A sea of biosynthesis: marine natural products meet the molecular age

Abstract

The years 2000 through mid-2010 marked a transformational period in understanding of the biosynthesis of marine natural products. During this decade the field emerged from one largely dominated by chemical approaches to understanding biosynthetic pathways to one incorporating the full force of modern molecular biology and bioinformatics. Fusion of chemical and biological approaches yielded great advances in understanding the genetic and enzymatic basis for marine natural product biosynthesis. Progress was particularly pronounced for marine microbes, especially actinomycetes and cyanobacteria. During this single decade, both the first complete marine microbial natural product biosynthetic gene cluster sequence was released as well as the first entire genome sequence for a secondary metabolite-rich marine microbe. The decade also saw tremendous progress in recognizing the key role of marine microbial symbionts of invertebrates in natural product biosynthesis. Application of genetic and enzymatic knowledge led to genetic engineering of novel “unnatural” natural products during this time, as well as opportunities for discovery of novel natural products through genome mining. The current review highlights selected seminal studies from 2000 through to June 2010 that illustrate breakthroughs in understanding of marine natural product biosynthesis at the genetic, enzymatic, and small-molecule natural product levels. A total of 154 references are cited.

Fig. 1

Enterocin and wailupemycin biosynthesis. (A) Organization of the enterocin and wailupemycin gene cluster, the first completed marine natural product biosynthetic gene cluster. (B) Elucidation of this gene cluster allowed in vitro and in vivo studies of the function of cluster genes and the encoded enzymes, supporting the current pathway for enterocin and wailupemycin biosynthesis.^,,-

Fig. 2

Barbamide biosynthesis. (A) Organization of the L. majuscula barbamide gene cluster, the first completed natural product biosynthetic gene cluster from a marine cyanobacterium. (B) Proposed scheme for biosynthesis of barbamide, including domain organization of PKS/NRPS enzymes encoded by genes from (A).^,, A, adenylation domain; ACP, acyl carrier protein; AT, acyltransferase domain; C, condensation domain; Cy, condensation/cyclization domain; KS, ketosynthase domain; MT, methyltransferase domain; PCP, peptidyl carrier protein; TE, thioesterase domain.

Fig. 3

Onnamide and theopederin gene cluster, revealed through metagenomic analysis of the sponge T. swinhoei. This gene cluster exhibits significant homology to the pederin and psymberin gene clusters, also identified through metagenomic approaches.^,

Fig. 4

The patellamide gene cluster from P. didemni. The substantial structural diversity observed in the patellamide family of natural products originates primarily from mutation within the patE gene.

Fig. 5

Proposed V-dependent haloperoxidase-mediated biosynthesis of the brominated α-snyderol (23) and the chlorinated A80915C (24).

Fig. 6

Biosynthesis of the chlorinated proteasome inhibitor salinosporamide A (12) involves the SAM-dependent chlorinase SalL.

Fig. 7

Proposed biosynthesis of the L. majuscula metabolites curacin A (25) and jamaicamide (26) proceeds via a parallel β-branch pathway that deviates with the decarboxylase ECH₂.

Fig. 8

Proposed chain initiation of curacin A (25) PKS catalyzed by the AD-GNAT-ACP tridomain.