Biosynthesis of tetrahymanol by Tetrahymena pyriformis: mechanistic and evolutionary implications

Abstract

Polyprenoids constitute a diverse, widely distributed group of natural products derived biologically from (3fi)-mevalonic acid1,2 (1). Based on geochemical3 and other studies,4 it was inferred that the biosynthetic processes of polyprenoids evolved in the very early stages of evolutionary development.5,6 Although polyprenoids play a vital role in numerous life processes, e.g., as sex or corticosteroidal hormones, as bile acids, in vision, in defense mechanisms, etc., it appears that their primary biological function is to provide a structural component(s) of cell membranes.6Many eucaryotes, and particularly higher species, produce a variety of 3-oxygenated triterpenes and sterols.1,2 The 3-oxygenated triterpenes are derived from squalene1,2 (2) which is converted to 2,3(5)-oxidosqualene7 (3). The enzymatic cationic cleavage of the oxygen-C-2 bond of 3 generates an electron deficiency at C-2 and precipitates the cyclization process. Depending on the characteristics of the enzyme system of the particular species, different products may be formed.1,2,8,9 In Fusidium coccineum, cyclization10 of 3 is presumed to result in the cation8 4a or its transiently stabilized equivalent9,11 4b, which loses the C-17 proton12 to yield the parent protosterol13 (5). The protosterol13 ( 5) is then further metabolized to fusidic acid (6). This hypothesis is supported by the results of studies on the mode of incorporation of C-2,12,14 C-4,11 and C-515 hydrogen atoms of MVA into 6 and by the

Thraustochytrids and Ciliates

“…The study of the biosynthesis of this pentacyclic triterpene showed that it was formed from mevalonic acid , and thus from squalene, but without the intermediate epoxysqualene Caspi, 1980). The cyclization of squalene is not oxidative and the oxygen atom comes from water, not from the atmosphereresearch having shown that the biosynthesis of tetrahymanol takes place in either aerobic or anaerobic conditions Zander and Caspi, 1969;Zander, Greig, and Caspi, 1970).…”

Revisited After 50 Years: The “Stereochemical Interpretation of the Biogenetic Isoprene Rule for the Triterpenes”

“…In an early investigation on the biosynthesis of tetrahymanol (14), in the protozoan T. pyriformis, the Caspi group demonstrated that during the cyclization process of the squalene precursor in D 2 O label from the solvent is incorporated exclusively in the 3bposition of the product, and that the OH group in the other terminal ring of 14 is derived from a H 2 O molecule (rather than from dioxygen) and thus represent the outcome of an (anti-Markovnikov) addition to the last double bond of the cyclizing chain [104]. The beautiful simplicity of this case, with its evident requirement for an all-chair folding of the aliphatic substrate, is a good testimonial for the general validity of the major postulates of the 1955 proposal.…”

Bacterial Squalene Cyclase

“…Squalene:hopene cyclase (SHC) from the thermoacidophilic bacterium Alicyclobacillus acidocaldarius has been well studied, and it was established that the enzyme binds squalene (1) in all-chair conformation, initiating the sequential carbon-carbon bonds forming reaction by an acid-catalyzed protonation of a terminal double bond. 9 No methyl or hydride migration takes place during the sequential ring-forming reactions. [4][5][6][7][8] On the other hand, the formation of tetrahymanol (6) by squalene:tetrahymanol cyclase (STC) from the protozoan Tetrahymena pyriformis is initiated by a proton attack on a terminal double bond of squalene, folded in all-chair conformation, but followed by addition of H 2 O to the resulting gammaceranyl C-21 cation (5) (Scheme 1(b)).…”

“…The polycyclization first produces the hopanyl C-22 carbocation (2) with a five-membered E-ring, which is followed by either regiospecific proton elimination from the terminal Z-methyl (Me-30) group or addition of H 2 O at the cationic center yielding hop-22(29)-ene (3) (80%) or hopan-22-ol (4) (20%) (Scheme 1(a)). 4,6,7,[10][11][12][13] Thus, the formation of lanosterol (9), which is the biosynthetic precursor of cholesterol, is initiated by an oxirane ring opening of (3S)-2,3-oxidosqualene (7) folded in chair-boat-chair conformation. 9 No methyl or hydride migration takes place during the sequential ring-forming reactions.…”