The structure and biosynthesis of heinamides A1–A3 and B1–B5, antifungal members of the laxaphycin lipopeptide family

Abstract

Laxaphycins are a family of cyclic lipopeptides with synergistic antifungal and antiproliferative activities.

Thirtieth Anniversary of the Discovery of Laxaphycins. Intriguing Peptides Keeping a Part of Their Mystery

“…Finally, a (2R,3R)-4-OH-Thr occupies position 8 as previously described in lobocyclamide B and C [30]. However, in view of the data obtained in the study of heinamide biosynthesis, it would seem that it is in fact a homoserine hydroxylated on carbon 3 rather than a threonine hydroxylated on carbon 4 [44]. Therefore, this amino acid will be named (2R,3R)-3-OH-Hse in the rest of this review, although this does not change the final structure.…”

“…Interestingly, type A laxaphycins potentiate the activity of type B laxaphycins when the two compounds are combined. This phenomenon was documented for almost all the cyanobacteria for which the two compound types were co-isolated albeit explanation about the mechanism of this synergism remains poorly understood [19,21,30,38,44]. The synergistic activity of laxaphycins and their derivatives would be linked to their shared biosynthesis mode.…”

“…Very recently, Sivonen's group identified eight new laxaphycins from Nostoc sp. UHCC 0702 (collected from lake Villähteen Kukkanen) and named heinamides, three of A-type and five of B-type laxaphycins [44]. By cultivating on 15 N-containing medium and comparing the masses of the labeled and unlabeled compounds, they showed that heinamides A1, A2, and A3 contain 11 nitrogen atoms, as do the A-type laxaphycins.…”

“…The origin of 4-hydroxyproline in scytoclamide A could not be determined since no enzyme allowing this type of reaction has been identified within the cluster of scytocylamide genes [38]. However, the study of heinamides biosynthesis showed that an enzyme in the gene cluster (LxaN) may be responsible for the hydroxylation of proline at position 4 [44].…”

“…In 2021, Heinilä et al reported the biosynthetic gene cluster involved in the biosynthesis of heinamides [44]. The 93-kb complete gene cluster is composed of 13 open reading frames (ORFs) named ORF 1 , ORF 2 , lxaI 1 -K 1 , lxaA2, ORF 3 , lxaB, lxaC1, lxaE-G, and lxaM (Figure 33).…”