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Review
. 2022 Mar 3;10(3):554.
doi: 10.3390/microorganisms10030554.

Production of Vitamin K by Wild-Type and Engineered Microorganisms

Min-Ji Kang  1 , Kwang-Rim Baek  1 , Ye-Rim Lee  1 , Geun-Hyung Kim  1 , Seung-Oh Seo  1
Affiliations
Review

Production of Vitamin K by Wild-Type and Engineered Microorganisms

Min-Ji Kang et al. Microorganisms. .

Abstract

Vitamin K is a fat-soluble vitamin that mainly exists as phylloquinone or menaquinone in nature. Vitamin K plays an important role in blood clotting and bone health in humans. For use as a nutraceutical, vitamin K is produced by natural extraction, chemical synthesis, and microbial fermentation. Natural extraction and chemical synthesis methods for vitamin K production have limitations, such as low yield of products and environmental concerns. Microbial fermentation is a more sustainable process for industrial production of natural vitamin K than two other methods. Recent advanced genetic technology facilitates industrial production of vitamin K by increasing the yield and productivity of microbial host strains. This review covers (i) general information about vitamin K and microbial host, (ii) current titers of vitamin K produced by wild-type microorganisms, and (iii) vitamin K production by engineered microorganisms, including the details of strain engineering strategies. Finally, current limitations and future directions for microbial production of vitamin K are also discussed.

Keywords: fermentation; metabolic engineering; microorganisms; production; vitamin K.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Vitamin K production using microorganisms. (A) Chemical structures of vitamin K and its biological functions, and (B) Methods of vitamin K production including natural extraction, chemical synthesis, and fermentation.
Figure 2
Figure 2
Biosynthetic pathway of menaquinone in Bacillus subtilis and Lactococcus lactis covered in this review. Metabolic pathways engineered in microorganisms for production of vitamin K were displayed. The prenyl chain structures are synthesized by the MEP pathway in B. subtilis and by the MVA pathway in L. lactis subsp. cremoris. The naphthoquinone ring structure is synthesized by the shikimate pathway and connected to side chains by the menaquinone pathway. The brown square with a dotted line refers to the pathway of menaquinone-7 synthesizing in B. subtilis. The blue square with a dotted line refers to the pathway of menaquinones synthesizing in L. lactis subsp. cremoris. The enzymes in bold were overexpressed to increase vitamin K production in the previous studies. PYR, pyruvate; G3P, glycerol-3-phosphate; DXP, 1-deoxyxylulose-5-phosphate; MEP, methyl-erythritol-4-diphosphate; CDP-ME, 4-(cytidine 5′-diphospho)-2-C-methylerythritol; CDP-MEP, 2-phospho-4-(cytidine 5′-diphospho)-2-C-methylerythritol; MECPP, HMBPP,2-C-Methylerythritol 2,4-cyclodiphosphate; HMBPP,1-hydroxy-2-methyl-2-butenyl 4-diphosphate; DMAPP, dimethylallyl diphosphate; IPP, isopentenyl diphosphate; GPP, geranyl diphosphate; FPP, farnesyl diphosphate; HPP, heptaprenyl diphosphate; PPP, polyprenyl diphosphate; PEP, phosphoenolpyruvate; E4P, erythrose-4-phosphate; IsoCHA, isochorismate; SHCHC, 2-succinyl-6-hydroxy-2,4-cyclohexadiene-1-carboxylate; DHNA, 1,4-dihydroxy-2-naphthoate; DMK, 2-demethylmeaquinone; MK-n, menaquinone-n; MVA, Mevalonate; M5P, Mevalonate 5-phosphate ;M5PP, 5-Diphosphomevalonate; [MEP pathway enzymes] DXS, 1-Deoxy-D-xylulose-5-phosphate synthase; DXR, 1-Deoxy-D-xylulose-5-phosphate reductoisomerase; IspD, 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase; IspE, 4-Diphosphocytidyl-2-C-methyl-D-erythritol kinase; IspF, 2-C-Methyl-D-erythritol 2,4-cyclodiphosphate synthase; IspG, 4-hydroxy-3-methylbut-2-en-1-yl diphosphate synthase; IspH, 4-Hydroxyl-3-methylbut-2-enyl diphosphate reductase; IspA, Farnesyl diphosphate synthase; HepS, Heptaprenyl diphosphatesynthase component; [Shikimate pathway enzymes (B. subtilis)] AroA, 3-Deoxy-7-phosphoheptulonate synthase; AroB, 3-Dehydroquinate synthase; AroC, 3-Dehydroquinate dehydratase; AroD, Shikimate dehydrogenase; AroK, Shikimate kinase; AroE, 3-Phosphoshikimate 1-carboxyvinyltransferase; AroF, Chorismate synthase; [Shikimate pathway enzymes (L. lactis)] AroH, Phospho-2-dehydro-3-deoxyheptonate aldolase; AroB, 3-Dehydroquinate synthase; AroD, 3-Dehydroquinate dehydratase; AroE, Shikimate dehydrogenase; AroK, Shikimate kinase; AroA, 3-Phosphoshikimate 1-carboxyvinyltransferase; AroC, Chorismate synthase; [Menaquinone pathway enzymes] MenF, isochorismate synthase; MenD, 2-Succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexene-1-carboxylate synthase; MenH, Demethylmenaquinone methyltransferase; MenC, O-Succinylbenzoate synthase; MenE, O-Succinylbenzoate-CoA ligase; MenB, 1,4-Dihydroxy-2-naphthoyl-CoA synthase; MenA, 1,4-Dihydroxy-2-naphthoate heptaprenyltransferase; MenG, Demethylmenaquinone methyltransferase; UbiE, Demethylmenaquinone methyltransferase; [Mevalonate pathway enzymes] ThiL, 3-Ketoacyl-CoA thiolase; HmcM, Hydroxymethylglutaryl-CoA synthase; MvaA, Hydroxymethylglutaryl-CoA reductase; Mvk, Mevalonate kinase; Pmk, Phosphomevalonate kinase; MvaD, Diphosphomevalonate decarboxylase; IspA, Geranyltranstransferase; Fni, Isopentenyl-diphosphate delta-isomerase; PreA, Prenyl diphosphate synthase.
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