OLSG:  Lipd Structure





Fatty acid structure and conformations

Fatty acids can be named in many ways. 

You should know the common name, systematic name, and symbolic representations for these saturated fatty:

  Learn the following unsaturated fatty acids - 

There is an alternative to the symbolic representation of fatty acids, in which the C's are numbered from the distal end (the n or ω end) of the acyl chain (the other end from the carboxyl group).  Hence 18:3 Δ 9,12,15 could be written as 18:3 (ω-3) or 18:3 (n-3) where the terminal C is numbered one and the first double bond starts at C3.  Arachidonic acid is an (ω-6) fatty acid while docosahexaenoic acid is an (ω-3) fatty acid.

Note that all naturally occurring double bonds are cis, with a methylene spacer between double bonds - i.e. the double bonds are not conjugated. For saturated fatty acids, melting point increases with C chain length, owing to increased likelihood of van der Waals (London or induced dipole) interactions between the overlapping and packed chains. Within chains of the same number of C’s, melting point decreases with increasing number of double bonds, owing to the kinking of the acyl chains, followed by decreased packing and reduced intermolecular forces (IMFs).  Fatty acid composition differs in different organisms:

Recent work has suggested that contrary to images of early hominids as hunters and scavengers of meat, human brain development might have required the consumption of fish which is highly enriched in arachidonic and docosahexaenoic acids.  ^0% of the brain consists of lipids, most which consists of these two fatty acids.  These acids are necessary for the proper development of the human brain and in adults, deficiencies in these might contribute to cognitive disorders like ADHD, dementia, and dyslexia. These fatty acids are essential in the diet, and probably could not have been derived in high enough amounts from the eating of brains of other animals.  

Saturated fatty acids chains can exist in many conformations resulting from free rotation around the C-C bonds of the acyl chains. A quick review of the conformations of n-butane shows that the energetically most favorable conformation is one in which the two CH3 groups attached to the 2 methylene C’s (C2 and C3) are trans to each other, which results in decreased steric strain. Looking at a Neuman projection of n-butane shows the dihedral or torsional angle to be 180 degrees. When the dihedral angle is 0 degrees, the two terminal CH3 groups are syn to each other, which is the conformation of highest energy. When the angle is 60 (gauche+) or 300 (gauche-) degrees, a higher, local minimum is observed in the energy profile. At a given temperature and  moment, a population of molecules of butane would consist of some in the g+ and g- state, with most in the t state. The same applies to fatty acids. To increase the number of chains with g+tg- conformations, for example, the temperature of the system can be increased.

Triacylglyeride/Glycerophospholipid Structure

A cartoon digram showing the generic structures of triacylglyerides, glycerophospholipid and spingolipids is show below. In addition, the most common glycerophospholipids are shown. Learn phosphatic acid (PI), phosphatidyethanolamine (PE),   phosphatidylcholine (PC) which is often called lechithin, and phosphatidylserine (PS) which is often called cephalin. 

Jmol di-18:0 PC Triacylglyceride   

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Triacylglyceride/Phospholipid Stereochemistry

Glycerol is an achiral molecule, since C2 has two identical substituents, CH2OH. Glycerol in the body can be chemically converted to triacylglycerides and phospholipids (PL) which are chiral, and which exist in one enantiomeric form. How can this be possible if the two CH2OH groups on glycerol are identical? It turns out that even though these groups are stereochemically equivalent, we can differentiate them as follows. Orient glycerol with the OH on C2 pointing to the left. Then replace the OH of C1 with OD, where D is deuterium. Now the two alcohol substituents are not identical and the resulting molecule is chiral. By rotating the molecule such that the H on C2 points to the back, and assigning priorities to the other substituents on C2 as follows: OH =1, DOCH2 =2, and CH2OH = 3, it can be see that the resulting molecule is in the S configuration. Hence we say that C1 is the proS carbon. Likewise, if we replaced the OH on C3 with OD, we will form the R enantiomer. Hence C3 is the proR carbon. This shows that in reality we can differentiate between the two identical CH2OH substituents. We say that glycerol is not chiral, but prochiral. (Think of this as glycerol has the potential to become chiral by modifying one of two identical substituents.)

Figure: Glycerol - A prochiral molecule

We can relate the configuation of glycerol above, (when the C2 OH is pointing to the left) to the absolute configuration of L-glyceraldehyde, a simple sugar (a polyhydroxyaldehyde or ketone), another 3C glycerol derivative. This molecule is chiral with the OH on C2 (the only chiral carbon) pointing to the left. It is easy to remember that any L sugar has the OH on the last chiral carbon pointing to the left. The enantiomer (mirror image isomer) of L-glyceraldehyde is D-glyeraldehyde, in which the OH on C2 points to the right. Biochemists use L and D for lipid, sugar, and amino acid stereochemistry, instead of the R,S nomenclature you used in organic chemistry. The stereochemical designation of all the sugars, amino acids, and glycerolipids can be determined from the absolute configuration of L- and D-glyceraldehyde.

The first step in the in vivo (in the body) synthesis of chiral derivatives from the achiral glycerol involves the phosphorylation of the OH on C3 by ATP, to produce the chiral molecule glycerol phosphate. Based on the absolute configuration of L-glyceraldehyde, and using this to draw glycerol (with the OH on C2 pointing to the left), we can see that the phosphorylated molecule can be named L-glycerol-3-phosphate. However, by rotating this molecule 180 degrees, without changing the stereochemistry of the molecule, we don't change the molecule at all, but using the D/L nomenclature above, we would name the rotated molecule as D-glycerol-1-phosphate. We can’t give the same molecule two different names. Hence biochemists have developed the stereospecific numbering system (sn), which assigns the 1-position of a prochiral molecule to the group occupying the proS position. Using this nomenclature, we can see that the chiral molecule described above, glycerol-phosphate, can be unambiguously named as sn-glycerol-3-phosphate.  The hydroxyl substituent on the proR carbon was phosphorylated.

Figure: The biological synthesis of triacylglycerides and phosphatidic acid from prochiral glycerol.

The enzymatic phosphorylation of prochiral glycerol on the proR carbon OH to form sn-glycerol-3-phosphate is illustrated in the link below. As we were able to differentiate the 2 identical CH2OH substitutents as containing either the proS or proR carbons, so can the enzyme. The enzyme can differentiate identical substituents on a prochiral molecule if the prochiral molecule interacts with the enzyme at 3 points. Another example of a prochiral reactants/enzyme system involves the oxidation of the prochiral molecule ethanol by the enzyme alcohol dehydrogenase, in which only the proR H of the 2 H’s on C2 is removed. (We will discuss this later.)

Figure: How an enzyme (glycerol kinase) transfers a PO4 from ATP to only the proR CH2OH of glycerol in formation of chiral triacylglycerols and phosphatidic acid.

Recent References

  1. Mescar and Koshland. A new model for protein stereospecificity (other than 3 point binding).  Nature. 403, pg 614 (2000)