A platform pathway for production of 3-hydroxyacids provides a biosynthetic route to 3-hydroxy-γ-butyrolactone.
The replacement of petroleum feedstocks with biomass to produce platform chemicals requires the development of appropriate conversion technologies. 3-Hydroxy-γ-butyrolactone has been identified as one such chemical; however, there are no naturally occurring biosynthetic pathways for this molecule or its hydrolyzed form, 3,4-dihydroxybutyric acid. Here we design a novel pathway to produce various chiral 3-hydroxyacids, including 3,4-dihydroxybutyric acid, consisting of enzymes that condense two acyl-CoAs, stereospecifically reduce the resulting β-ketone and hydrolyze the CoA thioester to release the free acid. Acetyl-CoA serves as one substrate for the condensation reaction, whereas the second is produced intracellularly by a pathway enzyme that converts exogenously supplied organic acids. Feeding of butyrate, isobutyrate and glycolate results in the production of 3-hydroxyhexanoate, 3-hydroxy-4-methylvalerate and 3,4-dihydroxybutyric acid+3-hydroxy-γ-butyrolactone, respectively, molecules with potential uses in applications from materials to medicines. We also unexpectedly observe the condensation reaction resulting in the production of the 2,3-dihydroxybutyric acid isomer, a potential value-added monomer.
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Collin H
CH
Martin
Himanshu
H
Dhamankar
Hsien-Chung
HC
Tseng
Micah J
MJ
Sheppard
Christopher R
CR
Reisch
Kristala L J
KL
Prather
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000096:biosynthesis; D053898:Biosynthetic Pathways / Q000187:drug effects / Q000235:genetics; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D005798:Genes, Bacterial / Q000235:genetics; D005947:Glucose / Q000378:metabolism; D006016:Glycolates / Q000378:metabolism; D006851:Hydrochloric Acid / Q000494:pharmacology; D006880:Hydroxy Acids / Q000737:chemistry / Q000378:metabolism*; D007536:Isomerism; D055432:Metabolomics; D011995:Recombination, Genetic / Q000235:genetics; D015203:Reproducibility of Results
C511346:3-hydroxy-gamma-butyrolactone; D006016:Glycolates; D006880:Hydroxy Acids; C031149:glycolic acid; D005947:Glucose; D015107:4-Butyrolactone; D006851:Hydrochloric Acid