Plant Copper Metalloenzymes As Prospects for New Metabolism Involving Aromatic Compounds

Abstract

Copper is an important transition metal cofactor in plant metabolism, which enables diverse biocatalysis in aerobic environments. Multiple classes of plant metalloenzymes evolved and underwent genetic expansions during the evolution of terrestrial plants and, to date, several representatives of these copper enzyme classes have characterized mechanisms. In this review, we give an updated overview of chemistry, structure, mechanism, function and phylogenetic distribution of plant copper metalloenzymes with an emphasis on biosynthesis of aromatic compounds such as phenylpropanoids (lignin, lignan, flavonoids) and cyclic peptides with macrocyclizations via aromatic amino acids. We also review a recent addition to plant copper enzymology in a copper-dependent peptide cyclase called the BURP domain. Given growing plant genetic resources, a large pool of copper biocatalysts remains to be characterized from plants as plant genomes contain on average more than 70 copper enzyme genes. A major challenge in characterization of copper biocatalysts from plant genomes is the identification of endogenous substrates and catalyzed reactions. We highlight some recent and future trends in filling these knowledge gaps in plant metabolism and the potential for genomic discovery of copper-based enzymology from plants.

The Biosynthetic Landscape of Triceptides Reveals Radical SAM Enzymes That Catalyze Cyclophane Formation on Tyr- and His-Containing Motifs

“…Paliurine F and selanine A are two plant natural products from this subfamily (Figure A). Recently, Cu-dependent BURP domain proteins have been identified as the general macrocyclases for the plant cyclopeptide alkaloids. , The third source are from bacteria that use enzymes of the radical S -adenosylmethionine (rSAM) superfamily. − All rSAM enzymes harbor a radical SAM binding domain (typically CX 3 CX 2 C) that catalyzes the homolytic cleavage of S -adenosyl- l -methionine to generate a highly reactive 5′-deoxyadenosyl radical . Two examples of such rSAM enzymes are RrrB and DarE in the formation of ryptides and darobactin, respectively.…”

“…PhomYb and AprY are suspected to be involved in the cyclization of phomopsin A and asperipin-2a, respectively. Plant cyclopeptide alkaloids are represented by paliurine F and selanine A and are biosynthesized by Cu-dependent BURP domain proteins. , Ryptides and darobactin originating from bacteria are created by the rSAM enzymes RrrB and DarE, respectively. (B) Examples of products formed by three-residue cyclophane forming enzymes (3-CyFEs) in the biosynthesis of triceptides.…”

Gene-Guided Discovery and Ribosomal Biosynthesis of Moroidin Peptides

“…Moroidins are defined by a new posttranslational modification, in which a stephanotic acid-type cross-link between Leu-2 and Trp-5 forms the first ring and a tryptophan-histidine-bond yields the second ring. Compared to all known classes of BURP-domain-derived RiPPs, moroidin core peptides do not have a tyrosine or tryptophan as a C-terminal residue , but a histidine. The imidazole-indole connection in moroidins extends BURP-domain RiPP biosynthesis to cross-coupling of two aromatic side chains compared to known BURP-domain-derived RiPPs such as stephanotic acid, which are defined by cross-links of an aromatic side chain to an unactivated carbon in another amino acid side chain .…”

“…Compared to all known classes of BURP-domain-derived RiPPs, moroidin core peptides do not have a tyrosine or tryptophan as a C-terminal residue , but a histidine. The imidazole-indole connection in moroidins extends BURP-domain RiPP biosynthesis to cross-coupling of two aromatic side chains compared to known BURP-domain-derived RiPPs such as stephanotic acid, which are defined by cross-links of an aromatic side chain to an unactivated carbon in another amino acid side chain . Moroidin bicyclization in KjaBURP may be evolutionarily related to stephanotic acid cyclases such as CcaBURP2, which also contains moroidin core peptides in its N-terminal domain, but no moroidin analytes have been characterized from CcaBURP2 reconstitution or source plants (Figure S27).…”

Widely Distributed Biosynthetic Cassette Is Responsible for Diverse Plant Side-Chain-Cross-Linked Cyclopeptides

“…Structurally, cyclopeptide alkaloids are related to diverse plant side chain cross-linked cyclopeptides that include lyciumins [5] , selanines [6] , moroidins [7] , and hibispeptins [14,15] (Figure 1C). Recent work demonstrated that many of these cyclic peptides are derived from autocatalytic BURP-domains that install the characteristic amino acid side chain macrocyclizations [5–7,16,17] . In these systems, the core peptides are fused to the copper-dependent BURPdomains.…”