Horizontal transfer of a pathway for coumarate catabolism unexpectedly inhibits purine nucleotide biosynthesis

Close, Dan; Cooper, Conner J.; Wang, Xingyou; Chirania, Payal; Gupta, Madhulika; Ossyra, John R.; Giannone, Richard J.; Engle, Nancy L.; Tschaplinski, Timothy J.; Smith, Jeremy C.; Hedstrom, Lizbeth; Parks, Jerry M.; Michener, Josh

doi:10.1111/MMI.14393

Title: Horizontal transfer of a pathway for coumarate catabolism unexpectedly inhibits purine nucleotide biosynthesis

Journal Article · 18 September 2019 · Molecular Microbiology

DOI: https://doi.org/10.1111/MMI.14393 · OSTI ID:1570140

^[1]; Cooper, Conner J. ^[2]; Wang, Xingyou ^[3]; Chirania, Payal ^[2]; Gupta, Madhulika ^[1]; Ossyra, John R. ^[4];

^[1];

^[2]; Hedstrom, Lizbeth ^[3];

^[2];

^[1]

Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Univ. of Tennessee, Knoxville, TN (United States)
Brandeis Univ., Waltham, MA (United States)
Univ. of Tennessee, Knoxville, TN (United States)

A microbe’s ecological niche and biotechnological utility are confirmed by its specific set of co-evolved metabolic pathways. The acquisition of new pathways, through horizontal gene transfer or genetic engineering, can have unpredictable consequences. In this work, we show that two different pathways for coumarate catabolism failed to function when initially transferred into Escherichia coli. Using laboratory evolution, we elucidated the factors limiting activity of the newly acquired pathways and the modifications required to overcome these limitations. Both pathways required host mutations to enable effective growth with coumarate, but the necessary mutations differed. In one case, a pathway intermediate inhibited purine nucleotide biosynthesis, and this inhibition was relieved by single amino acid replacements in IMP dehydrogenase. A strain that natively contains this coumarate catabolism pathway, Acinetobacter baumannii, is resistant to inhibition by the relevant intermediate, indicating that natural pathway transfers have faced and overcome similar challenges. Molecular dynamics simulation of the wild type and a representative single-residue mutant provide insight into the structural and dynamic changes that relieve inhibition. These results reflect how deleterious interactions can limit pathway transfer, that these interactions can be traced to specific molecular interactions between host and pathway, and how evolution or engineering can alleviate these limitations.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); National Science Foundation (NSF)

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1570140

Journal Information:: Molecular Microbiology, Journal Name: Molecular Microbiology Journal Issue: 6 Vol. 112; ISSN 0950-382X

Publisher:: WileyCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
IMPDH
biosystem design
lignin catabolism
molecular dynamics
pathway optimization

Title: Horizontal transfer of a pathway for coumarate catabolism unexpectedly inhibits purine nucleotide biosynthesis

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