A tree bark suspension and a Nobel Prize later…. We wonder less about the structural basis of the action of aspirin

Today we be under the necessity another guest post from Lawrence Norris of @BlackPhysicists.  A super appear in ~ing that charts how the every sunshine drug aspirin went from being old medicine to how modern crystallography could reduce to law how it works.  Enjoy!

Today’s disgrace spans the bridge between ancient pharmacognosy and present biophysics. The history of aspirin and its curative use can be traced back to the back millennium BC.  Medicines from osier and other salicylate-rich plants crop out in the Egyptian pharmacology papyri.  Hippocrates, the maker or modern medicine, administered willow tree bark to women to help relieve affliction associated with childbirth.  Later the tree bark was used to alleviate general distress and fevers.

In 1763 Oxford University chemist, Edward Stone, detached the active compound from Hippocrates case, which turned out to be salicylic sour.  In 1853 French chemist Charles Frédéric Gerhardt synthesized acetylsalicylic tart, albeit in an unstable and immodest form.  In 1897 German chemist Felix Hoffman, in operation for Bayer, first synthesize pure acetyl salicylic stinging, which later became known as aspirin.  Bayer took aspirin to mart almost immediately, and established a thorough market association of Bayer AG through the drug.  “Bayer Aspirin” had been without interrupti~ the market for nearly 50 years which time Wheatly determined the crystal structure of aspirin in 1964 [1].  There bring forth been several reports of an evasive. second crystal polymorphs of aspirin. (See 7 Feb 2014 set on this blog.)

Aspirin-3D-balls“. Licensed subordinate to Public domain via Wikimedia Commons.

Aspirin took put ~ the moniker of “wonder drug” in the same manner with it worked wonders against the miseries of aches, toilsome effort, fever and inflammation, and scientists wondered wherefore.   Here is where the story of aspirin merges with the Nobel Prize pleasing work of Bergstrom, Samuelsson and Vane [2] .   This trio and their co-workers elucidated the construction [3] and function of prostaglandins, what one. are paracrine hormones that mediate ~ persons physiological functions having to do with platelet aggregation and smooth muscle state of mind.   They identified prostaglandin H synthase (PGHS),  viewed like being the key control point enzyme in the “prostaglandin cascade”.   Vane in minute showed that it was possible to fill up the synthesis and thus the performing of prostaglandins with aspirin [4].

Still it was not known exactly in what manner aspirin works.  Enter the moil of Picot, Loll and Garavito who solved the crystal erection of PGHS (aka COX)  in 1994 [5].  It bears mentioning hither that the crystallization of PGHS, being a membrane protein,  was a trip de force in protein crystallography.  When its configuration was published in 1994, there were not so much than a dozen other membrane proteins in the PDB database.

COX-2 inhibited by Aspirin.png
“COX-2 inhibited ~ the agency of Aspirin” by Jeff Dahl – self-made, relinquish to public domain. Licensed under Public region via Wikimedia Commons.

Following their commencing work, Loll, et. al., were able to disentangle the structure of the enzyme through aspirin bound [6], and also through other drugs that compete with aspirin in the marketplace, e.g., ibuprofen [7].   Others showed by what means Naproxen (Alleve) binds to the enzyme [8].   Aspirin, it turns wanting, is an irreversible inhibitor of PGHS.  It acetylates a elucidation serine residue in the enzyme’s unremitting site, and that prevents the in the course of nature substrate from situating itself for producing enzyme activity.

Alas though, this is not the gross story of how this wonder put ~s into works physiologically.  Recent results signify that aspirin is an antiporter participant to protons in mitochondria.  Also aspirin manifestly induces formation of inflammation-reducing NO radicals, and signaling from one side NF-κB.

[1]  Wheatley, P. J. “The crystal and molecular structure of aspirin.” J. Chem. Soc., 1163 (1964), 6036-6048, 10.1039/JR9640006036

[2] “The Nobel Prize in Physiology or Medicine 1982″. Nobelprize.org. Nobel Media AB 2014. Web. 25 Nov 2014. <http://www.nobelprize.org/nobel_prizes/physic/laureates/1982/>

[3]   Abrahamsson, S. “A address determination of the molecular structure of prostaglandin F2-1.” Acta Crystallographica 16.5 (1963), 409-418, 10.1107/S0365110X63001079

[4]  Vane, J. R. “Inhibition of prostaglandin composition as a mechanism of action since aspirin-like drugs.” Nature 231.25 (1971): 232-235, 10.1038/newbio231232a0

[5]  Picot, D, P. J. Loll, and R. M. Garavito. “The X-sight crystal structure of the membrane protein prostaglandin H2 synthase-1.” Nature 367.6460 (1994), 243-249, 10.1038/367243a0

[6]  Loll, P. J., D. Picot, and R. M. Garavito. “The structural ground of aspirin activity inferred from the crystal manner of making of inactivated prostaglandin H2 synthase.” Nature Structural & Molecular Biology 2.8 (1995), 637-643, 10.1038/nsb0895-637

[7]  Selinsky, Barry S., et al. “Structural dissection of NSAID binding by prostaglandin H2 synthase: time-unable to exist without and time-independent inhibitors elicit same enzyme conformations.” Biochemistry 40.17,  5172-5180, (2001), 10.1021/bi010045s

[8]  Duggan, Kelsey C., et al. “Molecular ground for cyclooxygenase inhibition by the non-steroidal anti-inflammatory drug naproxen.”  Journal of Biological Chemistry 285.45 (2010), 34950-34959, 10.1074/jbc.M110.162982

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