Prenyltransferase Mediated Biosynthesis of Aromatic Natural Products

Prenyltransferases catalyse the transfer of isoprenoid units onto aromatic scaffolds, creating a vast array of natural products with enhanced biological properties. These enzymes link the isoprenoid pathway—via donors such as dimethylallyl diphosphate (DMAPP), geranyl diphosphate (GPP) or farnesyl diphosphate (FPP)—to aromatic acceptors derived from the shikimate, polyketide or phenylpropanoid routes. Two major structural classes are recognised: soluble cytosolic enzymes typified by the ABBA fold or the dimethylallyl tryptophan synthase (DMATS) fold, and membrane-embedded enzymes of the UbiA superfamily. Substrate specificity ranges from highly regiospecific prenylations, which define the position and stereochemistry of the appended isoprenoid chain, to promiscuous biocatalysts capable of accepting diverse aromatic molecules. Structure–function studies have revealed conserved catalytic motifs, metal-coordinating residues and flexible binding pockets that govern donor and acceptor selection. Prenylated aromatics encompass flavonoids, isoflavonoids, indoles, naphthoquinones and phenylpropanes, many of which exhibit antimicrobial, anti-inflammatory or anticancer activities. Advances in enzyme engineering, structural biology and synthetic biology have enabled the rational redesign of prenyltransferase specificity and the assembly of microbial or plant-based production platforms for high-value prenylated compounds.

Research from Nature Portfolio

Recent studies have elucidated the molecular basis of stepwise di-prenylation of phenolic acids. A membrane-bound UbiA-type enzyme from Artemisia capillaris was shown to accept p-coumaric acid and sequentially install two prenyl residues to yield artepillin C. Structural analysis highlighted active-site adaptations that permit multiple prenyl transfers and informed the construction of a yeast cell factory for sustainable production. In parallel, bacterial indolactam prenyltransferases TleC and MpnD were examined by crystallography and mutagenesis. These enzymes catalyse “reverse” C-prenylation of indole alkaloid precursors and display relaxed donor specificity. Structure-guided engineering altered chain-length preference and regioselectivity, enabling the biosynthesis of novel indolactam analogues. Additionally, a fungal prenyltransferase from Fusarium oxysporum was characterised as a highly regiospecific biocatalyst that exclusively generates 6-C-prenylated flavonoids across a broad substrate range. Docking and mutagenesis pinpointed key residues that confer strict control over both donor and acceptor orientation.

Prenyltransferase Mediated Biosynthesis of Aromatic Natural Products publication trend

The graph below shows the total number of articles in prenyltransferase mediated biosynthesis of aromatic natural products across all publications each year (not limited to Nature Index journals).

Technical terms

Prenyltransferase: Enzyme that transfers an isoprenoid moiety to an acceptor molecule.

Isoprenoid donor: Activated prenyl diphosphate such as DMAPP, GPP or FPP.

ABBA fold: A ten-stranded β-barrel structural motif found in soluble aromatic prenyltransferases.

DMATS fold: Structural family typified by dimethylallyl tryptophan synthases, catalysing indole prenylation.

UbiA superfamily: Membrane-embedded prenyltransferases involved in quinone and phenolic lipid biosynthesis.

Regioselectivity: The selectivity of an enzyme for a specific position on the aromatic ring.

Substrate promiscuity: The ability of an enzyme to accept multiple structurally diverse substrates.

References

1. Enzymatic studies on aromatic prenyltransferases. Journal of Natural Medicines (2020).
2. Manipulation of prenylation reactions by structure-based engineering of bacterial indolactam prenyltransferases. Nature Communications (2016).
3. Structure of a Membrane-Embedded Prenyltransferase Homologous to UBIAD1. PLOS Biology (2014).
4. Regiospecific synthesis of prenylated flavonoids by a prenyltransferase cloned from Fusarium oxysporum. Scientific Reports (2016).
5. Isolation of Artemisia capillaris membrane-bound di-prenyltransferase for phenylpropanoids and redesign of artepillin C in yeast. Communications Biology (2019).
6. Acceptor substrate determines donor specificity of an aromatic prenyltransferase: expanding the biocatalytic potential of NphB. Applied Microbiology and Biotechnology (2020).