My laboratory's research on lipids has focused on phospholipases and lipidomics and in many ways has evolved in parallel to the evolution of the lipid field over the past half century. I have reviewed our research elsewhere. Herein, I describe the "side stories" or "outtakes" that parallel the main story that focuses on our laboratory's research. I will emphasize the importance of community activities and describe how I came to initiate and lead the international effort on the Lipid Metabolites and Pathways Strategy (LIPID MAPS). Several of these side activities had a significant effect on discoveries in my laboratory research and its evolution as well as contributing significantly to the development of the LIPID MAPS initiative. These included experience and influences from serving as Editor-in-Chief of the Journal of Lipid Research and Chair and President of the Keystone Symposia on Cell and Molecular Biology as well as other experiences in organizing lipid conferences, teaching on lipid structure and mechanism, and earlier formative administrative and leadership experiences. The relevant influences are summarized herein.

In 1970, it was well accepted that the central role of lipids was in energy storage and metabolism, and it was assumed that amphipathic lipids simply served a passive structural role as the backbone of biological membranes. As a result, the scientific community was focused on nucleic acids, proteins, and carbohydrates as information-containing molecules. It took considerable effort until scientists accepted that lipids also "encode" specific and unique biological information and play a central role in cell signaling. Along with this realization came the recognition that the enzymes that act on lipid substrates residing in or on membranes and micelles must also have important signaling roles, spurring curiosity into their potentially unique modes of action differing from those acting on water-soluble substrates. This led to the creation of the concept of "surface dilution kinetics" for describing the mechanism of enzymes acting on lipid substrates, as well as the demonstration that lipid enzymes such as phospholipase A₂ (PLA₂) contain allosteric activator sites for specific phospholipids as well as for membranes. As our understanding of phospholipases advanced, so did the understanding that many of the lipids released by these enzymes are chiral information-containing signaling molecules; for example, PLA₂ regulates the generation of precursors for the biosynthesis of eicosanoids and other bioactive lipid mediators of inflammation and resolution underlying disease progression. The creation of the LIPID MAPS initiative in 2003 and the ensuing development of the lipidomics field have revealed that lipid metabolites are central to human metabolism. Today lipids are recognized as key mediators of health and disease as we enter a new era of biomarkers and personalized medicine. This article is my personal "reflection" on these scientific advances.

Lipids play critical roles in several major chronic diseases of our times, including those that involve inflammatory sequelae such as metabolic syndrome including obesity, insulin sensitivity, and cardiovascular diseases. However, defining the substrate specificity of enzymes of lipid metabolism is a challenging task. For example, phospholipase A₂ (PLA₂) enzymes constitute a superfamily of degradative, biosynthetic, and signaling enzymes that all act stereospecifically to hydrolyze and release the fatty acids of membrane phospholipids. This review focuses on how membranes interact allosterically with enzymes to regulate cell signaling and metabolic pathways leading to inflammation and other diseases. Our group has developed "substrate lipidomics" to quantify the substrate phospholipid specificity of each PLA₂ and coupled this with molecular dynamics simulations to reveal that enzyme specificity is linked to specific hydrophobic binding subsites for membrane phospholipid substrates. We have also defined unexpected headgroup and acyl chain specificity for each of the major human PLA₂ enzymes, which explains the observed specificity at a structural level. Finally, we discovered that a unique hydrophobic binding site-and not each enzyme's catalytic residues or polar headgroup binding site-predominantly determines enzyme specificity. We also discuss how PLA₂s release specific fatty acids after allosteric enzyme association with membranes and extraction of the phospholipid substrate, which can be blocked by stereospecific inhibitors. After decades of work, we can now correlate PLA₂ specificity and inhibition potency with molecular structure and physiological function.

The Journal of Lipid Research was founded in October, 1959 and has had a long and distinguished history. It evolved from an initial concept of a loose-leaf methodology handbook to a major journal for the lipid field. Its growth has in many ways paralleled the growth and expansion of lipid research. Today, it is operated as a journal of the American Society for Biochemistry and Molecular Biology at the forefront of biomedical research on lipids.