Hybrid PKS-NRPS synthetase; part of the gene cluster that mediates the biosynthesis of burnettramic acids, an unusual class of bolaamphiphilic pyrrolizidinediones that display potent antibacterial, antifungal, and cytotoxic activities (PubMed:30735051). The first step of the biosynthesis of burnettramic acids is the hydroxylation of proline by the proline hydroxylase buaE to generate 4-hydroxyproline (PubMed:30735051). The PKS-NRPS buaA and trans-enoyl reductase buaC construct the highly reduced polyketide chain, and the condensation (C) domain of buaA then catalyzes the amide bond formation with the activated 4-hydroxyproline (PubMed:30735051). This is followed by the R domain releasing the nascent polyketide-peptide directly via a Dieckmann condensation to afford a tetramic acid fused to the hydroxyproline, generating the bicyclic pyrrolidinedione moiety (PubMed:30735051). The cytochrome P450 monooxygenases buaD and buaG are likely responsible for the multiple hydroxylations on the polyketide chain and its terminus, although in a heterologous context, buaD does not appear to be required. Therefore, while buaG may be a multifunctional cytochrome P450 monooxygenase, it cannot be ruled out that the two secondary alcohols on the polyketide chain could have an acetate origin (PubMed:30735051). Finally, the glycosyltransferase buaB transfers beta-D-mannose to the aglycone burnettramic acid A to form burnettramic acid A (PubMed:30735051). Burnettramic acid B is a minor cis-pyrrolizidine epimer of burnettramic acid A and it is likely that small amounts of it form naturally in acidic environments (PubMed:30735051). Mycotoxin biosynthesis. NRP synthetases are composed of discrete domains (adenylation (A), thiolation (T) or peptidyl carrier protein (PCP) and condensation (C) domains) which when grouped together are referred to as a single module. Each module is responsible for the recognition (via the A domain) and incorporation of a single amino acid into the growing peptide product. Thus, an NRP synthetase is generally composed of one or more modules and can terminate in a thioesterase domain (TE) that releases the newly synthesized peptide from the enzyme. Occasionally, epimerase (E) domains (responsible for L- to D-amino acid conversion) are present within the NRP synthetase (By similarity). BuaA contains also a polyketide synthase module (PKS) consisting of several catalytic domains including a ketoacyl synthase domain (KS), an acyl transferase domain (AT), a dehydratase domain (DH), a methyltransferase domain (MT), and a ketoreductase domain (KR) (Probable). Instead of a thioesterase domain (TE), buaA finishes with a reductase-like domain (R) for peptide release. BuaA has the following architecture: KS-AT-DH-KR-PCP-C-A-T-R (Probable). In the C-terminal section; belongs to the NRP synthetase family.