Lipid metabolites are often seen as key elements in cellular signaling. Is this unique? Please provide several examples of the function of lipids as key elements in signal arrays and list the biologic functions these signals affect?
Biological signaling that involves the use of a lipid messenger to bind a protein target in order to certain cellular responses is termed as cellular signaling by lipid metabolites or lipid signaling. Yes, lipid signaling is unique when compared to other signaling metabolites because lipids diffuse freely through membranes. As a result, lipid metabolites are not stored in the vesicles and are rather synthesized when needed on the required site. Also, lipid signaling metabolites are not found circulating freely in solutions but exist in bound state with career proteins (Lipid signaling, 2012).
Some examples of lipid functions in signal array are:
1. Lipid metabolites are present as sphingolipids [some are but by no means are all. Sphingolipids are among the types of lipids that do serve as signals but it is only one set of such hydrophobic molecular entities that serve such roles. Can you think of others?]to function as second messengers for a number of cellular processes. Ceramide being the central for sphingolipids formation is itself produced by sphingomyelinases by breaking down sphingomyelin. Ceramide can also be generated by Ceramide synthase and serine palmitoyl transferase. Ceramide aids in the formation of other sphingolipids by various modifications mainly at its C1 hydroxyl site. Containing two hydrophobic chains, Ceramide has limited water solubility making it restricted to the site of formation. However, this property of Ceramide allows easy flip flopping across the membranes which in turn produces effects on Ceramide signaling functions. Ceramide as a second messenger mediates cell-stress responses that include apoptosis and senescence. Accumulation of Ceramide is known to activate PP2A resulting in dephosphorylation and subsequent AKT inactivation. This forms an important mediator of insulin signaling and resulting metabolic control. This may even result in reduction of insulin responsive ability and death of islets of Langerhans (Lipid signaling, 2012).
2. Sphingosine synthesized from Ceramide by ceramidase in the lysosomes being a single chain lipid is water soluble and thus, has the potential to move out to the endoplasmic reticulum without requiring intermittent transporters (Lipid signaling, 2012).
3. Glucosylceramide formed from Ceramide after its glycosylation is known to be a precursor of glycosphingolipids that forms the building blocks of bio membranes. These lipids are also involved in formation, growth and differentiation of tumor cells (Lipid signaling, 2012).
4. Phosphatidylinositol second messenger system works in four steps starting from the activation of membrane bound receptors followed by G-protein activation to produce effectors (phosphoinositide 3-kinase and phospholipase). This in turn results in stimulation of second messenger (such as Diacylglycerol [this is definitely lipophylic, however, does inositol triphosphate belong in this cat3egory?]and inositol triphosphate) synthesis which signals cellular processes. Inositol triphosphate being soluble freely diffuses into the cytoplasm to be recognized by inositol triphosphate receptor which is a calcium ion channel of endoplasmic reticulum. The binding of the molecule with its receptor releases calcium ions triggering calcium ion signaling (Lipid signaling, 2012).
5. G-protein coupled receptors activators such as sphingosine-1-phosphate, platelet activating factors, prostaglandins and retinol derivates are also lipid metabolites that induce cellular signaling.[Quite true and a significant set of lipophylic signaling entities. Do you know how and where these lipid signals occur?]For example. Platelet activating factor essential for signaling the activation of platelet aggregation and inflammation (Lipid signaling, 2012).
6. Nuclear receptors activators are also lipid signaling metabolites such as steroid hormones, retinoic acid and prostaglandins (Lipid signaling, 2012).
Please describe how one might search for chemical structure, biologic function relationships, involving small molecular weight lipophylic compounds. Provide one example.
X-ray crystallography or X-ray diffraction analysis can be used to determine the chemical structure, composition, and molecular weight and formula along with determination of stereo configuration of small molecular weight lipophylic steroids. [check on your use of X-
Ray crystallography here. When is this technique employed and for what kinds of molecules? Chemical degradation analysis can also be used structural determination. Apart from that various estimates such as cLogP and structure activity relationships can be used to determine the amount of lipophilicity, and biological function relationships of these compounds. The class of steroids is one example of small molecular weight lipophylic compounds. These steroids are derived from parent compound cholesterol which contains three hexagonal carbon rings, one pentagonal carbon ring and a side chain that attaches two methyl groups. Usually, the different positions of these methyl groups determine the structure of different classes of steroids. However, presence of other functional groups such as hydroxyl or aldehyde groups can also be the structural determining factor (Stauffer & Meyer, 1997).[What ar the structural differences between the steroid hormones in humans that are associated with reprpductive function?]
In the earlier periods, microwave radiations were used to determine steroid structures. Later, degradation reactions were used to breakdown steroids into smaller molecules of known structures.[not likely for small molecular weight substances such as these. NMR, IR, UV, Mass Spec, are the primary sources of data on the molecular make up of these entities. Why not crystallography, thought it is, occasionally a possibility?] With the advent of concepts of infrared absorption, nuclear magnetic resonance and X-ray crystallography, determination of chemical structure of steroids was made easy. In humans, steroids are secreted by endocrine glands like gonads and are necessary to regulate the biological reproduction functions of various reproductive glands. Target tissue metabolism is a determining factor for governing the biological activity of steroids. Even small changes in steroid structure can alter the biological activities of steroids because of the alteration in target tissue metabolism (Stauffer & Meyer, 1997).
Lipid rafts provide another example of the complexity of cell surfaces in both their structural character and biologic functionality. Please explain the nature of these structures and their functionality.
Cellular plasma membranes are formed by combination of various protein receptors and glycosphingolipids[Whata are the primary lipid componetsw from which plasma membranes are formed? Glycosphingolipids are componets, but are these the primary lipid components from which the PM is constituted?] that are organized as glycolipoprotein microdomains which are known as lipid rafts. It is estimated that lipid patches aggregate with proteins to form islands called lipid rafts of size 10-200 nm with higher cholesterol concentrations. Lipid rafts are found to vary in structures with their outer leaflets containing glycerophospholipids, cholesterol and sphingolipids coupled with different type of proteins such as acylated proteins. Planar and glycolipid forms of lipid rafts have been found. While planar types lie in the plane of plasma membranes, glycolipids rafts can be seen as flask shaped folding that lie inward to the plasma membrane (Structural biochemistry/Lipid/Lipid Rafts, 2012).
Lipids rafts are known to collect proteins for signal transduction. These rafts with the protein signaling property and by recruiting molecules in their microdomains might play a role in signaling neurotransmitters. The lipid rafts favor signal transduction interactions kinetically and are associated with certain diseases such as AIDS. Lipid rafts being difficult to visualize under light microscope owing to their small size has led to a controversy in their mere existence.[What measurable property cvan one use to "see" ;ipids rafts, where this does prove possible?] Apart from this, it is believed that lipid rafts are transitory[assemblages of] molecules that remain intact for a short time period and therefore are irrelevant[Is this truly what is claimed? How would it orove possible for these rafts to have short life times, yet remain critical and causative factors in cellular signal responses? Especially at the PM receptor, lipid interface??] for biological processes. This again has increased the controversy on the existence of lipid rafts (Structural biochemistry/Lipid/Lipid Rafts, 2012).