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Edited by Alexis T. Bell, University of California, Berkeley, CA, and approved November 21, 2018 (received for review July 31, 2018)
Significance
Isoprenoids are a class of natural products with applications in many fields, including medicine and agriculture. Biosynthesis of isoprenoids has emerged as the most commercially viable option for their mass production. We report the creation of an enzymatic pathway for the biological production of isoprenoids, which uses externally provided isoprenol as its substrate instead of a glucose-derived catabolite, making it radically different from naturally occurring pathways or their engineered variants. The pathway is only two steps long and uses a single cofactor, ATP. Our results show that it is decoupled from central carbon metabolism and can sustain a very high flux. These advantages make it a noteworthy alternative to known isoprenoid pathways.
Abstract
Isoprenoids comprise a large class of chemicals of significant interest due to their diverse properties. Biological production of isoprenoids is considered to be the most efficient way for their large-scale production. Isoprenoid biosynthesis has thus far been dependent on pathways inextricably linked to glucose metabolism. These pathways suffer from inherent limitations due to their length, complex regulation, and extensive cofactor requirements. Here, we present a synthetic isoprenoid pathway that aims to overcome these limitations. This isopentenol utilization pathway (IUP) can produce isopentenyl diphosphate or dimethylallyl diphosphate, the main precursors to isoprenoid synthesis, through sequential phosphorylation of isopentenol isomers isoprenol or prenol. After identifying suitable enzymes and constructing the pathway, we attempted to probe the limits of the IUP for producing various isoprenoid downstream products. The IUP flux exceeded the capacity of almost all downstream pathways tested and was competitive with the highest isoprenoid fluxes reported.
Footnotes
- ↵1To whom correspondence should be addressed. Email: gregstep{at}mit.edu.
Author contributions: A.O.C., V.W., S.M.E., and G.S. designed research; A.O.C. and V.W. performed research; V.W. contributed new reagents/analytic tools; A.O.C. and V.W. analyzed data; and A.O.C. wrote the paper.
Conflict of interest statement: The authors are listed as inventors in a pending patent application (no. US 62/677,421; applicant, Massachusetts Institute of Technology) encompassing all the information presented here, as well as additional applications.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1812935116/-/DCSupplemental.
Published under the PNAS license.
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Two-step pathway for isoprenoid synthesis
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