If I told you that a lack of lipids were responsible for causing ageing in yeast but too many is associated with insulin resistance in humans, and that although lipids dominate the membrane of the cell envelope in E. coli, they may not be essential, and if I added that lipids could be used to make fluorescent molecules that could be used to probe cellular systems, can be a raw material for making secondary messengers and also be a sort of chemical exchanger to repair other molecules, what would you say?

You might tell me, gently, that you have read The Lipid Chronicles before and so of course I am going to tell you that lipids are the renaissance–how on Earth would anyone be able to write 50 blog posts about a subject that did not have a bit of sparkle?

And you would be right, but perhaps in a crook. All of these things are not the responsibility of lipids, they are the responsibility of one lipid. Phosphatidylethanolamine, PE (structure shown in the figure).


Figure. The structure of phosphatidyl ethanolamine (PE). The head group and glyceryl moiety are shown in red and the lipophilic part is shown in blue. The NH3+ is the primary amine group, that exists in this protonated form at physiological pH.

No one would have expected PE to be a renaissance man. It is rather ordinary in many ways, old and a bulk lipid to boot. It makes up >70% of the phospholipid fraction of E. coli and does not really form membranes in its pure form. But in my opinion, therein lies much of the scope for the variety: what we see is that small changes can shift the behaviour of this lipid over the line in one direction or another, showing lots of different guises. This multi-guise idea is strengthened by another contributor, the nucleophilic primary amine group –NH2, that is at the top of the head group. This functionality is the principle difference between PE and phosphatidylcholine (PC) in practice, as well as being a precursor for it. This gives PE a distinct ‘feel’ with respect to other lipids, especially other bulk lipids with a similar structure. This uniqueness gives rise to the ready identification of PE as responsible for its actions.

There is evidence that a lack of PE appears to be responsible for premature ageing in yeast [1]. This comes from a study by Rockenfeller et al. in which the production of PE was stopped at a genetic level*. This switching off of PE production accelerated the production of molecular species that cause age-related damage to cells, and thus eventually cell death. When the PE production machinery has not been switched off, cells can recognise when this damage is happening and engage in a process called autophagy, that removes damaged components and replaces them.

This is rather a contrast to what appears to happen in humans, in a condition where there is too much PE. Obesity-induced insulin resistance, the principle form of type II diabetes, correlates with a shift in the lipid profile in erythrocytes [2], including an increase in PE. The amount of PE is reduced upon exercise-induced weight loss. It is not clear from the study whether underweight mammals have too little PE, but there is evidence that autophagy is stronger when PE is higher in mammalian cells [1]. There is clearly a balance to be struck between too much and too little PE.

This balance may not exist for all species, however. PE typically makes up >70% of the phospholipid fraction of the cell envelope of E. coli cells, and so one might think that it is really rather important. However, there is evidence that although growth is not as strong as in normal E. coli, it is possible for cultures to grow with membranes consisting of only the other lipids that would usually be there, phosphatidyl glycerol (PG) and cardiolipin (CL)[3, 4]. The only absolute requirement in this situation is for the presence of divalent cations (doubly-positively-charged ions) such as calcium and magnesium (Ca++ and Mg++) in the growth medium [3]. This is because in the presence of the cations, the CL causes the membrane to curve in the same way the PE would make it do. Thus, the job of the PE as a lipid that elicits membrane curvature, is replaced. However, I think that the fact that the cells grow poorly despite this suggests that this lipid has other functions in E. coli than merely a bulk lipid.

This is certainly the case in mammalian retina cells. The primary amine group in PE is used in the management of de-oxidation of 11-cis-retinal [5]. PE forms an imine with the aldehyde group, that anchors the retinal to the membrane. Various drugs have been tested that mimic this activity, providing some hope for patients with blinding illnesses [6] (and also features in an earlier post).

Aside from this more chemical use of PE, it can also be used as a raw material for a biological action. It can be used as a carrier of ethanolamine, for producing a signalling molecule, N-acyl ethanolamine. The steps in this process are (i) PE is acylated with a fatty acid, (ii) the phosphate di-ester to is hydrolysed to give phosphatidic acid (PA) and the signal, the acylated ethanolamine. When the fatty acid is arachidonic acid, the final signal is called anandamide. The second step is carried out by a phospholipase D (PLD) enzyme [7].

This rather bewildering set of studies invites a number of general conclusions. PE can be, and is, used for some quite different functions, that controlling it is important, and that it has distinct chemical, biological and physical roles. The remaining question is whether this is the end for research into this lipid, or the beginning. Have we found out all there is to find out, of shock value at least, or are there other secrets—is this the tip of the iceberg?

It certainly seems that iceberg lettuce is no way to improve your PE levels, at least for snails. At least two species of snail show that those fed hen’s eggs have higher PE levels by about 40% than those fed only lettuce [8, 9]. Let us hope that the pace of finding out more about this exciting lipid proceeds faster than the average snail.


* The gene that codes for the enzyme that produces PE from its precursor, phosphatidylserine, was removed from the organism

[1] P. Rockenfeller, M. Koska, F. Pietrocola, N. Minois, O. Knittelfelder, V. Sica, J. Franz, D. Carmona-Gutierrez, G. Kroemer and F. Madeo, Cell Death Differ, 2015, 22, 499-508. 10.1038/cdd.2014.219.

[2] M. Younsi, D. Quilliot, N. Al-Makdissy, I. Delbachian, P. Drouin, M. Donner and O. Ziegler, Metabolism, 2002, 51, 1261-1268. 10.1053/meta.2002.35184.

[3] J. A. Killian, M. C. Koorengevel, J. A. Bouwstra, G. Gooris, W. Dowhan and B. de Kruijff, Biochimica et Biophysica Acta , 1994, 1189, 225-232. http://dx.doi.org/10.1016/0005-2736(94)90069-8.

[4] A. DeChavigny, P. N. Heacock and W. Dowhan, Journal of Biological Chemistry, 1991, 266, 5323-5332.

[5] M. Zhong, L. L. Molday and R. S. Molday, Journal of Biological Chemistry, 2009, 284, 3640-3649. 10.1074/jbc.M806580200.

[6] A. Maeda, M. Golczak, Y. Chen, K. Okano, H. Kohno, S. Shiose, K. Ishikawa, W. Harte, G. Palczewska, T. Maeda and K. Palczewski, Nat Chem Biol, 2012, 8, 170-178. 10.1038/nchembio.759.

[7] Y. Okamoto, J. Morishita, K. Tsuboi, T. Tonai and N. Ueda, Journal of Biological Chemistry, 2004, 279, 5298-5305. 10.1074/jbc.M306642200.

[8] J. L. Schneck, B. Fried and J. Sherma, Veliger, 2003, 46, 325-328.

[9] K. R. Sousa, B. Fried and J. Sherma, Journal of Liquid Chromatography, 1990, 13, 3963-3972. 10.1080/01483919008049582.