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Arachidonic acid: a very important fatty acid

Arachidonic acid is a fatty acid (a carboxylic acid with a long carbon tail) with 20 carbons and 4 double bonds. Counting from the end without the carboxylic acid group, the first double bond appears at the 6th position from the end, making this an omega-6 fatty acid.

Chemical structure of arachidonic acid. Credits: Wikimedia (Public domain) https://commons.wikimedia.org/wiki/File:AAnumbering.png

Arachidonic acid is incorporated into phospholipids in cell membranes. In the process of some cell signalling events such as the inflammatory cascade, it is cleaved from phospholipids by phospholipase A2 (PLA2), after which it can be modified into many signalling molecules including the prostaglandins (PGs), thromboxanes (TXs), and leukotrienes (LTs). These are the most well-known and well-studied of the metabolites derived from arachidonic acid; however, there are also many other compounds including the endocannabinoids (ECs), and several less understood groups such as the eoxins (EXs)lipoxins (LXs), epoxyeicosatrienoic acids (EETs), hepoxilins (HXs), isoprostanes (IsoPs), and isofurans (IsoFs). Some of these compounds are quite recent discoveries and thus have little information available about them. Nevertheless, many of these compounds have biological activity associated with the inflammatory response, either with anti-inflammatory or pro-inflammatory effects. The latter molecules are still under active investigation in order to better understand the way they mediate actions in the body. [1]

The actions of all these molecules are too numerous to explain here. Some of the most well-known actions are those of the prostaglandins. If you have ever taken NSAIDs such as ibuprofen or naproxen, you will have affected this system. These drugs inhibit the cyclooxygenase enzyme, a critical enzyme in prostaglandin synthesis. Prostaglandins have diverse effects such as acting as pro-inflammatory mediators and regulating smooth muscle contraction and relaxation (such as PGE2), or causing vasodilation and preventing platelet aggregation (such as PGI2, also known as prostacyclin). Other molecules in the cyclooxygenase pathway, such as thromboxane, promote clotting and causing blood vessels to contract (such as TXA2). [2] The leukotrienes, synthesized from the lipooxygenase pathway, are inflammatory mediators. Some asthma medications, such as montelukast and zafirlukast, block the actions of the leukotriene LTD4 which can help with the bronchospasms in asthma. [3]

The endocannabinoid system is also a growing area of interest. The compound N-arachidonoylethanolamine, also known as anandamide, is probably the most well-known compound. The effects of this compound include pain sensation modulation, reward processes in the brain, and immune system modulation. [4]

This is only a small peek at the world of arachidonic acid metabolites: there remains much to be explained outside of this blog post, and much to be discovered!

Sources:

[1] Wang, B., Wu, L., Chen, J., Dong, L., Chen, C., Wen, Z., Hu, J., Fleming, I., & Wang, D. W. (2021). Metabolism pathways of arachidonic acids: Mechanisms and potential therapeutic targets. Signal Transduction and Targeted Therapy, 6(1), 1–30. https://doi.org/10.1038/s41392-020-00443-w
[2] Ricciotti, E., & FitzGerald, G. A. (2011). Prostaglandins and inflammation. Arteriosclerosis, Thrombosis, and Vascular Biology, 31(5), 986–1000. https://doi.org/10.1161/ATVBAHA.110.207449
[3] Dempsey, O. J. (2000). Leukotriene receptor antagonist therapy. Postgraduate Medical Journal, 76(902), 767–773. https://doi.org/10.1136/pmj.76.902.767
[4] Lu, H.-C., & Mackie, K. (2016). An Introduction to the Endogenous Cannabinoid System. Biological Psychiatry, 79(7), 516–525. https://doi.org/10.1016/j.biopsych.2015.07.028

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– The Undergraduate Scientist Team

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Hello everyone! We’re looking for UBC Science students to join our blogging team. Our blog is designed to highlight the interesting life of an undergraduate science student! There’s content from student interviews to course reviews, as well as tips and tricks to university life. We occasionally feature fascinating research as well. If you’re interested in being involved in some recreational blog writing then these positions are for you.

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Gold: Precious in a Different Way

Let’s face it, to most people gold is just an over-glorified rock with no real value; however, that’s not the case at all! Just this month, researchers from University College London have created a novel light-activated coating that kills infectious bacteria. The key ingredient? Gold.

upgrading with gold…

The invention of a bacteria-killing coating sounds ingenious; however, Hwang’s team was actually not the first to come up with this idea. Previous studies have already shown that coatings incorporating the chemical crystal violet can adequately kill bacteria. The problem was that the coating had to be light-activated by UV rays, which harm the skin by promoting skin cancer.

This was exactly the problem Hwang’s team looked to solve; to make a coating that did not require harmful wavelengths of light. They overcame this challenge by incorporating small clusters of gold into a polymer containing crystal violet. The result? Now this new coating could effectively eliminate bacteria upon activation with low intensity white light – the level of light found in offices.

Concentration of bacteria (CFU/mL) across three conditions after 6 hours exposure to low-intensity white light. Star indicates bacterial concentration is undetected. Sample size = 6 per treatment, error bars are standard deviation. Adapted from Hwang et al.’s data

The figure above perfectly illustrates their result. Statistical analyses show that bacterial concentration does not significantly differ between the violet crystal and control (no coating) condition. This indicates that low-intensity white light cannot activate the bacterial-killing function in the violet crystal coating. What’s interesting is that addition of gold with the violet crystal, reduces the bacterial concentration significantly to near zero values, indicating successful activation.

More than a novelty…

The results of Hwang’s study are truly impactful. It is well known that hospitals are a hotbed for infectious bacteria. In fact, 27% of surfaces in hospital rooms are contaminated with bacteria even after regular and thorough cleaning. As such, applying the coating on these surfaces will definitely reduce the chances of contracting a hospital-related disease. Who would have thought? Not only is gold more than just a hunk of rock, it can also save lives.

More steroids, plants, fungi

Steroids are not only relegated to the animal world; fungi and plants synthesize many steroids as well. One particular example of clinical relevance is ergosterol, found in the cell membranes of fungi where it serves a similar role to cholesterol in animal cell membranes. This can be exploited by antifungal medications: azole drugs such as clotrimazole and miconazole function by inhibiting ergosterol synthesis. Specifically, they inhibit the 14α-demethylase enzyme that converts lanosterol to ergosterol (note the similarities to the cholesterol pathway discussed in this previous post). [1]

Ergosterol can also be converted to ergocalciferol in a UV-light dependent reaction, similarly to the synthesis of Vitamin D3 in animals. In fact, ergocalciferol is also known as Vitamin D2, and like cholecalciferol, ergocalciferol can be hydroxylated twice to 1,25-dihydroxyergocalciferol or ercalcitriol, which binds to the Vitamin D receptor and causes its effects, although the binding of Vitamin D2 may not be as strong. [2]

There are diverse steroids made by plants, some of which have toxic effects. Of note are digoxin and digitoxin produced by the foxglove plant. These two chemicals consisted of a carbohydrate chain attached to a modified steroid, and they can be fatal if ingested. They inhibit the Na+/K+ ATPase responsible for establishing the electrochemical gradient within the cell, which is exploited for the use of digoxin as a drug for arrhythmias and heart failure due to the ability of the medication to increase the contractility of the heart when given at low doses. [3]

These are only some of the steroids occurring in plants and fungi. In the future, maybe more will be discovered with important biological activities!

Sources:
[1] Herrick, E. J., & Hashmi, M. F. (2021). Antifungal Ergosterol Synthesis Inhibitors. In StatPearls. StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK551581/
[2] Houghton, L. A., & Vieth, R. (2006). The case against ergocalciferol (vitamin D2) as a vitamin supplement. The American Journal of Clinical Nutrition, 84(4), 694–697. https://doi.org/10.1093/ajcn/84.4.694
[3] Hauptman, P. J., & Kelly, R. A. (1999). Digitalis. Circulation, 99(9), 1265–1270. https://doi.org/10.1161/01.cir.99.9.1265

Steroids, salt, sugar, sex

Steroids are biologically active compounds composed of four fused rings. Although the word “steroid” is commonly associated with anabolic steroids and muscle growth, steroids are in fact a diverse group of compounds with varying effects on the human body.

The steroid cholesterol can be either synthesized via the mevalonate pathway or are obtained from the diet. The mevalonate pathway starts with acetyl-CoA, which is converted in a series of steps to isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are the building blocks of isoprenoids, a diverse group of compounds that include steroids. The enzyme HMG-CoA reductase, which catalyzes the step converting HMG-CoA to mevalonate, is blocked by statins which are used for the treatment of high cholesterol levels. The IPP units are combined to form farnesyl pyrophosphate, which are then used to form squalene. From there, the squalene is cyclized to form lanosterol, which is then converted to cholesterol. Cholesterol is important for moderating cell membrane fluidity, and also participates in the formation of lipid rafts which are theorized to be involved in cell signalling. [1]

Cholesterol can then be converted into a variety of signalling molecules such as neurosteroids, vitamin D, glucocorticoids, mineralocorticoids, and sex steroids. Neurosteroids modulate complex activities in the brain, such as neural plasticity. They can act in an excitatory manner (such as dehydroepiandrosterone (DHEA), which modulates NMDA receptor activity) or inhibitory manner (such as pregnanolone, which modulates GABA A receptor activity). [2]

Vitamin D is involved in calcium homeostasis, increasing calcium absorption in the intestines and modulating bone remodulating. It is synthesized from cholesterol, including a step that involves UV radiation. It is then hydroxylated twice in order to be in the active form, 1,25-dihydroxycholecalciferol, also known as calcitriol, which binds to the vitamin D receptor to produce its effects. [3]

Glucocorticoids such as cortisol modulate metabolism and immune function. Cortisol promotes gluconeogenesis, which produces glucose, as well as promoting the breakdown of lipids and proteins. It also diminishes immune function by inhibiting the effects of various cytokines that promote inflammation and immune responses. [4]

Mineralocorticoids such as aldosterone helps to maintain blood pressure and electrolyte balance. Aldosterone acts in the kidneys to increase sodium reabsorption and potassium excretion, thus increasing sodium levels and decreasing potassium levels in the blood. Because of the sodium reabsorption, water is then retained, increasing blood volume and thus increasing blood pressure. Glucocorticoids and mineralocorticoids are both synthesized from cholesterol via progestogens in the adrenal cortex by 21-hydroxylase and 11β-hydroxylase. [5]

Sex steroids are classified as progestogens (such as progesterone), androgens (such as testosterone), or estrogens (such as estradiol). Estrogens are synthesized from androgens by the enzyme aromatase, while androgens are synthesized from progestogens by 17α-hydroxylase. Progestogens are synthesized by the conversion of cholesterol by cholesterol side-chain cleavage enzyme. Sex steroids regulate a variety of activities. Progesterone is important in the secretory phase of the uterus during the menstrual cycle, where it is produced by the corpus luteum to maintain the endometrial lining for implantation. Testosterone is important for sperm development, as well as increasing muscle growth and contributing to male secondary sex characteristics. Estradiol is responsible for inducing ovulation, bone maintenance, and female secondary sex characteristics. However, all sex steroids have diverse roles in people of all genders that are not described here. [6][7][8]

Steroids are a diverse group of compounds, and this is only the beginning. You can read about more steroids here!

Sources:
[1] Russell, D. W. (1992). Cholesterol biosynthesis and metabolism. Cardiovascular Drugs and Therapy, 6(2), 103–110. https://doi.org/10.1007/BF00054556
[2] Robel, P., & Baulieu, E. E. (1995). Neurosteroids: Biosynthesis and function. Critical Reviews in Neurobiology, 9(4), 383–394.
[3] Bikle, D. (2000). Vitamin D: Production, Metabolism, and Mechanisms of Action. In K. R. Feingold, B. Anawalt, A. Boyce, G. Chrousos, W. W. de Herder, K. Dhatariya, K. Dungan, A. Grossman, J. M. Hershman, J. Hofland, S. Kalra, G. Kaltsas, C. Koch, P. Kopp, M. Korbonits, C. S. Kovacs, W. Kuohung, B. Laferrère, E. A. McGee, … D. P. Wilson (Eds.), Endotext. MDText.com, Inc. http://www.ncbi.nlm.nih.gov/books/NBK278935/
[3] Arlt, W., & Stewart, P. M. (2005). Adrenal corticosteroid biosynthesis, metabolism, and action. Endocrinology and Metabolism Clinics of North America, 34(2), 293–313, viii. https://doi.org/10.1016/j.ecl.2005.01.002
[5] Connell, J. M., Fraser, R., & Davies, E. (2001). Disorders of mineralocorticoid synthesis. Best Practice & Research. Clinical Endocrinology & Metabolism, 15(1), 43–60. https://doi.org/10.1053/beem.2000.0118
[6] Aizawa, K., Iemitsu, M., Maeda, S., Jesmin, S., Otsuki, T., Mowa, C. N., Miyauchi, T., & Mesaki, N. (2007). Expression of steroidogenic enzymes and synthesis of sex steroid hormones from DHEA in skeletal muscle of rats. American Journal of Physiology. Endocrinology and Metabolism, 292(2), E577-584. https://doi.org/10.1152/ajpendo.00367.2006
[7] Penning, T. M. (2010). New Frontiers in Androgen Biosynthesis and Metabolism. Current Opinion in Endocrinology, Diabetes, and Obesity, 17(3), 233–239. https://doi.org/10.1097/MED.0b013e3283381a31
[8] Cui, J., Shen, Y., & Li, R. (2013). Estrogen synthesis and signaling pathways during ageing: From periphery to brain. Trends in Molecular Medicine, 19(3), 197–209. https://doi.org/10.1016/j.molmed.2012.12.007