Table 1.

Metabolic engineering strategies for 3-hydroxypropionate production in yeast.

Metabolic engineering strategies	Beneficial effect for 3-HP production	Reference
Increasing the supply of malonyl-CoA: Overexpression the enzymes (ALD6, ACSse, ADH2) for acetyl-CoA accumulation; Deleting the MLS1 to block the consumption of acetyl-CoA; Overexpression the ACC1 catalyzing acetyl-CoA to malonyl-CoA. Increasing the supply of NADPH: Overexpression the GAPN catalyzing the formation of extra NADPH. Establishing the MCR pathway: Overexpression the CaMCR.	3-HP production was increased to 463 mg/L	Chen et al., 2014
Generating the ACC1 mutant (ACC1Ser659Ala Ser1157Ala) through mutating the potential phosphorylation sites to abolish the post-translational regulation Increasing the ACC1 activity by overexpression of the ACC1 mutant	3-HP production was up to ∼2.2-fold more than that of the wild-type ACC1	Shi et al., 2014
Constructing the β-alanine pathway by overexpressing AAT2, PYC1, PYC2, ALT, BcBAPAT, EcHPDH, and multiple copies of TcPAND	13.7 g/L 3-HP was generated through the constructed β-alanine pathway from glucose in fed-batch fermentation at low pH.	Borodina et al., 2015
Increasing the supply of acetyl-CoA by overexpressing PDC1, ALD6, and ACSse; Engineering the cofactor specificity of the GAPN to increase the production of NADPH at the expense of NADH and thus improve 3-HP production and reduce formation of glycerol as by-product; Integrating multiple copies of CaMCR and ACC1 mutant genes into the genome.	3-HP was produced at a titer 7.37 g/L in a carbon-limited fed-batch fermentation	Kildegaard et al., 2016
Developing a malonyl-CoA biosensor based on the bacterial transcription factor FapR to monitor and precisely control the intracellular malonyl-CoA concentration	3-HP titer was enhanced i by 120%	Li et al., 2015
A hierarchical dynamic control strategy to control the expression level of CaMCR depending on the intracellular malonyl-CoA concentration: The upper level of control was to dynamically downregulate fatty acid biosynthesis using HXT1 promoter. The lower level was based on the malonyl-CoA biosensor.	3-HP production was increased by 10-fold	David et al., 2016
Improving the availability of malonyl-CoA through down-regulating lipid synthesis. Manipulating the phospholipid synthesis transcriptional regulators including Ino2p, Ino4p, Opi1p, and a series of synthetic Ino2p variants, combining with studying the inositol and choline effect.	3-HP production was increased by 9-fold	Chen et al., 2017
Identifying and characterizing promoters that depend on glucose concentration for use as dynamic control elements. Identifying 34 candidate promoters that strongly responded to glucose presence or absence. A subset of promoters, pADH2, pICL1, and pHXT7, were demonstrated as suitable for dynamic control of 3-HP production.	Regulating the 3-HP pathway by the ICL1 promoter resulted in 70% improvement of 3-HP titer in comparison to PGK1 promoter.	Maury et al., 2018

AAT2, aspartate aminotransferase 2; ACC1, acetyl-CoA carboxylase; ACSse, acetylation-insensitive acetyl-CoA synthetase from Salmonella enterica; ADH2, alcohol dehydrogenase; ALD6, NADP-dependent aldehyde dehydrogenase; ALT, alanine aminotransferase; BcBAPAT, β-alanine-pyruvate aminotransferase from Bacillus cereus; EcHPDH, 3-hydroxypropionate dehydrogenase from E. coli; GAPN, NADP-dependent G3P dehydrogenase; CaMCR, malonyl-CoA reductase from Chloroflexus aurantiacus; MLS1, cytosolic malate synthase; PDC1, pyruvate decarboxylase; PYC1/2, pyruvate carboxylase 1/2; TcPAND, aspartate decarboxylase from Tribolium castaneum.