Abstract
Recently, several studies have indicated that an adequate intake of menaquinone-7 (MK-7) offers numerous health benefits. However, the low availability of MK-7 in the diet necessitates the development of dietary supplements or functional food products to complement natural food sources and meet the daily intake requirements. Like most biological molecules, MK-7 can exist as geometric isomers that can occur in the cis, trans, and cis/trans forms; however, only the all-trans form is biologically significant. MK-7 is traditionally produced through bacterial fermentation, but various synthetic preparations have lately become available. The isomer composition in the final product is influenced by numerous factors, including the methods of production and purification, as well as particular environmental and storage conditions. The MK-7 profile obtained from the various production methods has not yet been elucidated, and the ideal method for the synthesis of the all-trans form of the vitamin is also debatable. Consequently, the quantification of the MK-7 profile of various products is necessary to develop an understanding of the factors that influence the proportion of isomers that are obtained in different preparations. Several possible methods exist for the quantification of MK-7 isomers, and of these, liquid chromatography in conjunction with mass spectrometry techniques appears to be the most promising. Evaluation of the isomer composition is an important consideration, as only the all-trans form sustains biological activity. Furthermore, knowledge of the prominent factors that influence the MK-7 composition may also enable their manipulation to obtain a more favorable MK-7 profile in the final product.
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References
Baj A, Walejko P, Kutner A, Kaczmarek L, Morzycki JW, Witkowski S (2016) Convergent Synthesis of Menaquinone-7 (MK-7). Org Process Res Dev 20:1026–1033. https://doi.org/10.1021/acs.oprd.6b00037
Basset G, Latimer S, Fatihi A, Soubeyrand E, Block A (2017) Phylloquinone (vitamin K1): occurrence, biosynthesis and functions. Mini-Rev Med Chem 17(12):1028–1038
Berenjian A, Chan NL-C, Mahanama R, Talbot A, Regtop H, Kavanagh J, Dehghani F (2012a) Effect of biofilm formation by Bacillus subtilis natto on menaquinone-7 biosynthesis. Mol Biotechnol 54(2):371–378
Berenjian A, Mahanama R, Kavanagh J, Dehghani F (2015) Vitamin K series: current status and future prospects. Crit Rev Biotechnol 35(2):199–208
Berenjian A, Mahanama R, Talbot A, Biffin R, Regtop H, Valtchev P, Kavanagh J, Dehghani F (2011) Efficient media for high menaquinone-7 production: response surface methodology approach. New Biotechnol 28(6):665–672
Berenjian A, Mahanama R, Talbot A, Regtop H, Kavanagh J, Dehghani F (2012b) Advances in menaquinone-7 production by Bacillus subtilis natto: fed-batch glycerol addition. Am J Biochem Biotechnol 8(2):105–110
Berenjian A, Mahanama R, Talbot A, Regtop H, Kavanagh J, Dehghani F (2013) Designing of an intensification process for biosynthesis and recovery of menaquinone-7. Appl Biochem Biotechnol 172(3):1347–1357
Beulens J, Booth S, van Den Heuvel E, Stoecklin E, Baka A, Vermeer C (2013) The role of menaquinones (vitamin K2) in human health. Br J Nutr 110(8):1357–1368. https://doi.org/10.1017/S0007114513001013
Booth SL (2012) Vitamin K: food composition and dietary intakes. Food Nutr Res 56
CanPrev (2019) What form of vitamin K2 should I take? https://www.vitamink2.ca/best-form-of-vitamink2#mk7-same. Accessed 8 August 2019
Cook KK, Mitchell GV, Grundel E, Rader JI (1999) HPLC analysis for trans-vitamin K1 and dihydro-vitamin K1 in margarines and margarine-like products using the C30 stationary phase. Food Chem 67(1):79–88. https://doi.org/10.1016/S0308-8146(99)00090-4
Daines AM, Payne RJ, Humphries ME, Abell AD (2003) The synthesis of naturally occurring vitamin K and vitamin K analogues. Curr Org Chem 7(16):1625–1634
Ducros V, Pollicand M, Laporte F, Favier A (2010) Quantitative determination of plasma vitamin K1 by high-performance liquid chromatography coupled to isotope dilution tandem mass spectrometry. Anal Biochem 401(1):7–14. https://doi.org/10.1016/j.ab.2010.02.018
European Food Safety Authority (2008) Vitamin K2 added for nutritional purposes in foods for particular nutritional uses, food supplements and foods intended for the general population and Vitamin K2 as a source of vitamin K added for nutritional purposes to foodstuffs, in the context of Regulation (EC) N° 258/97-Scientific Opinion of the Panel on Dietetic Products, Nutrition and Allergies. EFSA J 6(11):822
Fu X, Peterson JW, Hdeib M, Booth SL, Grusak MA, Lichtenstein AH, Dolnikowski GG (2009) Measurement of Deuterium-Labeled Phylloquinone in Plasma by High-Performance Liquid Chromatography/Mass Spectrometry. Anal Chem 81:5421–5425. https://doi.org/10.1021/ac900732w
Gentili A, Caretti F (2011) Evaluation of a method based on liquid chromatography–diode array detector–tandem mass spectrometry for a rapid and comprehensive characterization of the fat-soluble vitamin and carotenoid profile of selected plant foods. J Chromatogr A 1218(5):684–697. https://doi.org/10.1016/j.chroma.2010.12.001
Huang B, Zheng F, Fu S, Yao J, Tao B, Ren Y (2012) UPLC-ESI-MS/MS for determining trans- and cis-vitamin K-1 in infant formulas: method and applications. Eur Food Res Technol 235:873–879. https://doi.org/10.1007/s00217-012-1823-7
Jäpelt RB, Jakobsen J (2016) Analysis of vitamin K1 in fruits and vegetables using accelerated solvent extraction and liquid chromatography tandem mass spectrometry with atmospheric pressure chemical ionization. Food Chem 192:402–408. https://doi.org/10.1016/j.foodchem.2015.06.111
Kappa Bioscience (2019a) All-trans means all-bioactive. https://www.kappabio.com/papers/cistrans/. Accessed 8 August 2019
Kappa Bioscience (2019b) The different vitamins in the K family. https://www.kappabio.com/brochures/different-forms-of-k/. Accessed 4 September 2019
Karl JP, Fu X, Dolnikowski GG, Saltzman E, Booth SL (2014) Quantification of phylloquinone and menaquinones in feces, serum, and food by high-performance liquid chromatography–mass spectrometry. J Chromatogr B 963:128–133. https://doi.org/10.1016/j.jchromb.2014.05.056
Kishikawa N, Kuroda N (2014) Analytical techniques for the determination of biologically active quinones in biological and environmental samples. J Pharm Biomed Anal 87:261–270. https://doi.org/10.1016/j.jpba.2013.05.035
Knauer TE, Siegfried C, Willingham AK, Matschiner JT (1975) Metabolism and biological activity of cis-and trans-phylloquinone in the rat. J Nutr 105(12):1519–1524
Koivu TJ, Piironen VI, Henttonen SK, Mattila PH (1997) Determination of Phylloquinone in Vegetables, Fruits, and Berries by High-Performance Liquid Chromatography with Electrochemical Detection. J Agric Food Chem 45(12):4644–4649. https://doi.org/10.1021/jf970357v
Koivu-Tikkanen T (2001) Determination of phylloquinone and menaquinones in foods by HPLC. Dissertation, University of Helsinki
Koivu-Tikkanen TJ, Ollilainen V, Piironen VI (2000) Determination of phylloquinone and menaquinones in animal products with fluorescence detection after postcolumn reduction with metallic zinc. J Agric Food Chem 48:6325–6331
Kurilich AC, Britz SJ, Clevidence BA, Novotny JA (2003) Isotopic labeling and LC-APCI-MS quantification for investigating absorption of carotenoids and phylloquinone from kale (Brassica oleracea). J Agric Food Chem 51(17):4877–4883
Lal N, Seifan M, Novin D, Berenjian A (2019) Development of a Menaquinone-7 enriched product through the solid-state fermentation of Bacillus licheniformis. Biocatal Agric Biotechnol 19:101172. https://doi.org/10.1016/j.bcab.2019.101172
Lowenthal J, Rivera GV (1979) Comparison of the activity of the cis and trans isomer of vitamin K1 in vitamin K-deficient and coumarin anticoagulant-pretreated rats. J Pharmacol Exp Ther 209(3):330–333
Mahanama R, Berenjian A, Dehghani F, Kavanagh J (2012a) Modeling the effect of bed height and particle size for vitamin K2 production in a static bed fermenter. Eng Lett 20(1):16
Mahanama R, Berenjian A, Dehghani F, Kavanagh JM (2011a) Solid-substrate fermentation of menaquinone 7 with Bacillus subtilis: Comparison of continuous rotation with stationary bed fermentation at different initial moisture levels. Paper presented at the Chemeca: Engineering a Better World, Sydney Hilton Hotel, NSW, Australia.
Mahanama R, Berenjian A, Regtop H, Talbot A, Dehghani F, Kavanagh JM (2012b) Modeling Menaquinone 7 production in tray type solid state fermenter. ANZIAM J 53:354–372
Mahanama R, Berenjian A, Talbot A, Biffin R, Regtop H, Dehghani F, Kavanagh J (2011b) Effects of inoculation loading and substrate bed thickness on the production of menaquinone 7 via solid state fermentation. Cardiovasc Disord 2(2):19–22
Mahanma R, Berenjian A, Valtchev P, Talbot A, Biffin R, Regtop H, Dehghani F, Kavanagh JM (2011) Enhanced production of menaquinone 7 via solid substrate fermentation from Bacillus subtilis. Int J Food Eng 7(5). https://doi.org/10.2202/1556-3758.2314
Mahdinia E, Demirci A, Berenjian A (2017a) Production and application of menaquinone-7 (vitamin K2): a new perspective. World J Microbiol Biotechnol 33(1):1–7. https://doi.org/10.1007/s11274-016-2169-2
Mahdinia E, Demirci A, Berenjian A (2017b) Strain and plastic composite support (PCS) selection for vitamin K (Menaquinone-7) production in biofilm reactors. Bioprocess Biosyst Eng 40(10):1507–1517. https://doi.org/10.1007/s00449-017-1807-x
Mahdinia E, Demirci A, Berenjian A (2018a) Enhanced Vitamin K (Menaquinone-7) Production by Bacillus subtilis natto in Biofilm Reactors by Optimization of Glucose-based Medium. Curr Pharm Biotechnol 19(11):917–924
Mahdinia E, Demirci A, Berenjian A (2018b) Implementation of fed-batch strategies for vitamin K (menaquinone-7) production by Bacillus subtilis natto in biofilm reactors. Appl Microbiol Biotechnol 102(21):9147–9157. https://doi.org/10.1007/s00253-018-9340-7
Mahdinia E, Demirci A, Berenjian A (2018c) Optimization of Bacillus subtilis natto growth parameters in glycerol-based medium for vitamin K (Menaquinone-7) production in biofilm reactors. Bioprocess Biosyst Eng 41(2):195–204. https://doi.org/10.1007/s00449-017-1857-0
Mahdinia E, Demirci A, Berenjian A (2018d) Utilization of glucose-based medium and optimization of Bacillus subtilis natto growth parameters for vitamin K (menaquinone-7) production in biofilm reactors. Biocatal Agric Biotechnol 13:219–224. https://doi.org/10.1016/j.bcab.2017.12.009
Mahdinia E, Demirci A, Berenjian A (2019a) Biofilm reactors as a promising method for vitamin K (menaquinone-7) production. Appl Microbiol Biotechnol 103(14):5583–5592. https://doi.org/10.1007/s00253-019-09913-w
Mahdinia E, Demirci A, Berenjian A (2019b) Effects of medium components in a glycerol-based medium on vitamin K (menaquinone-7) production by Bacillus subtilis natto in biofilm reactors. Bioprocess Biosyst Eng 42(2):223–232. https://doi.org/10.1007/s00449-018-2027-8
Mahdinia E, Demirci A, Berenjian A (2019c) Evaluation of vitamin K (menaquinone-7) stability and secretion in glucose and glycerol-based media by Bacillus subtilis natto. Acta Aliment 48(4):405–414
Mahdinia E, Mamouri SJ, Puri VM, Demirci A, Berenjian A (2019d) Modeling of vitamin K (Menaquinoe-7) fermentation by Bacillus subtilis natto in biofilm reactors. Biocatal Agric Biotechnol 17:196–202. https://doi.org/10.1016/j.bcab.2018.11.022
Nacalai Tesque HPLC for Structural Isomers COSMOSIL CHOLESTER (n.d.). https://www.nacalai.co.jp/global/download/pdf/COSMOSIL_Cholester.pdf. Accessed 15 August 2019
Nannapaneni NK, Jalalpure SS, Muppavarapu R, Sirigiri SK (2017) A sensitive and rapid UFLC-APCI-MS/MS bioanalytical method for quantification of endogenous and exogenous Vitamin K1 isomers in human plasma: Development, validation and first application to a pharmacokinetic study. Talanta 164:233–243. https://doi.org/10.1016/j.talanta.2016.11.056
NattoPharma MenaQ7 varieties (n.d.). http://menaq7.com/why-menaq7/varieties/. Accessed 5 August 2019
NUTRA (2018) Focus on the active all-trans menaquinone MK7 in vitamin K2. https://www.nutraingredients-usa.com/News/Promotional-Features/Vitamin-K2-as-MK7-and-the-link-between-nature-and-all-trans-content. Accessed 8 August 2019
Paroni R, Faioni EM, Razzari C, Fontana G, Cattaneo M (2009) Determination of vitamin K1 in plasma by solid phase extraction and HPLC with fluorescence detection. J Chromatogr B: Anal Technol Biomed Life Sci 877(3):351–354. https://doi.org/10.1016/j.jchromb.2008.12.044
Patti A, Gennari L, Merlotti D, Dotta F, Nuti R (2013) Endocrine actions of osteocalcin. Int J Endocrinol 2013
Piironen V, Koivu T, Tammisalo O, Mattila P (1997) Determination of phylloquinone in oils, margarines and butter by high performance liquid chromatography with electrochemical detection. Food Chem 59(3):473–480. https://doi.org/10.1016/S0308-8146(96)00288-9
Pucaj K, Rasmussen H, Møller M, Preston T (2011) Safety and toxicological evaluation of a synthetic vitamin K2, menaquinone-7. Toxicol Mech Methods 21(7):520–532
Puri A, Iqubal M, Zafar R, Panda BP (2015) Influence of physical, chemical and inducer treatments on menaquinone-7 biosynthesis by Bacillus subtilis MTCC 2756. Songklanakarin J Sci Technol 37(3):283–289
Ravishankar B, Dound YA, Mehta DS, Ashok BK, de Souza A, Pan M-H, Ho C-T, Badmaev V, Vaidya ADB (2015) Safety assessment of menaquinone-7 for use in human nutrition. J Food Drug Anal 23(1):99–108. https://doi.org/10.1016/j.jfda.2014.03.001
Ren L, Peng C, Hu X, Han Y, Huang H (2019) Microbial production of vitamin K2: current status and future prospects. Biotechnol Adv 107453
Sato K, Inoue S, Saito K (1973) A new synthesis of vitamin K via π-allyinickel intermediates. J Chem Soc 2289
Scheiber D, Veulemans V, Horn P, Chatrou M, Potthoff S, Kelm M, Schurgers L, Westenfeld R (2015) High-Dose Menaquinone-7 Supplementation Reduces Cardiovascular Calcification in a Murine Model of Extraosseous Calcification. Nutrients 7(8):6991–7011. https://doi.org/10.3390/nu7085318
Shearer MJ, Newman P (2008) Metabolism and cell biology of vitamin K. Thromb Haemostasis 100(10):530–547
Singh R, Puri A, Panda B (2015) Development of menaquinone-7 enriched nutraceutical: inside into medium engineering and process modeling. J Food Sci Technol 52(8):5212–5219. https://doi.org/10.1007/s13197-014-1600-7
Sitkowski J, Bocian W, Szterk A (2018) The application of multidimensional NMR analysis to cis/trans isomers study of menaquinone-7 (vitamine K2MK-7), identification of the (E,Z3,E2,ω)-menaquinone-7 isomer in dietary supplements. J Mol Struct 1171:449–457. https://doi.org/10.1016/j.molstruc.2018.06.029
Snyder CD, Rapoport H (1974) Synthesis of Menaquinones. J Am Chem Soc 96(26):8046–8054. https://doi.org/10.1021/ja00833a035
Song J, Liu H, Wang L, Dai J, Liu Y, Liu H, Zhao G, Wang P, Zheng ZJ (2014) Enhanced Production of Vitamin K2 from Bacillus subtilis (natto) by Mutation and Optimization of the Fermentation Medium. Braz Arch Biol Technol 57(4):606–612
Song Q, Wen A, Ding L, Dai L, Yang L, Qi X (2008) HPLC-APCI-MS for the determination of vitamin K(1) in human plasma: method and clinical application. J Chromatogr B: Anal Technol Biomed Life Sci 875(2):541–545. https://doi.org/10.1016/j.jchromb.2008.10.009
Southee R, Haroon S, Ebrahiminezad A, Ghasemi Y, Berenjian A (2016) Novel functional fermented dairy product rich in menaquinone-7. Biocatal Agric Biotechnol 7:31–35
Suhara Y, Kamao M, Tsugawa N, Okano T (2005) Method for the determination of vitamin K homologues in human plasma using high-performance liquid chromatography-tandem mass spectrometry. Anal Chem 77:757–763. https://doi.org/10.1021/ac0489667
Szterk A, Bus K, Zmysłowski A, Ofiara K (2018a) Analysis of Menaquinone-7 Content and Impurities in Oil and Non-Oil Dietary Supplements. Molecules 23(5):1056. https://doi.org/10.3390/molecules23051056
Szterk A, Zmysłowski A, Bus K (2018b) Identification of cis/trans isomers of menaquinone-7 in food as exemplified by dietary supplements. Food Chem 243:403–409. https://doi.org/10.1016/j.foodchem.2017.10.001
Tarvainen M, Fabritius M, Yang B (2019) Determination of vitamin K composition of fermented food. Food Chem 275:515–522. https://doi.org/10.1016/j.foodchem.2018.09.136
Thermo Scientific (2012) Acclaim C30 Columns Product Manual. http://unitylabservices.info/content/dam/tfs/ATG/CMD/CMD%20Documents/Product%20Manuals%20&%20Specifications/Chromatography%20Columns%20and%20Supplies/HPLC%20Columns/HPLC%20Columns%20(3um)/110364-Man-065416-02-Acclaim-C30-Feb12.pdf. Accessed 15 August 2019
Vermeer C, Raes J, Knapen M, Xanthoulea S (2018) Menaquinone Content of Cheese. Nutrients 10(4):446. https://doi.org/10.3390/nu10040446
Viñas P, Bravo-Bravo M, López-García I, Hernández-Córdoba M (2013) Dispersive liquid-liquid microextraction for the determination of vitamins D and K in foods by liquid chromatography with diode-array and atmospheric pressure chemical ionization-mass spectrometry detection. Talanta 115:806–813. https://doi.org/10.1016/j.talanta.2013.06.050
Vyňuchalová K, Jandera P (2015) Comparison of a C30 bonded silica column and columns with shorter bonded ligands in reversed-phase LC. Chromatographia 78(13):861–871. https://doi.org/10.1007/s10337-015-2899-6
Walther B, Karl PJ, Booth SL, Boyaval P (2013) Menaquinones, Bacteria, and the Food Supply: The Relevance of Dairy and Fermented Food Products to Vitamin K Requirements. Adv Nutr 4:463. https://doi.org/10.3945/an.113.003855
Wang LY, Bates CJ, Yan L, Prentice A, Harrington DJ, Shearer MJ (2004) Determination of phylloquinone (vitamin K1) in plasma and serum by HPLC with fluorescence detection. Clin Chim Acta 347(1-2):199–207. https://doi.org/10.1016/j.cccn.2004.04.030
Waters (2019) HPLC Separation Modes. https://www.waters.com/waters/en_US/HPLC-Separation-Modes/nav.htm?locale=en_US&cid=10049076. Accessed 15 August 2019
Woollard DC, Indyk HE, Fong BY, Cook KK (2002) Determination of vitamin K1 isomers in foods by liquid chromatography with C30 bonded-phase column. J AOAC Int 85(3):682–691
Xiao P, Li H-M, Li M, Song D-W, Li X-M, Dai X-H, Hu Z-S (2015) Structural characterization and thermally induced isomerization investigation of cis- and trans-vitamin K1 using ion mobility mass spectrometry. Anal Methods 7(19):8432
Yamada Y, Aoki K, Tahara Y (1982) The structure of the hexahydrogenated isoprenoid side-chain menaquinone with nine isoprene units isolated from Actinomadura madurae. J Gen Appl Microbiol 28(4):321–329. https://doi.org/10.2323/jgam.28.321
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Lal, N., Berenjian, A. Cis and trans isomers of the vitamin menaquinone-7: which one is biologically significant?. Appl Microbiol Biotechnol 104, 2765–2776 (2020). https://doi.org/10.1007/s00253-020-10409-1
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DOI: https://doi.org/10.1007/s00253-020-10409-1