Different Reaction Specificities of F420H2-Dependent Reductases Facilitate Pyrrolobenzodiazepines and Lincomycin To Fit Their Biological Targets

0539841 - MBÚ 2021 RIV US eng J - Journal Article
Steiningerová, Lucie - Kameník, Zdeněk - Gažák, Radek - Kadlčík, Stanislav - Bashiri, G. - Man, Petr - Kuzma, Marek - Pavlíková, Magdaléna - Janata, Jiří
Different Reaction Specificities of F420H2-Dependent Reductases Facilitate Pyrrolobenzodiazepines and Lincomycin To Fit Their Biological Targets.
Journal of the American Chemical Society. Roč. 142, č. 7 (2020), s. 3440-3448. ISSN 0002-7863. E-ISSN 1520-5126
R&D Projects: GA ČR(CZ) GJ17-13436Y; GA MŠMT(CZ) ED1.1.00/02.0109; GA MŠMT(CZ) LQ1604
Research Infrastructure: CIISB - 90043
Institutional support: RVO:61388971
Keywords : antibody-drug conjugate * antitumor antibiotics * sequence-analysis * gene-cluster * biosynthesis * strain * lincosamides * tuberculosis * tomaymycin
OECD category: Microbiology
Impact factor: 15.419, year: 2020
Method of publishing: Limited access
https://pubs.acs.org/doi/abs/10.1021/jacs.9b11234

Antitumor pyrrolobenzodiazepines (PBDs), lincosamide antibiotics, quorum-sensing molecule hormaomycin, and antimicrobial griselimycin are structurally and functionally diverse groups of actinobacterial metabolites. The common feature of these compounds is the incorporation of L-tyrosine- or L-leucine-derived 4-alkyl-L-proline derivatives (APDs) in their structures. Here, we report that the last reaction in the biosynthetic pathway of APDs, catalyzed by F420H2-dependent Apd6 reductases, contributes to the structural diversity of APD precursors. Specifically, the heterologous overproduction of six Apd6 enzymes demonstrated that Apd6 from the biosynthesis of PBDs and hormaomycin can reduce only an endocyclic imine double bond, whereas Apd6 LmbY and partially GriH from the biosyntheses of lincomycin and griselimycin, respectively, also reduce the more inert exocyclic double bond of the same 4-substituted Delta 1-pyrroline-2-carboxylic acid substrate, making LmbY and GriH unusual, if not unique, among reductases. Furthermore, the differences in the reaction specificity of the Apd6 reductases determine the formation of the fully saturated APD moiety of lincomycin versus the unsaturated APD moiety of PBDs, providing molecules with optimal shapes to bind their distinct biological targets. Moreover, the Apd6 reductases establish the first F420H2-dependent enzymes from the luciferase-like hydride transferase protein superfamily in the biosynthesis of bioactive molecules. Finally, our bioinformatics analysis demonstrates that Apd6 and their homologues, widely distributed within several bacterial phyla, play a role in the formation of novel yet unknown natural products with incorporated L-proline-like precursors and likely in the microbial central metabolism.
Permanent Link: http://hdl.handle.net/11104/0317538