A Common Origin for Guanidinobutanoate Starter Units in Antifungal Natural Products

Abstract

Keeping it basic: Arginine provides the exotic 4-guanidinobutanoate starter unit for two different types of zwitterionic polyketide (an example for one type is shown in the picture) produced by the same Streptomyces bacterium. The three-step precursor pathway is initiated by a remarkable decarboxylating monooxygenase with high specificity for arginine.

Recent advances in the biosynthesis of unusual polyketide synthase substrates

“…However deleting both genes encoding the AHs resulted in the abolishment in production of 13 and the clethramycins. 21 This ability of the azalomycin and clethramycin pathways to complement each other extends to the AT domains responsible for the loading of 12 onto the ACPs within the loading module of the PKS. 21 …”

An Amidinohydrolase Provides the Missing Link in the Biosynthesis of Amino Marginolactone Antibiotics

“…[8] In contrast, 4-guanidylbutanoyl-CoA and 4-guanidinylbutanoyl-ACP are both stable in neutral aqueous buffers at room temperature. [6] It would appear that protective-group chemistry in biosynthetic pathways only evolves where it is most needed.…”

“…[6] Biosynthesis of the amino-containing marginolactones has been suggested to follow an analogous pathway from ornithine, [5,7] but we have previously proposed an alternative hypothesis,i nw hich amino marginolactones are derived from their guanidino-substituted counterparts in adeprotection [8,9] step catalyzed by an amidinohydrolase as al ate step in biosynthesis.T he biosynthetic gene cluster for the aminopolyene ECO-02301 has been reported to contain agene for apotential amidinohydrolase enzyme. [10] We report herein agenome-based approach to identifying and characterizing amidinohydrolases acting in marginolactone biosynthesis,a nd we show that the novel amidinohydrolase DstH is indeed necessary and sufficient for the deprotection of desertomycin B [11] to form desertomycin A.…”

“…[14] We also determined high-quality whole-genome sequences for Saccharomonospora azurea (syn. S. caesia), which produces the 36-membered arabinosyl marginolactone primycin (2,S cheme 1), [15] and for Streptomyces violaceusniger DSM4137 [16] which produces the guanidino marginolactone azalomycin F. [17] Using ap reviously characterized arginine oxidase gene [6] from the S. violaceusniger strain as ap robe,a ll six target gene clusters were located within their respective genome sequences.T he desertomycin gene cluster in S. olivaceus and the primycin gene cluster in S. azurea are arranged as shown in Scheme S1 in the Supporting Information. Detailed information about each gene is given in the Supporting Information (Tables S4-S9) for all clusters.T he arrangement of enzymatic domains within each modular PKS (Figures S1 and S2 in the Supporting Information), and the predicted configuration of the full-length polyketide chains ( Figure S3), were deduced by using previously validated sequence motifs in each type of domain:a cyltransferase (AT), [18] ketoreductase (KR), [19] dehydratase (DH), [20] and enoylreductase (ER) [21] domains.F or primycin and desertomycin, [22,23] there is (almost) exact correspondence between the enzyme arrangement in each extension module and the chemical structure of the polyketide product.…”

Evidence for an iterative module in chain elongation on the azalomycin polyketide synthase

“…Two of these are the near-identical PKSs (Figure S1, Supporting Information File 1) for the antifungal 36-membered marginolactones azalomycin 1a–c (from Streptomyces malaysiensis (formerly Streptomyces violaceusniger ) DSM4137) and kanchanamycin 1d [35–36] from Streptomyces olivaceus Tü4018; and the third is the PKS for the β-lactone ebelactone, a potent esterase inhibitor from Streptomyces aburaviensis 2a,b (Fig. 1) [30].…”