Structure, catalysis, and inhibition mechanism of prenyltransferase

Abstract

Isoprenoids, also known as terpenes or terpenoids, represent a large family of natural products composed of five-carbon isopentenyl diphosphate or its isomer dimethylallyl diphosphate as the building blocks. Isoprenoids are structurally and functionally diverse and include dolichols, steroid hormones, carotenoids, retinoids, aromatic metabolites, the isoprenoid side-chain of ubiquinone, and isoprenoid attached signaling proteins. Productions of isoprenoids are catalyzed by a group of enzymes known as prenyltransferases, such as farnesyltransferases, geranylgeranyltransferases, terpenoid cyclase, squalene synthase, aromatic prenyltransferase, and cis-and trans-prenyltransferases. Because these enzymes are key in cellular processes and metabolic pathways, they are expected to be potential targets in new drug discovery. In this review, six distinct subsets of characterized prenyltransferases are structurally and mechanistically classified, including (1) head-to-tail prenyl synthase, (2) head-to-head prenyl synthase, (3) head-tomiddle prenyl synthase, (4) terpenoid cyclase, (5) aromatic prenyltransferase, and (6) protein prenylation. Inhibitors of those enzymes for potential therapies against several diseases are discussed. Lastly, recent results on the structures of integral membrane enzyme, undecaprenyl pyrophosphate phosphatase, are also discussed.

Heterologous biosynthesis of isobavachalcone in tobacco based on in planta screening of prenyltransferases

“…Another fact is that prenyltransferases have putative transmembrane domains and are localized in plastids ( Chang et al., 2021 ). In previous attempts to produce prenylflavonoid in transgenic plants, overexpression of prenyltransferases in the plastid exhibited the highest activities than that in the cytosol and mitochondria ( Koeduka et al., 2011 ; Sugiyama et al., 2011 ).…”

Heterologous biosynthesis of isobavachalcone in tobacco based on in planta screening of prenyltransferases

“…Another fact is that prenyltransferases have putative transmembrane domains and are localized in plastids (Chang et al 2021). However, the avonoid biosynthetic enzyme complexes, as well as the avonoids as substrates, are localized in ER.…”

Total Heterologous Biosynthesis of Fungal Natural Products in Aspergillus nidulans

“…Using similar methodology to the construction of pKW20088, the Tang group utilized pYTU, pYTP, and pYTR expression vectors carrying Af pyrG, Af pyroA, and Af riboB auxotrophic markers, respectively, to reconstitute fungal biosynthesis pathways. Their total biosynthesis works using A. nidulans are summarized and organized according to the class of fungal natural products expressed, i.e., PKS (Figures 4 and 5), NRPS (Figure 6 Pyriculol (5), Sordarial (6), and Trichoxide (7). Pyriculol ( 5) is a salicylaldehyde produced by Magnaporthe oryzae.…”

“…2 Typically, the carbon backbone of a fungal natural product is biosynthesized by one or two core enzyme(s) such as polyketide synthases (PKSs), 3,4 nonribosomal peptide synthetases (NRPSs), 5 terpene cyclases (TCs), 6 or prenyltransferases. 7 These core enzymes use primary metabolites such as acyl-CoAs (PKSs), amino acids (NRPSs), or isoprenoids (TCs and prenyltransferases) to generate carbon backbones which define the chemical class of the metabolite. The scaffolds synthesized by core enzymes are further modified by various tailoring enzymes, such as cytochromes P450 monooxygenases, flavin-dependent monooxygenases (FMOs), short-chain dehydrogenase/reductases (SDRs), and methyltransferases (MTs).…”