Polyketide stereocontrol: a study in chemical biology

Weissman, Kira J.

doi:10.3762/bjoc.13.39

Cited by 39 publications

(46 citation statements)

References 124 publications

(180 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A prediction was also not made for the C-22 methyl group incorporated by module 9 given evidence that some type A1 KR domains can in fact have epimerase activity. 39,40…”

Section: Resultsmentioning

confidence: 99%

Integration of Genomic Data with NMR Analysis Enables Assignment of the Full Stereostructure of Neaumycin B, a Potent Inhibitor of Glioblastoma from a Marine-Derived Micromonospora

et al. 2018

View full text Add to dashboard Cite

The microbial metabolites known as the macrolides are some of the most successful natural products used to treat infectious and immune diseases. Describing the structures of these complex metabolites, however, is often extremely difficult due to the presence of multiple stereogenic centers inherent in this class of polyketide-derived metabolites. With the availability of genome sequence data and a better understanding of the molecular genetics of natural product biosynthesis, it is now possible to use bioinformatic approaches in tandem with spectroscopic tools to assign the full stereostructures of these complex metabolites. In our quest to discover and develop new agents for the treatment of cancer, we observed the production of a highly cytotoxic macrolide, neaumycin B, by a marine-derived actinomycete bacterium of the genus Micromonospora. Neaumycin B is a complex polycyclic macrolide possessing 19 asymmetric centers, usually requiring selective degradation, crystallization, derivatization, X-ray diffraction analysis, synthesis, or other time-consuming approaches to assign the complete stereostructure. As an alternative approach, we sequenced the genome of the producing strain and identified the neaumycin gene cluster ( neu). By integrating the known stereospecificities of biosynthetic enzymes with comprehensive NMR analysis, the full stereostructure of neaumycin B was confidently assigned. This approach exemplifies how mining gene cluster information while integrating NMR-based structure data can achieve rapid, efficient, and accurate stereostructural assignments for complex macrolides.

show abstract

“…A prediction was also not made for the C-22 methyl group incorporated by module 9 given evidence that some type A1 KR domains can in fact have epimerase activity. 39,40…”

Section: Resultsmentioning

confidence: 99%

Integration of Genomic Data with NMR Analysis Enables Assignment of the Full Stereostructure of Neaumycin B, a Potent Inhibitor of Glioblastoma from a Marine-Derived Micromonospora

et al. 2018

View full text Add to dashboard Cite

show abstract

“…For non‐physiological substrates, the situation is different: with lipophilic esters such as ethyl or tert ‐butyl ( R / S )‐2‐methyl‐3‐oxovalerate, the enzymatic reduction yields the corresponding S , S ‐hydroxy esters, suggesting that Tyl‐KR1 also has hidden A2‐type properties . This finding somewhat challenges the previously postulated correlation of the stereoselectivity of a KR with diagnostic motifs in its amino acid sequence—a paradigm considered a milestone for the long‐term goal of identifying patterns that allow the prediction of the stereoselectivity of enzymatic reactions directly from genome sequencing data . Recently, such paradigms have also been incorporated as heuristics for computational polyketide synthase design .…”

Section: Methodsmentioning

confidence: 99%

Hidden Specificities in Enzyme Catalysis: Structural Basis of Substrate Structure‐Selectivity Relationship of a Ketoreductase

et al. 2019

View full text Add to dashboard Cite

Enzymes often convert both physiological and non‐physiological substrates with high stereoselectivity; yet, for some enzymes, opposite product chirality is observed. A possible explanation is the existence of hidden specificities becoming apparent when non‐physiological substrates confer different substrate–enzyme interactions than the physiological substrate. To test this hypothesis, a series of α‐methylated β‐keto esters were converted with Tyl‐KR1, a ketoreductase from polyketide synthesis in Streptomyces fradiae. The conversions of six substrates with different physicochemical properties exhibited enantioselectivities ranging from 84 % ee for R,R to 84 % ee for S,S, yet high and uniform diastereoselectivity (anti, d.r.>9:1). The exchange of a single atom, namely an oxygen ester instead of a thioester, led to almost complete loss of enantioselectivity (<5 % ee). An additional S,S‐selective binding mode as a hidden specificity in Tyl‐KR1 has been identified through molecular modeling and site‐directed mutagenesis.

show abstract

“…Exquisite control of stereochemistry is seen when substituted extender units are utilised and during reductive processing of the b-ketone. 5,6 Cleavage of the growing chain from the PKS may be achieved in a variety of ways, e.g. through hydrolysis of the thioester bond, cyclisation, transesterication, peptide bond formation or macrolactonisation.…”

Section: Introductionmentioning

confidence: 99%