Structure and nomenclature

DICARBOXYLIC ACIDS




Dicarboxylic acids derive classically from medium and long-chain monocarboxylic fatty acids by an oxidation mechanism named w-oxidation which is followed in the cell by a b-oxidation. This w-oxidation is of minor significance in the normal cell physiology but the production of dicarboxylic acids may be increased by other mechanisms in particular situations of reaction-induced lipid peroxidation. It was shown that dicarboxylic acids may be the end products of oxidative attack on both free and esterified unsaturated fatty acids. The species formed are thus a distinctive feature of the positions of the double bonds in the intact fatty acid molecule. A novel cytotoxic phospholipid, 2-azelaoyl phospholipid, was thus described when phosphatidylcholines are peroxidized in vitro (Itabe H et al., Biochim Biophys Acta 1988, 962, 8).

The exact mechanism of dicarboxylic acid acid formation is not completely known but several experiments suggest that a single unsaturated fatty acid gives two types of dicarboxylic acids: a primary one related to the double bond nearest to the acid function and a secondary two carbon atoms lower homologue.

To illustrate the mechanism, the next figures represent the main steps of the   oxidative attack of oleic acid (18:1 n-9) which will form azelaidic and pimelic acids.

First, oleic acid generates a peroxy radical at the carbon 9 and then may undergo a direct degradation to azelaic acid via the successive formation of peroxy, hydroperoxy and alkoxy radicals also at C9. The scission  of the carbon chain at C9 will give an aldehyde-acid (azelaic hemialdehyde) and then a diacid (azelaidic acid).

 

wpe8.jpg (15142 octets)

The second possibility is the formation of a peroxy radical at C9 followed by an intramolecular hydrogen transfer resulting in the formation of a radical at C7. A new sequence of reactions forms pimelic hemialdehyde and then the diacid, pimelic acid.

 

wpe9.jpg (18612 octets)

It was demonstrated that all free or esterified unsaturated fatty acids (mono- or polyunsaturated) under chemical, physical or biological oxidation generate dicarboxylic acids, their chain length depending on the position of the first double bond (Passi S et al., Biochim Biophys Acta 1993, 1168, 190).

Thus, linoleic acid (18:2n-6) may generate C9 and C7 diacids
a-linolenic acid (18:3n-3) may generate the same diacids
g-linolenic acid (18:3n-6) may generate C6 and C4 diacids
arachidonic acid (20:4n-6) may generate C5 diacid (C3 was not detected)
EPA (20:5n-3) may generate the same diacid
DHA (22:6n-3) may generate C4 diacid.

It was shown that dicarboxylic acids may be use as markers of fatty acid peroxidation. Thus, in diabetes, where an imbalance between the generation of free radicals and antioxidant defense systems increases  oxidative stress, the dicarboxylic acid excretion is increased in urine. It was shown that the urinary excretion increased by 5.5 and 7.5 times for adipic acid (C6) and suberic acid (C8), respectively (Inouye et al., Atherosclerosis 2000, 148, 197).

 

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