Saturday, 29 November 2014

Prostaglandins: Molecule(s) of the month for December

I was driving to Liverpool a few days ago listening to the first part of the annual BBC Radio, Reith Lectures. In fact I was probably at the same point on Edge Lane, when I was struck by Grayson Perry's disruptive, irreverent and insightful take on the art world last year. This year, Dr. Atul Gawande is tackling the topic of contemporary medicine and in his first lecture, he posed the question: Why do doctors fail? In his moving description of his son's encounter with the medical profession, he mentioned the use of a class of drugs based on the prostaglandins. In the case of his son, Walker; an early tragedy was averted by the doctor's administration of Prostaglandin E1. This prevented closure of the patent ductus arteriosus in the newly born, Walker, had symptoms of a cyanotic (Gk dark blue colour) heart defect (the skin has a blue/purple colouration, owing to a deficiency in the supply of oxygenated blood, for which there are a number of causes). It made me think that prostaglandins (PGs) are often overlooked in mainstream Biochemistry courses, and yet they are a potent class of molecules. This is an attempt to whet your appetite for the prostaglandins!

Prostaglandins are derived enzymatically from essential fatty acids: they are 20 carbon molecules with a 5-membered ring, as shown on the RHS for Prostaglandin E1 (or Alprostadil). The enzyme Phospholipase A2, converts diacylglycerol to arachidonic acid, which in turn is converted to the prostaglandins by the enzyme called cyclooxygenase (or COX, for short). The main function of COX is to catalyse the formation of the "signature" ring, found in all prostaglandins, through ring closure and the addition of oxygen. You may have come across these enzymes, since they are the targets of one of the most
commonly taken drugs, aspirin. The mechanism of action of aspirin, lies in its irreversible acetylation of a key Serine side chain in the COX enzyme. Other pain killers/anti inflammatories, such as ibuprofen act on the same target, but are reversible (ie non-covalent) inhibitors. This work was recognised by the award of a Nobel Prize in 1982 to (Sir) John Vane, along with two others. The structure of aspirin (purple) is shown in the active site of a COX enzyme on the LHS. The Serine at position is acetylated as the aspirin molecule is hydrolysed in the active site. As a result, arachidonic acid is now prevented from entering the active site of the enzyme and consequently no PGs can be synthesised. 

There are around 10 receptors that specifically recognise and mediate the potent effects of PGs. These interactions are in turn "transduced" by G-protein coupled receptors (GPCRs, shown on the RHS) leading to reprogramming of normal hormonal responses, contraction and dilation of smooth muscle cells and a wide range of other physiological effects. We do not yet have a high resolution structure of the PG receptors, but I am sure it wont be long. The interest from my perspective, is in a compound class that is so potent. It reminds me of the story surrounding thalidomide, which you can read in an earlier Blog. The combination of the hydrophobicity, the structurally constraining ring and the oxygen atoms, give PGs their potency, when coupled to the GPCR pathways. But, as a simple biochemist, the challenges brought by working in the lab with such insoluble molecules, make me think I took the easy route early in my career by choosing amino acid dehydrogenases and DNA modifying enzymes, where everything can be carried out in the aqueous phase. Now, every time you take an aspirin, think of the molecular pharmacological events that you have triggered!

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