 3.2). The Claisen reaction follows giving acetoacetyl-ACP (P-keto acyl-ACP; R=H), which is reduced stereospecifically to the corresponding P-hydroxy ester, consuming NADPH in the reaction. Then follows elimination of water giving the E (trans) a,P-unsaturated ester. Reduction of the double bond again utilizes NADPH and generates a saturated acyl-ACP (fatty acyl-ACP; R=H) which is two carbons longer than the starting material. This can feed back into the system, condensing again with malonyl-ACP, and going through successive reduction, dehydration, and reduction steps, gradually increasing the chain length by two carbons for each cycle, until the required chain length is obtained. At that point, the fatty acyl chain can be released as a fatty acyl-CoA or as the free acid. The chain length actually elaborated is probably controlled by the specificity of the thioesterase enzymes that subsequently catalyse release from the enzyme.

The fatty acid synthase protein is known to contain an acyl carrier protein binding site, and also an active site cysteine residue in the P-ketoacyl synthase domain. Acetyl and malonyl groups are successively transferred from coenzyme A esters and attached to the thiol groups of Cys and ACP (Figure 3.3). The Claisen condensation occurs, and the processes of reduction, dehydration, and reduction then occur whilst the growing chain is attached to ACP. The ACP carries a phosphopantatheine group exactly analogous to that in coenzyme A, and this provides a long flexible arm, enabling the growing fatty acid chain to reach the active site of each enzyme in the complex, allowing the different chemical reactions to be performed without releasing intermediates from the enzyme (compare polyketide synthesis page 62 and peptide synthesis, page 421). Then the chain is transferred to the thiol of Cys, and the process can co2h

CH2CO-SCoA malonyl-CoA

acyl carrier protein (ACP)

co2h ch2co-s-acp malonyl-ACP

CH3CO — SCoA acetyl-CoA

NADPH

H OH

rch2yR'ch2co-s-acp -

ß-hydroxy acyl-ACP stereospecific

E2 elimination I _ H2O ofH2O \

Claisen reaction f- RCH2CO-S-Enz acyl-enzyme thioester

reduction of carbonyl

NADPH

each turn of the cycle extends the chain length of the acyl group by two carbons

CO-S-ACP

RCH2^^ a,ß-unsaturated acyl-ACP

reduction of double bond

RCH2CH2CH2CO - S - ACP fatty acyl-ACP

HSCoA

RCH2CH2CH2CO - SCoA fatty acyl-CoA

RCH2CH2CH2CO2H fatty acid

Figure 3.2

SH ACP)

growing fatty acyl chain

ACP) fatty acid synthase transfer acetyl-CoA malonyl-CoA (acetyl/malonyl transacylases)

transfer

reduction dehydration reduction f(

(P-ketoacyl reductase; P-hydroxyacyl dehydratase; enoyl reductase)

acetyl-CoA malonyl-CoA (acetyl/malonyl transacylases)

ch3 AJio-H

Claisen reaction (ß-ketoacyl synthase)

ACP.

! Hi

H OH

■ OH

cysteamine

pantothenic acid

pantotheine bound to serine group of ACP through phosphate phosphopantotheine

Figure 3.3

Ser-ACP

pantotheine bound to serine group of ACP through phosphate phosphopantotheine

Figure 3.3

continue. Making the process even more efficient, animal fatty acid synthase is a dimeric protein containing two catalytic centres and is able to generate two growing chains. The monomeric subunits are also arranged head to tail so that the acyl group of one unit actually picks up a malonyl extender from the other unit (Figure 3.4). Note that the sequence of enzyme activities along the protein chain of the enzyme complex does not correspond with the order in which they are employed.

Thus, combination of one acetate starter unit with seven malonates would give the C16 fatty acid, palmitic acid, and with eight malonates the C18 fatty acid, stearic acid. Note that the two carbons at the head of the chain (methyl end) are provided by acetate, not malonate, whilst the remainder are derived from malonate, which itself

TE ACP KR ER

ER KR ACP TE

dimeric fatty acid synthase dotted lines indicate two sites for fatty acid synthesis, utilizing enzyme activities from both subunits

ACP: acyl carrier protein DH: dehydratase ER: enoylreductase KR: ß-ketoacylreductase KS: ß-ketoacylsynthase MAT: malonyl/acetyltransferase TE: thioesterase

Figure 3.4

Table 3.1 Common naturally occurring fatty acids

Saturated

butyric

CH3(CH2)2CO2H

4:0

stearic

CH3 (CH2)16CO2H

18:0

caproic*

CH3(CH2)4CO2H

6:0

arachidic

CH3 (CH2)18CO2H

20:0

caprylic*

CH3(CH2)6CO2H

8:0

behenic

CH3 (CH2)20CO2H

22:0

capric*

CH3(CH2)8CO2H

10:0

lignoceric

CH3 (CH2) 22CO2H

24:0

lauric

CH3(CH2)10CO2H

12:0

cerotic

CH3 (CH2) 24CO2H

26:0

myristic

CH3(CH2)12CO2H

14:0

montanic

CH3 (CH2)26CO2H

28:0

palmitic

CH3(CH2)14CO2H

16:0

melissic

CH3 (CH2)28CO2H

*To avoid confusion, systematic nomenclature (hexanoic, octanoic, decanoic) is recommended Unsaturated palmitoleic CH3 (CH2)5CH=CH(CH2)7CO2H

oleic CH3(CH2)7CH=CH(CH2)7CO2H

cis-vaccenic CH3(CH2)5CH=CH(CH2)9CO2H

linoleic CH3 (CH2)4CH=CHCH2CH=CH(CH2)7CO2H

a-linolenic CH3CH2CH=CHCH2CH=CHCH2CH=CH(CH2)7CO2H

Y-linolenic CH3 (CH2)4CH=CHCH2CH=CHCH2CH=CH(CH2)4CO2H

gadoleic CH3(CH2)9CH=CH(CH2)7CO2H

arachidonic CH3(CH2)4CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)3CO2H

eicosapentaenoic CH3CH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)3CO2H (EPA) 20:5 (5c,8c,11c,14c,17c)

docosapentaenoic CH3CH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)5CO2H (DPA) 22:5 (7c,10c,13c,16c,19c)

docosahexaenoic CH3CH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)2CO2H (DHA) 22:6 (4c,7c,10c,13c,16c,19c)

nervonic CH3(CH2)7CH=CH(CH2)J3CO2H 24:1 (15c)

all double bonds are Z (cis)

Number of carbon atoms

Abbreviations:

Position of double bonds

Stereochemistry of double bonds (c = cis/Z; t = trans/E)

Number of double bonds is produced by carboxylation of acetate. This means that all carbons in the fatty acid originate from acetate, but malonate will only provide the C2 chain extension units and not the C2 starter group. The linear combination of acetate C2 units as in Figure 3.2 explains why the common fatty acids are straight chained and possess an even number of carbon atoms. Natural fatty acids may contain from four to 30, or even more, carbon atoms, the most abundant being those with 16 or 18 carbons. Some naturally occurring fatty acids are shown in Table 3.1. The rarer fatty acids containing an odd number of carbon atoms typically originate from incorporation of a different starter unit, e.g.

propionic acid, or can arise by loss of one carbon from an even-numbered acid.

Fatty acids are mainly found in ester combination with glycerol in the form of triglycerides (Figure 3.5). These materials are called fats or oils, depending on whether they are solid or liquid at room temperature. If all three esterifying acids are the same, the triglyceride is termed simple, whereas a mixed triglyceride is produced if two or more of the fatty acids are different. Most natural fats and oils are composed largely of mixed triglycerides. In this case, isomers can exist, including potential optical isomers, since if the primary alcohols are esterified with different fatty acids the central carbon of glycerol will become chiral. In practice, only one of each pair of enantiomers is formed in nature. Triglycerides are produced from glycerol 3-phosphate by esterification with fatty acyl-CoA residues, the phosphate being removed prior to the last esterification (Figure 3.5). The di-acyl ester of glycerol 3-phosphate is also known as a phosphatidic acid, and is the basis of phos-pholipid structures. In these structures, the phosphate is also esterified with an alcohol, which is usually choline, ethanolamine, serine, or myoinositol, e.g. phosphatidyl choline (Figure 3.6). Phospholipids are important structural components of cell membranes, and because of the polar and non-polar regions in their structure, they have detergent-like properties. They are also able to form liposomes, which have considerable potential as drug delivery systems. A particularly important natural phospholipid is platelet-activating factor (PAF) (Figure 3.6), which resembles a phos-phatidylcholine, though this compound possesses an ether linkage to a long chain fatty alcohol,

R^O-SCoA

OP esterification j—OCOR1 HO»/

R2C0-SCoA

glycerol 3-P with first fatty acyl-CoA

esterification 1-acylglycerol 3-P with second fatty acyl-CoA

OCOR

R2C00" x

1,2-diacylglycerol 3-P (phosphatidic acid)

r2coo x

X -OCOR

triacylglycerol (triglyceride)

R3C0-SCoA

esterification with third fatty acyl-CoA

H2O hydrolysis of phosphate

1,2-diacylglycerol

Figure 3.5

r2coo

O-P-OR3 OH

¡J-CH2CH2NH3

-0-P-0CH2CH2NMe3 OH

platelet-activating factor (PAF)

!>-ch2-chco2h NH2

phosphatidylcholine phosphatidylethanolamine phosphatidylserine phosphatidyl-myo-inositol usually hexadecanol, rather than an ester linkage. The central hydroxyl of glycerol is esterified, but to acetic acid rather than to a long chain fatty acid. PAF functions at nanomolar concentrations, activates blood platelets and contributes to diverse biological effects, including thrombosis, inflammatory reactions, allergies, and tissue rejection. Long chain alcohols are reduction products from fatty acids and also feature in natural waxes. These are complex mixtures of esters of long chain fatty acids, usually C20-C24, with long chain monohy-dric alcohols or sterols.

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Responses

  • ulrich eichelberger
    What bond acp and growing fatty chain?
    8 years ago

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