Abstract:Enzymes catalyzing [4+2] cycloaddition have attracted increasing attention because of their key roles in natural product biosynthesis. Here, we solved the X‐ray crystal structures of a pair of decalin synthases, Fsa2 and Phm7, that catalyze intramolecular [4+2] cycloadditions to form enantiomeric decalin scaffolds during biosynthesis of the HIV‐1 integrase inhibitor equisetin and its stereochemical opposite, phomasetin. Computational modeling, using molecular dynamics simulations as well as quantum chemical ca… Show more
“…To date, lipocalin-type DAases that generate three out of the four possible structural isomers of decalin adducts that can be produced from a linear polyene substrate via a DA reaction have been identified (Fig. 12 ) [ 115 ]. The only remaining type of lipocalin-type DAase is the one that would produce the 2 S ,3 S ,6 R ,11 R type of decalin-containing natural products represented by compounds such as 24 , 23 , 25 (Figs.…”
Section: Discussionmentioning
confidence: 99%
“… Fig. 12 Lipocalin-type DAases can catalyze the generation of four diastereomeric decalin cores of pyrrolidine-2-one-bearing decalin natural products from an achiral linear polyene polyketide substrate [ 115 ]. Equisetin-forming Fsa2 represents the 2 S ,3 R ,6 S ,11 R trans- decalin core-forming DAases.…”
Section: Discussionmentioning
confidence: 99%
“…The result also suggested high substrate tolerance of the lipocalin-type DAase and opened a new way for producing analogs of pyrrolidine-2-one-bearing decalins having different stereochemistry using molecular genetic techniques. Most recently, the apo crystal structures of Fsa2 and Phm7 were reported [ 11 , 115 ]. Through extensive computational analyses and docking experiments, a rational explanation as to how the two enzymes catalyze [4 + 2] cycloaddition reactions on the same substrate to generate enantiomerically opposite adducts.…”
Section: Daase Catalyzing Decalin Ring Formation Of Pyrrolidine-2-one...mentioning
confidence: 99%
“…Furthermore, the study proposes a comprehensive model for the production of four different diastereomeric decalin scaffolds from the same tetramic acid-bearing linear triene substrate by four types of lipocalinic DAases. The key distinction is thought to be made by how the tetramic acid moiety of the substrate is oriented and the flexible triene polyketide chain is preorganized within the binding pocket of lipocalinic DAases [ 115 ]. Those studies will pave the way toward answering the long-standing question about naturally occurring DAases and engineering those fascinating catalysts for biotechnological applications.…”
Section: Daase Catalyzing Decalin Ring Formation Of Pyrrolidine-2-one...mentioning
The Diels–Alder (DA) reaction refers to a [4 + 2] cycloaddition reaction that falls under the category of pericyclic reactions. It is a reaction that allows regio- and stereo-selective construction of two carbon–carbon bonds simultaneously in a concerted manner to generate a six-membered ring structure through a six-electron cyclic transition state. The DA reaction is one of the most widely applied reactions in organic synthesis, yet its role in biological systems has been debated intensely over the last four decades. A survey of secondary metabolites produced by microorganisms suggests strongly that many of the compounds possess features that are likely formed through DA reactions, and most of them are considered to be catalyzed by enzymes that are commonly referred to as Diels–Alderases (DAases). In recent years, especially over the past 10 years or so, we have seen an accumulation of a substantial body of work that substantiates the argument that DAases indeed exist and play a critical role in the biosynthesis of complex metabolites. This review will cover the DAases involved in the biosynthesis of decalin moieties, which are found in many of the medicinally important natural products, especially those produced by fungi. In particular, we will focus on a subset of secondary metabolites referred to as pyrrolidine-2-one-bearing decalin compounds and discuss the decalin ring stereochemistry and the biological activities of those compounds. We will also look into the genes and enzymes that drive the biosynthetic construction of those complex natural products, and highlight the recent progress made on the structural and mechanistic understanding of DAases, especially regarding how those enzymes exert stereochemical control over the [4 + 2] cycloaddition reactions they catalyze.
“…To date, lipocalin-type DAases that generate three out of the four possible structural isomers of decalin adducts that can be produced from a linear polyene substrate via a DA reaction have been identified (Fig. 12 ) [ 115 ]. The only remaining type of lipocalin-type DAase is the one that would produce the 2 S ,3 S ,6 R ,11 R type of decalin-containing natural products represented by compounds such as 24 , 23 , 25 (Figs.…”
Section: Discussionmentioning
confidence: 99%
“… Fig. 12 Lipocalin-type DAases can catalyze the generation of four diastereomeric decalin cores of pyrrolidine-2-one-bearing decalin natural products from an achiral linear polyene polyketide substrate [ 115 ]. Equisetin-forming Fsa2 represents the 2 S ,3 R ,6 S ,11 R trans- decalin core-forming DAases.…”
Section: Discussionmentioning
confidence: 99%
“…The result also suggested high substrate tolerance of the lipocalin-type DAase and opened a new way for producing analogs of pyrrolidine-2-one-bearing decalins having different stereochemistry using molecular genetic techniques. Most recently, the apo crystal structures of Fsa2 and Phm7 were reported [ 11 , 115 ]. Through extensive computational analyses and docking experiments, a rational explanation as to how the two enzymes catalyze [4 + 2] cycloaddition reactions on the same substrate to generate enantiomerically opposite adducts.…”
Section: Daase Catalyzing Decalin Ring Formation Of Pyrrolidine-2-one...mentioning
confidence: 99%
“…Furthermore, the study proposes a comprehensive model for the production of four different diastereomeric decalin scaffolds from the same tetramic acid-bearing linear triene substrate by four types of lipocalinic DAases. The key distinction is thought to be made by how the tetramic acid moiety of the substrate is oriented and the flexible triene polyketide chain is preorganized within the binding pocket of lipocalinic DAases [ 115 ]. Those studies will pave the way toward answering the long-standing question about naturally occurring DAases and engineering those fascinating catalysts for biotechnological applications.…”
Section: Daase Catalyzing Decalin Ring Formation Of Pyrrolidine-2-one...mentioning
The Diels–Alder (DA) reaction refers to a [4 + 2] cycloaddition reaction that falls under the category of pericyclic reactions. It is a reaction that allows regio- and stereo-selective construction of two carbon–carbon bonds simultaneously in a concerted manner to generate a six-membered ring structure through a six-electron cyclic transition state. The DA reaction is one of the most widely applied reactions in organic synthesis, yet its role in biological systems has been debated intensely over the last four decades. A survey of secondary metabolites produced by microorganisms suggests strongly that many of the compounds possess features that are likely formed through DA reactions, and most of them are considered to be catalyzed by enzymes that are commonly referred to as Diels–Alderases (DAases). In recent years, especially over the past 10 years or so, we have seen an accumulation of a substantial body of work that substantiates the argument that DAases indeed exist and play a critical role in the biosynthesis of complex metabolites. This review will cover the DAases involved in the biosynthesis of decalin moieties, which are found in many of the medicinally important natural products, especially those produced by fungi. In particular, we will focus on a subset of secondary metabolites referred to as pyrrolidine-2-one-bearing decalin compounds and discuss the decalin ring stereochemistry and the biological activities of those compounds. We will also look into the genes and enzymes that drive the biosynthetic construction of those complex natural products, and highlight the recent progress made on the structural and mechanistic understanding of DAases, especially regarding how those enzymes exert stereochemical control over the [4 + 2] cycloaddition reactions they catalyze.
“…The Diels–Alder (DA) reaction is a powerful transformation capable of constructing complex cyclic structures within a single synthetic step with remarkable regio- and stereocontrol . In the past decades, great attention has been paid to the discovery of natural Diels–Alderases (DAases), − which was paralleled by the development of artificial enzymes and biomimetic catalysts for DA reactions. Mechanistic insights have been proven essential for understanding biocatalytic DA reactions ,,, and motivating the design of artificial DAases .…”
The
biosynthesis of pyrroindomycins A and B features a complexity-building
[4 + 2] cycloaddition cascade, which generates the spirotetramate
core under the catalytic effects of monofunctional Diels–Alderases
PyrE3 and PyrI4. We recently showed that the main functions of PyrI4
include acid catalysis and induced-fit/conformational selection. We
now present quantum mechanical and molecular dynamics studies implicating
a different mode of action by PyrE3, which prearranges an anionic
polyene substrate into a high-energy reactive conformation at which
an inverse-electron-demand Diels–Alder reaction can occur with
a low barrier. Stereoselection is realized by strong binding interactions
at the endo stereochemical relationship and a local
steric constraint on the endo-1,3-diene unit. These
findings, illustrating distinct mechanisms for PyrE3 and PyrI4, highlight
how nature has evolved multiple ways to catalyze Diels–Alder
reactions.
Among the natural tetramic acids with a decalinoyl part, signermycin B is unique because it contains a cis‐decalin. In this paper, we demonstrate that the cis‐decalin section of signermycin B can be accessed by an anionic oxy‐Cope rearrangement. The substrate, a tricyclic dienol was prepared by an intramolecular Diels‐Alder reaction of a masked ortho‐benzoquinone, generated by oxidation of an α‐methoxyphenol in presence of cis‐2‐hexenol. After a superfluous bromine on the cycloadduct was removed, reaction of the tricyclic ketone with isopropenylmagnesium bromide led to the tricyclic trienol that underwent the oxy‐Cope rearrangement to a cis‐decalinone. While we could show, that introduction of the 4‐ethyl substituent (signermycin B numbering) is possible by enolate alkylation, the 4‐epi‐isomer was formed.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
