The approach of determining the lipid composition of living systems, called lipidomics [1], has demonstrated that a huge number of lipids are present in living systems.  Recent publications showing this in sharp focus include reports of the complete lipidome of part of the murine (mouse) immune system [2] and human plasma [3].  What this work shows, is that there are over 500 distinct molecular species distributed amongst the established lipid categories.  Reasoning would suggest that this is a large number of lipid types for the physical job of producing a cellular membrane (despite the need for several types of lipid in order produce a cellular membrane).

This begs the question: what are the remaining lipids for?  It is tempting to believe they have no function, however evolution suggests that this possibility is unlikely in nature, i.e., what evolutionary advantage would there be to produce lipids that are of no use?  What is far more likely is that there is a function.  And indeed this turns out to be the case.

Several of the minor lipid components of these systems are known to be biological signals.  Inositides are the dominant example of this.  One member of this group, called PIP3, forms part of the system that manages the release of insulin from the β-cells of the islets of Langerhans [4].  However, there is also much evidence [5] that PIP3 is also involved in the activation of a protein called PKB.  This protein is an enzyme that phosphorylates other proteins, activating them.  Enzymes that phosphorylate are called kinases, hence PKB: Protein Kinase B.  This enzyme, or more specifically, the phosphorylation it performs, is at the heart of the body’s control of growth.  It is therefore similar to the sort of signalling systems that go wrong in diseases such as cancer.

The research into PIP3 has been seen as important, and the development of an understanding arising from them, significant. This lipid has even been prepared using synthetic organic chemistry [6], such that sufficient stock of this lipid is available for further research. However, the fact that this lipid has proved to be so important in biological systems has made the other seven inositides rather more attractive than they once were. Thus, attention is now turning towards them. Phosphatidylinositol itself is the precursor to all other inositides. Kinase activity similar to that elicited by PKB turns phosphatidylinositol into inositides such as the phosphatidylinositol phosphates. There are three types of phosphatidylinositoldiphosphate head group, but only one phosphatidylinositoltriphosphate. Although no signalling role has been discovered for phosphatidylinositol, what has been discovered is that it can have a pronounced effect on the curvature of the lipid system of which it is part [7].

The demonstration of a pronounced effect on membrane curvature and an important biological signalling role for lipids that are closely related chemically is a bewildering thought. Are inositides an unappreciated force in vivo?


[1] E. A. Dennis, Proceedings of the National Academy of Sciences, 2009, 106, 2089–2090.

[2] E. A. Dennis, R. A. Deems, R. Harkewicz, O. Quehenberger, H. A. Brown, S. B. Milne, D. S. Myers, C. K. Glass, G. Hardiman, D. Reichart, A. H. Merrill, M. C. Sullards, E. Wang, R. C. Murphy, C. R. H. Raetz, T. A. Garrett, Z. Guan, A. C. Ryan, D. W. Russell, J. G. McDonald, B. M. Thompson, W. A. Shaw, M. Sud, Y. Zhao, S. Gupta, M. R. Maurya, E. Fahy, and S. Subramaniam, Journal of Biological Chemistry, 2010, 285, 39976-39985.

[3] O. Quehenberger, A. M. Armando, A. H. Brown, S. B. Milne, D. S. Myers, A. H. Merrill, S. Bandyopadhyay, K. N. Jones, S. Kelly, R. L. Shaner, C. M. Sullards, E. Wang, R. C. Murphy, R. M. Barkley, T. J. Leiker, C. R. H. Raetz, Z. Guan, G. M. Laird, D. A. Six, D. W. Russell, J. G. McDonald, S. Subramaniam, E. Fahy, and E. A. Dennis, Journal of Lipid Research, 2010, 51, 3299-3305.

[4] O. I. Hagren and A. Tengholm, Journal of Biological Chemistry, 2006, 281, 39121-39127.

[5] B. A. Hemmings, Science, 1997, 277, 534.

[6] P. R. J. Gaffney and C. B. Reece, Journal of the Chemical Society, Perkin Transactions 1, 2001, 192-205.

[7] X. Mulet, R. H. Templer, R. Woscholski and O. Ces, Langmuir, 2008, 24, 8443–8447.