Pivalic acid acts as a starter unit in a fatty acid and antibiotic biosynthetic pathway in Alicyclobacillus, Rhodococcus and Streptomyces

Abstract

A biosynthetic pathway using pivalic acid as a starter unit was found in three bacterial species, Alicyclobacillus acidoterrestris, Rhodococcus erythropolis and Streptomyces avermitilis. When deuterium-labelled pivalic acid was added to A. acidoterrestris and R. erythropolis nutrient media it was incorporated into fatty acids to give rise to tert-butyl fatty acids (t-FAs). In addition, in R. erythropolis, pivalic acid was transformed into two starter units, i.e. isobutyric and 2-methylbutyric acid, which served as precursors of corresponding iso-even FAs and anteiso-FAs. In S. avermitilis the biosynthesis also yielded all three branched FAs; apart from this pathway, both pivalic and 2-methylbutyric acids were incorporated into the antibiotic avermectin.

Novel Coenzyme B12-dependent Interconversion of Isovaleryl-CoA and Pivalyl-CoA

“…Depending on the organism, the isovaleryl-CoA/pivalyl-CoA mutase activity of IcmF was ϳ150 -2,200-fold lower than the conversion of n-butyryl-CoA to isobutyryl-CoA (Table 1). Recently, it was shown that pivalic acid can be incorporated as a starter unit in fatty acids in several bacteria (32). Thus, the production of pivalyl-CoA catalyzed by IcmF might be important in bacteria that use this starter unit for the biosynthesis of branched fatty acids containing a quaternary carbon.…”

Precursor-Directed Biosynthesis and Biological Testing of omega-Alicyclic- and neo-Branched Tunicamycin N-Acyl Variants

“…This mutant was also complemented when supplied with 2-methylvalerate, 2-ethylbutyrate, or trimethyl acetate (pivalate) in the growth medium and consequently produced cellular FAs that included these primers at the omega -terminus. Pivalic acid also acts as a primer unit for fatty acid and antibiotic biosynthetic pathways in Alicyclobacillus , Rhodococcus , and Streptomyces . We have shown previously that exogenous pivalate is incorporated by TUN-producing Streptomyces into both the cellular membrane lipids, as neo -FAs, and the N -acyl groups of the neo -TUN (Figure S4).…”

“…Pivalic acid also acts as a primer unit for fatty acid and antibiotic biosynthetic pathways in Alicyclobacillus, Rhodococcus, and Streptomyces. 33 We have shown previously that exogenous pivalate is incorporated by TUN-producing Streptomyces into both the cellular membrane lipids, as neo-FAs, and the N-acyl groups of the neo-TUN 21 (Figure S4). Pivalate incorporation was observed with four different TUN-producing actinomycetes strains but not with wild-type B. subtilis, confirming the earlier report by Willecke and Pardee.…”

“…In S. avermitilis, pivalate incorporates into three neo -branched FAs, and both pivalic and 2-methylbutyric acids are utilized for biosynthetic incorporation into avermectin. , A coenzyme B 12 -dependent mutase (IcmF) has been identified that interconverts pivalyl-CoA and isovaleryl-CoA, , and a similar mutase family member designated MeaA has been found in Streptomyces cinnamonensis to redirect methylmalonyl-CoA biosynthesis for monensin production . Several other bacteria are able to convert valine-CoA into pivalate-CoA via C β -methylation, which is subsequently used for natural product biosynthesis. , However, our experiments with d -labeled valine showed that this was not the case for neo -TUN.…”

Engineered and Native Coenzyme B12-dependent Isovaleryl-CoA/Pivalyl-CoA Mutase

“…starter unit and incorporate it into tertiary-butyl fatty acids, iso-even or anteiso-fatty acids and in Streptomyces avermitilis, into the antibiotic avermectin (27). In addition, pivalic acid (or pivalyl-CoA) might be formed during catabolism of marine sponge-derived polytheonamides in which the tert-butyl modification of threonine is introduced post-translationally (28).…”