Song: Oxidosqualene (OS) cyclase—Lanosterol synthase (to the tune of “Oh Christmas Tree”)

Abstract

This song deals with oxidosqualene cyclases, a class of enzymes that catalyze among the most fascinating and complex monoenzymatic reactions. While in photosynthetic eukaryotes there are dozens of different oxidosqualene cyclases that form a plethora of different cyclization products, in non-photosynthetic organisms, fungi and animals (vertebrates), the only product of cyclization is lanosterol, precursor of ergosterol and cholesterol, respectively. Therefore, in these organisms, the only oxidosqualene cyclase present is lanosterol synthase. Since all the steroid compounds occurring in vertebrates (bile salts, steroid hormones, neuroactive steroids, etc.) derive from cholesterol, they all owe their tetracyclic structure to the action of this enzyme. In the cyclization process of lanosterol synthase, what happens between the initial protonation and the final deprotonation is truly amazing: four rings are formed, several chiral centres are created, a positive charge travels through the triterpene skeleton of the substrate back and forth, and methyls and hydrides literally dance from one position to another. The structural comparison between the starting substrate and the final product is absolutely outstanding. It is, therefore, not surprising that such a fascinating enzyme was called The Lord of the Rings . To this Lord, the present poem is dedicated, composed of seven stanzas, which can be sung on a well-known Christmas melody. To grasp well the different steps of the catalytic process described by the stanzas, one can resort to the numerous images available on the web. 1. OS-Cyclase, OS-Cyclase, a great enzyme are you OS-Cyclase, OS-Cyclase, the sterol pathway needs you You take open squalene oxide, And quickly form four rings from it OS-Cyclase, OS-Cyclase, you shape the steroid backbone. 2. OS-Cyclase, OS-Cyclase, in eukaryotes you spread out OS-Cyclase, OS-Cyclase, bacteria cells do not lodge you In fungi and animals you form Just triterpene lanosterol, In plants your creativity bursts into plenty of compounds. 3. Lord of the Rings, Lord of the Rings, your mechanism is magic Your action starts from (an) aspartate, that protonates the substrate The target is its epoxide, Which opens forming alcohol group, From then no one, from then no one, can stop cyclizing process. 4. Electron cloud of double bond starts soon to be excited And as a hungry dog to a bone it throws itself on C-2 Forming the first of the four rings, Leaving a new plus charge behind, A thrill knocks on the door of all the other double bond clouds. Received: 15 September 2020 Revised: 4 January 2021 Accepted: 21 January 2021 DOI: 10.1002/bmb.21490 Biochem Mol Biol Educ. 2021;49:301–302. wileyonlinelibrary.com/journal/bmb © 2021 International Union of Biochemistry and Molecular Biology 301 5. The positive charge moves through the squalene carbon backbone Creating a new ring each time, thus hardening the structure Till (a) tetracylic nucleus Is properly assembled, But now you know you are half-way through the entire process. 6. The four-ring intermediate now is forcibly rearranged Some hydrides and some methyl groups move to the adjacent places Leading the complex mechanism Close to the final event A proton will be soon pulled out, and double bond is formed. 7. Lord of the Rings, Lord of the Rings, what you have made is outstanding A great smile appears now on your satisfied face New born cyclized lanosterol Is free to leave your active site Lord of the Rings you are ready for a new cyclizing process. ORCID Gianni Balliano https://orcid.org/0000-0002-0879-4533