Die biosynthetische Grundlage der Polyketid‐Vielfalt

Abstract

Molekulares Lego: Polyketide bilden eine äußerst vielfältige Gruppe von Naturstoffen mit faszinierenden Kohlenstoffgerüsten (siehe Beispiele), die aus einfachen Acyl‐Bausteinen synthetisiert werden. Das Zusammenspiel von Chemie, Biochemie und Genetik lieferte wichtige Einblicke in die Programmierung des Polyketid‐Aufbaus und die beteiligten, komplexen Enzymsysteme. Dieser Aufsatz behandelt aktuelle Entwicklungen auf diesem Forschungsgebiet.magnified imagePolyketide bilden eine der größten Naturstoffklassen. Viele dieser Verbindungen – oder Derivate davon – sind wichtige Therapeutika, aber viele sind auch berüchtigte, Lebensmittel verderbende Toxine oder Virulenzfaktoren. Besonders bemerkenswert ist, dass sich die Verbindungen dieser heterogenen Gruppe, zu denen Polyether, Polyene, Polyphenole, Makrolide und Endiine gehören, hauptsächlich von einem der einfachsten natürlichen Bausteine ableiten: Essigsäure. Chemische, genetische und biochemische Untersuchungen haben Aufschluss über die Biosyntheseprogramme gegeben, die zur enormen Strukturvielfalt von Polyketiden führen. Dieser Aufsatz behandelt kürzlich aufgeklärte Biosynthesemechanismen, nach denen höchst unterschiedliche und komplexe Moleküle synthetisiert werden.

An Unusual Thioesterase Promotes Isochromanone Ring Formation in Ajudazol Biosynthesis

“…PKS and NRPS are large, multimodular enzymes that are responsible for the generation of natural products by stepwise assembly from simple acyl-coenzyme A thioesters and amino acids, respectively. [3][4][5][6] Each module consists of multiple specialized catalytic domains, which together exhibit all the enzymatic functions required for the activation and incorporation of a single building block into the growing chain, as well as its optional modification. The common catalytic strategy used by PKS and NRPS is based around carrier protein (CP) domains (acyl carrier protein (ACP) and peptidyl carrier protein (PCP), respectively), which are present in each module.…”

Formation of 1,3‐Cyclohexanediones and Resorcinols Catalyzed by a Widely Occuring Ketosynthase

“…They can be part of large multifunctional enzymes like the type I polyketide synthases (PKS) and type I fatty acid synthases, or they exist as stand-alone enzymes as in the type II fatty acid synthases, type II PKS, or chalcone synthases (type III PKS). [1] In type II fatty acid and polyketide biosynthesis, functionally different ketosynthase classes are known, which either catalyze the first (KS III or FabH) or the consecutive elongation steps (FabF and FabB). [1,2] Despite their different functions, all ketosynthases are members of the thiolase protein family and catalyze CÀC bond formation.…”

“…[1] In type II fatty acid and polyketide biosynthesis, functionally different ketosynthase classes are known, which either catalyze the first (KS III or FabH) or the consecutive elongation steps (FabF and FabB). [1,2] Despite their different functions, all ketosynthases are members of the thiolase protein family and catalyze CÀC bond formation. However, recently the first member of the KS III class has been described that is a functional malonyltransferase.…”

Arimetamycin A: Improving Clinically Relevant Families of Natural Products through Sequence‐Guided Screening of Soil Metagenomes

“…[6] The biosyntheses of these metabolites, although differing in detail, all originate with the production of a polyacetate precursor by a conserved minimal polyketide synthase (min-PKS) that is composed of three proteins [ β -ketoacyl synthase alpha (KS α ), β -ketoacyl synthase beta (KS β ), acyl carrier protein (ACP)] (Figure 1). [6] KS α and KS β genes clade into groups that correlate strongly with the specific aromatic polyketide structural classes that are encoded by the gene clusters in which they reside.…”

“…[6] The biosyntheses of these metabolites, although differing in detail, all originate with the production of a polyacetate precursor by a conserved minimal polyketide synthase (min-PKS) that is composed of three proteins [ β -ketoacyl synthase alpha (KS α ), β -ketoacyl synthase beta (KS β ), acyl carrier protein (ACP)] (Figure 1). [6] KS α and KS β genes clade into groups that correlate strongly with the specific aromatic polyketide structural classes that are encoded by the gene clusters in which they reside. [7] Extrapolating from this observation, we hypothesized that it should be possible to systematically screen large eDNA libraries for biosynthetic gene clusters capable of encoding novel members of clinically relevant aromatic polyketide structural classes using only PCR amplified min-PKS gene fragments as sequence tags.…”