Biochemical and Structural Characterization of TtnD, a Prenylated FMN-Dependent Decarboxylase from the Tautomycetin Biosynthetic Pathway
Abstract
Tautomycetin (TTN) is a polyketide natural product featuring a terminal alkene. Functional characterization of the genes within the ttn gene cluster from Streptomyces griseochromogenes established the biosynthesis of the TTN polyketide backbone, its dialkylmaleic anhydride moiety, the coupling of the two moieties to form the nascent intermediate TTN F-1, and the tailoring steps converting TTN F-1 to TTN. Here, we report biochemical and structural characterization of TtnD, a prenylated FMN (prFMN)-dependent decarboxylase belonging to the UbiD family that catalyzes the penultimate step of TTN biosynthesis. TtnD catalyzes decarboxylation of TTN D-1 to TTN I-1, utilizing prFMN as a cofactor generated by the TtnC flavin prenyltransferase; both TtnD and TtnC are encoded within the ttn biosynthetic gene cluster. TtnD exhibits substrate promiscuity but accepts only TTN D-1 congeners that feature an α,β-unsaturated acid, supporting the [3+2] cycloaddition mechanism during catalysis that requires the double bond of an α,β-unsaturated acid substrate. TtnD shares a similar overall structure with other members of the UbiD family but forms a homotetramer in solution. Each protomer is composed of three domains with the active site located between the middle and C-terminal domains; R169-E272-E277, constituting the catalytic triad, and E228, involved in Mn(II)-mediated binding of prFMN, weremore »
- Authors:
-
- The Scripps Research Inst., Jupiter, FL (United States)
- Rice Univ., Houston, TX (United States)
- The Scripps Research Inst., Jupiter, FL (United States); Univ. of Electronic Science and Technology of China, Chengdu (China)
- The Scripps Research Inst., Jupiter, FL (United States); Peking Univ., Beijing (China)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Biological and Environmental Research (BER); National Inst. of Health; National Science Foundation (NSF)
- OSTI Identifier:
- 1476086
- Grant/Contract Number:
- AC02-06CH11357; AC02-06CH113; GM098248; CA078747
- Resource Type:
- Accepted Manuscript
- Journal Name:
- ACS Chemical Biology
- Additional Journal Information:
- Journal Volume: 13; Journal Issue: 9; Journal ID: ISSN 1554-8929
- Publisher:
- American Chemical Society (ACS)
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; flavins; peptides and proteins; metabolism; organic reactions; chemical structure
Citation Formats
Annaval, Thibault, Han, Lu, Rudolf, Jeffrey D., Xie, Guangbo, Yang, Dong, Chang, Chin-Yuan, Ma, Ming, Crnovcic, Ivana, Miller, Mitchell D., Soman, Jayashree, Xu, Weijun, Phillips, Jr., George N., and Shen, Ben. Biochemical and Structural Characterization of TtnD, a Prenylated FMN-Dependent Decarboxylase from the Tautomycetin Biosynthetic Pathway. United States: N. p., 2018.
Web. doi:10.1021/acschembio.8b00673.
Annaval, Thibault, Han, Lu, Rudolf, Jeffrey D., Xie, Guangbo, Yang, Dong, Chang, Chin-Yuan, Ma, Ming, Crnovcic, Ivana, Miller, Mitchell D., Soman, Jayashree, Xu, Weijun, Phillips, Jr., George N., & Shen, Ben. Biochemical and Structural Characterization of TtnD, a Prenylated FMN-Dependent Decarboxylase from the Tautomycetin Biosynthetic Pathway. United States. https://doi.org/10.1021/acschembio.8b00673
Annaval, Thibault, Han, Lu, Rudolf, Jeffrey D., Xie, Guangbo, Yang, Dong, Chang, Chin-Yuan, Ma, Ming, Crnovcic, Ivana, Miller, Mitchell D., Soman, Jayashree, Xu, Weijun, Phillips, Jr., George N., and Shen, Ben. Tue .
"Biochemical and Structural Characterization of TtnD, a Prenylated FMN-Dependent Decarboxylase from the Tautomycetin Biosynthetic Pathway". United States. https://doi.org/10.1021/acschembio.8b00673. https://www.osti.gov/servlets/purl/1476086.
@article{osti_1476086,
title = {Biochemical and Structural Characterization of TtnD, a Prenylated FMN-Dependent Decarboxylase from the Tautomycetin Biosynthetic Pathway},
author = {Annaval, Thibault and Han, Lu and Rudolf, Jeffrey D. and Xie, Guangbo and Yang, Dong and Chang, Chin-Yuan and Ma, Ming and Crnovcic, Ivana and Miller, Mitchell D. and Soman, Jayashree and Xu, Weijun and Phillips, Jr., George N. and Shen, Ben},
abstractNote = {Tautomycetin (TTN) is a polyketide natural product featuring a terminal alkene. Functional characterization of the genes within the ttn gene cluster from Streptomyces griseochromogenes established the biosynthesis of the TTN polyketide backbone, its dialkylmaleic anhydride moiety, the coupling of the two moieties to form the nascent intermediate TTN F-1, and the tailoring steps converting TTN F-1 to TTN. Here, we report biochemical and structural characterization of TtnD, a prenylated FMN (prFMN)-dependent decarboxylase belonging to the UbiD family that catalyzes the penultimate step of TTN biosynthesis. TtnD catalyzes decarboxylation of TTN D-1 to TTN I-1, utilizing prFMN as a cofactor generated by the TtnC flavin prenyltransferase; both TtnD and TtnC are encoded within the ttn biosynthetic gene cluster. TtnD exhibits substrate promiscuity but accepts only TTN D-1 congeners that feature an α,β-unsaturated acid, supporting the [3+2] cycloaddition mechanism during catalysis that requires the double bond of an α,β-unsaturated acid substrate. TtnD shares a similar overall structure with other members of the UbiD family but forms a homotetramer in solution. Each protomer is composed of three domains with the active site located between the middle and C-terminal domains; R169-E272-E277, constituting the catalytic triad, and E228, involved in Mn(II)-mediated binding of prFMN, were confirmed by site-directed mutagenesis. TtnD represents the first example of a prFMN-dependent decarboxylase involved in polyketide biosynthesis, expanding the substrate scope of the UbiD family of decarboxylases beyond simple aromatic and cinnamic acids. In conclusion, TtnD and its homologues are widespread in nature and could be exploited as biocatalysts for organic synthesis.},
doi = {10.1021/acschembio.8b00673},
journal = {ACS Chemical Biology},
number = 9,
volume = 13,
place = {United States},
year = {Tue Aug 28 00:00:00 EDT 2018},
month = {Tue Aug 28 00:00:00 EDT 2018}
}
Web of Science
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