TABLE 1.
Metabolic engineering of Yarrowia lipolytica for terpenoid biosynthesis.
| Compound | Carbon Source | Parental Strain | Relevant modifications related to terpenoid biosynthesis | Titer | References |
| Monoterpenoids | |||||
| Limonene | Glucose | Po1g | ↑HMG (↑ClLS or ↑MsLS) | D-limonene: 11.7 mg/L L-limonene: 11.1 mg/L (bioreactor) | Pang et al., 2019 |
| Glycerol Citrate | Po1f | ↑ArtLS ↑SltNDPS1 ↑HMG1 ↑ERG12 | 165.3 mg/L (bioreactor) | Cheng et al., 2019 | |
| Glucose Pyruvic acid | Po1f | ↑ArtLS ↑SltNDPS1 ↑HMG1 ↑ERG12 | 23.6 mg/L (shake flask) | Cao et al., 2016 | |
| Glucose | ATCC 20460 | ↑HMG1 ↑ERG12 ↑ACL1 ↑SeACS ↑IDI ↑ERG20F88W–N119W ↓SQS ↑PfLS | 35.9 mg/L (glass tube) | This study | |
| Linalool | Citrate Pyruvate | Po1f | ↑AaLIS ↑ERG20F88W–N119W ↑HMG ↑IDI | 6.96 mg/L (shake flask) | Cao et al., 2017 |
| Sesquiterpenoids | |||||
| α-farnesene | Glucose Fructose | Po1h | ↑SctHMG ↑IDI ↑MdFS-L-ERG20 | 259.98 mg/L (bioreactor) | Yang et al., 2016 |
| Glucose | Po1f | ↑BdHMG ↑ERG13 ↑MdFS-L-ERG20 ↑ERG12 ↑IDI ↑ERG8,19 ↑GPPS | 25.55 g/L (bioreactor) | Liu et al., 2019 | |
| β-farnesene | Glucose | ATCC 20460 | ↑HMG1 ↑ERG12 ↑ACL1 ↑SeACS ↑IDI ↑ERG20 ↑AaBFS | 955 mg/L (glass tube) | This study |
| β-ionone | Glucose | Po1f | ↑carB ↑carRP ↑PhCCD1 ↑GGPPS ↑tHMG ↑ERG8,10,12,13,19,20Δpox3,5 ↑IDI ↑bbPK ↑bsPTA | 0.98 g/L (bioreactor) | Lu et al., 2020 |
| Glucose | Po1f | ↑carB ↑carRP ↑OfCCD1 ↑SsNphT7 ↑HpIDI ↑ERG8,10,12,13,19 ↑tHMG1 ↑GPPS ↑ERG20-GGPPS | 380 mg/L (bioreactor) | Czajka et al., 2018 | |
| α-santalene | Glucose | ATCC 201249 | ↑ClSTS ↑ERG8 ↑HMG | 27.92 mg/L (bioreactor) | Jia et al., 2019 |
| Nootkatone valencene | Glucose | ATCC 201249 | ↑CnVS ↑CnCYP706M1-AtATR1 ↑tHMG ↑ERG20 | Nootkatone: 978.2 μg/L Valencene: 22.8 mg/L (shake flask) | Guo et al., 2018 |
| Valencene | Glucose | ATCC 20460 | ↑HMG1 ↑ERG12 ↑ACL1 ↑SeACS ↑IDI ↑ERG20 ↓SQS ↑CnVS | 113.9 mg/L (glass tube) | This study |
| Amorphadiene | Glucose | Po1g | ↑AaADS ↑HMG1 ↑ERG12 | 171.5 mg/L (shake flask) | Marsafari and Xu, 2020 |
| Triterpenoids | |||||
| Campesterol | Sunflower seed oil | ATCC 201249 | ΔERG5 ↑XlDHCR7 | 453 mg/L (bioreactor) | Du et al., 2016 |
| Sunflower seed oil | ATCC 201249 | ΔERG5 ↑DrDHCR7 ↑POX2 | 942 mg/L (bioreactor) | Zhang et al., 2017b | |
| Ginsenoside K | Glucose | ATCC 201249 | ↑tHMG ↑ERG20 ↑SQS ↑PgDS ↑PgPPDS ↑AtATR1 ↑PgUGT1 | 161.8 mg/L (bioreactor) | Li et al., 2019 |
| Oleanolic Acid | Glucose | ATCC 201249 | ↑tHMG ↑ERG20 ↑SQS ↑GgBAS ↑MtCYP716A12-L-AtATR1 | 540.7 mg/L (bioreactor) | Li et al., 2020 |
| Betulinic acid | Glycerol | ATCC 201249 | ↑tHMG1 ↑SQS ↑AtLUP1 ↑MtCYP716A12 ↑AtATR1 | 26.53 mg/L (shake flask) | Sun et al., 2019 |
| Glucose | ATCC 201249 | ↑RcLUS ↑BPLO ↑LjCPR ↑SQS ↑SQE ↑HMG1 ↑MFE1 | 204.89 mg/L (shake flask) | Jin et al., 2019 | |
| Squalene | Glucose Citrate | Po1f | ↑HMG1 ↑ACL1 ↑SeACS | 10 mg/gDCW (shake flask) | Huang et al., 2018 |
| Glucose | ATCC MYA2613 | ↑carB ↑carRP ↑ERG8,10,12,13,19,20 ↑tHMG ↑IDI Δgut2 Δpox3,4,5,6 | 531.6 mg/L | Gao et al., 2017 | |
| Glucose | ATCC 20460 | ↑HMG1 ↑ERG12 ↓ERG7 ↑ACL1 ↑SeACS ↑IDI ↑ERG20 ↑SQS | 402.4 mg/L (deepwell plate) | This study | |
| 2,3-oxidosqualene | Glucose | ATCC 20460 | ↑HMG1 ↑ERG12 ↓ERG7 ↑ACL1 ↑SeACS ↑IDI ↑ERG20 ↑SQS ↑SQE | 22 mg/L (deepwell plate) | This study |
| Protopanaxadiol | Xylose | ATCC 201249 | ↑SsXYL1 ↑SsXYL2 ↑XKS ↑PgDS ↑PgPPDS-L-AtATR1 ↑tHMG ↑ERG20 ↑SQS ↑TKL ↑TAL ↑TXΔpox1,2,3 | 300.63 mg/L (bioreactor) | Wu et al., 2019 |
| Carotenoids | |||||
| Lycopene | Glucose | H222 | ↑PaCrtB ↑PaCrtI ↑GGPPS ↑HMG1 Δpox1–6 Δgut2 | 16 mg/gDCW (bioreactor) | Matthäus et al., 2014 |
| Glucose | Po1f | ↑HMG ↑PaCrtE ↑PaCrtB ↑PaCrtI ↑ERG19 | 21.1 mg/gDCW (bioreactor) | Schwartz et al., 2017 | |
| β-Carotene | Glucose | ATCC MYA2613 | ↑carB ↑carRP ↑ERG8,10,12, 13,19,20 ↑GGPPS ↑tHMG ↑IDI Δpox3,4,5,6 | 4 g/L (bioreactor) | Gao et al., 2017 |
| Glucose | Po1f | ↑carB ↑carRP ↑GGPPS ↑HMG ↑ERG13 Δpox2,3 | 4.5 g/L (bioreactor) | Zhang et al., 2020 | |
| Glucose | ATCC 20460 | ↑carB ↑carRP ↑HMG ↑GGPPS ↑DGA2 ↑GPD1Δpox1–6 Δtgl4 | 6.5 g/L (bioreactor) | Larroude et al., 2018 | |
| Glucose | ATCC 20460 | ↑HMG1 ↑ERG12 ↑ACL1 ↑SeACS ↑IDI ↑GGPPS↓SQS ↑XdcrtYB ↑XdcrtI | 164 mg/L (deepwell plate) | This study | |
| Astaxanthin | Glucose | GB20 | ↑XdcrtYB ↑XdcrtI ↑HMG ↓SQS ↑XdcrtE ↑PscrtW ↑PacrtZ | 54.6 mg/L (microtiter plate) | Kildegaard et al., 2017 |
| Glucose | GB20 | ↑XdcrtYB ↑XdcrtI ↑HMG (↑SQS ↑XdcrtE ↑SsGGPPS ↑HpBKT ↑HpCrtZ | 285 mg/L (bioreactor) | Tramontin et al., 2019 |
Genes modified in this study are bolded in the table. AaADS, Artemisia annua amorphadiene synthase; AaBFS, A. annua β-farnesene synthase; AaLIS, Actinidia arguta linalool synthase; ACL1, ATP citrate lyase 1; ArtLS, Agastache rugosa limonene synthase; AtATR1, Arabidopsis thaliana NADPH-cytochrome P450 reductase 1; AtLUP1, A. thaliana lupeol synthase; BbPK, Bifidobacterium bifidum phosphoketolase; BdHMG, Bordetella petrii HMG; BpLO, Betula platyphylla lupeol C-28 oxidase; BsPTA, Bacillus subtilis phosphotransacetylase; carB, Mucor circinelloides phytoene dehydrogenase; carRP, M. circinelloides phytoene synthase/lycopene cyclase; CnCYP706M1-AtATR1, fusion of Callitropsis nootkatensis cytochrome P450 and AtATR1; CnVS, C. nootkatensis valencene synthase; ClLS, Citrus limon d-limonene synthase; ClSTS, Clausena lansium α-santalene synthase; DGA2, diacylglycerol acyltransferase 2; DrDHCR1, Danio rerio 7-dehydrocholesterol reductase; ERG5, C22-sterol desaturase; ERG7, lanosterol synthase; ERG8, phosphomevalonate kinase gene; ERG10, acetyl-CoA C-acetyltransferase; ERG12, mevalonate kinase; ERG13, Hydroxymethylglutaryl-CoA synthase; ERG19, mevalonate diphosphate decarboxylase encoding gene; ERG20, farnesyl diphosphate synthase; ERG20F88W–N119W, geranyl diphosphate synthase; ERG20-GGPPS, fusion of ERG20 and GGPPS, geranylgeranyl diphosphate synthase; GgBAS, Glycyrrhiza glabra β-amyrin synthase; GPD, glyceraldehyde-3-phosphate dehydrogenase; GPPS, geranyl diphosphate synthase; HMG, Hydroxymethylglutaryl-CoA reductase; HpBKT, Haematococcus pluvialis β-carotene ketolase; HpIPI, Haematococcus pluvialis isopentyl diphosphate isomerase; HpCrtZ, H. pluvialis β-carotene hydroxylase; IDI, isopentyl diphosphate isomerase; LjCPR, Lotus japonicus cytochrome P450 reductase; MdFS-L-ERG20, Malus domestica α-farnesene synthase linked to ERG20; MFE1, multifunctional β-oxidation enzyme 1; MsLS, Mentha spicata l-limonene synthase; MtCYP716A12-L-AtATR1, Medicago truncatula cytochrome P450 fused to AtATR1; OfCCD1, Osmanthus fragrans carotenoid cleavage dioxygenase 1; PaCrtB, Pantoea ananatis phytoene synthase; PaCrtE, P. ananatis geranylgeranyl diphosphate syntase; PaCrtI, P. ananatis phytoene desaturase; PacrtZ, P. ananatis β-carotene hydroxylase; PfLS, P. frutescens limonene synthase; PgDS, Panax ginseng dammarenediol II synthase; PgPPDS, P. ginseng cytochrome P450 enzyme; PgPPDS-L-AtATR1, PgPPDS linked to AtATR1; PgUGT1, P. ginseng UDP-glycosyltransferase; PhCCD1, Petunia hybrida carotenoid cleavage dioxygenase; POX, peroxisome acyl-CoA oxidase; PscrtW, Paracoccus sp. N81106 β-carotene ketolase; RcLUS, Ricinus communis lupeol synthase; SctHMG, Saccharomyces cerevisiae truncated HMG, SeACS, S. enterica Acetyl-CoA synthetase; SQE, squalene epoxidase; SQS, squalene synthase; SlNDPS1, Solanum lycopersicum neryl diphosphate synthase 1; SsGGPPS, Synechococcus sp. GGPPS; SsNphT7, Streptomyces sp. Acetoacetyl CoA synthase; SsXYL1, Scheffersomyces stipitis xylose reductase XR; SsXYL2, S. stipitis xylose reductase XDH; TAL, transaldolase; TGL, triacylglycerol lipase; TKL, transketolase; TX, xylose transporter; XdcrtE, X. dendrorhous geranylgeranyl diphosphate synthase; XdcrtI, X. dendrorhous phytoene desaturase; XdcrtYB, Xanthophyllomyces dendrorhous bi-functional phytoene synthase/lycopene cyclase; XKS, xylulose kinase; XlDHCR7, Xenopus laevis 7-dehydrocholesterol reductase.