If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
Locations of Mapped Genes:
Synonyms: vitamin K2 biosynthesis I, superpathway of menaquinone-8 biosynthesis I
|Superclasses:||Biosynthesis → Cofactors, Prosthetic Groups, Electron Carriers Biosynthesis → Quinol and Quinone Biosynthesis → Menaquinol Biosynthesis|
Pathway Summary from MetaCyc:
Menaquinones (MK) and demethylmenaquinones (DMK) are low-molecular weight lipophilic components of the cytoplasmic membrane, found in many bacterial species. These quinones function as a reversible redox component of the electron transfer chain, mediating electron transfer between hydrogenases and cytochromes. Menaquinones have also been implicated in regulation, as they are necessary for sporulation and proper regulation of cytochrome formation in some Gram-positive bacteria [Farrand73, Farrand74].
Most aerobic Gram-negative bacteria contain ubiquinone as the sole quinone, while most aerobic Gram-positive bacteria contain menaquinone and/or demethylmenaquinones as the main quinone. However, most of the anaerobic bacteria, regardless whether they are Gram-negative or Gram-positive, contain menaquinone or demethylmenaquinone as their main quinones. Some facultatively anaerobic bacteria, such as Escherichia coli, contain ubiquinone, menaquinone, and demethylmenaquinone, which they use under different growth conditions [Meganathan01a]. The main difference between these quinone molecules is their redox potential. For example, the redox potential for ubiquinone, demethylmenaquinone, and menaquinone has been measured as +112 mv, +36 mv, and -74 mv, respectively, in the bacterium Haemophilus parainfluenzae [Hollander76].
Menaquinones are considered a vitamin (vitamin K2), since they are essential for animals, mostly for the posttranslational modification of certain proteins required for blood coagulation. Animals can not synthesize menaquinones, but usually receive a sufficient amount from bacteria growing in their intestines. In the absence of menaquinone or the related compound phylloquinone (vitamin K1) which is synthesized in plants, animals suffer from hemorrhage [Dam35]. Menaquinone was first isolated from putrefied fish meal by McKee in 1939 [Doisy40], and its structure resolved in 1958 [Isler58].
The biosynthesis of menaquinones is essentially identical to that of demethylmenaquinones, with one additional step, comprising the addition of a methyl group to the naphthoquinone ring. Many bacterial species do not have this methylase and produce demethylmenaquinone as their sole quinone [Collins81].
All three quinones are synthesized from chorismate, an intermediate of aromatic amino acid biosynthesis. However, the pathways of (demethyl)menaquinone synthesis diverts from that for ubiquinones early on. Most organisms synthesize their menaquinones via isochorismate, although some organisms, including Helicobacter pylori, Campylobacter jejuni, Streptomyces coelicolor and Thermus thermophilus, synthesize menaquinones in alternative pathways, via futalosine or 6-amino-6-deoxyfutalosine [Hiratsuka08, Li11, Goble13].
Menaquinones are known to have side chains of different sizes in different organisms, and sometimes even within the same organism. The most common menaquinones contain 7, 8 and 9 isoprene units. However, menaquinones containing 4 [Hollander77, Cawthorne67], 5 [Cawthorne67, Dunphy71], 6 [Dunphy71, Shah80, Weber70, Maroc70], 10 [Shah80, Collins80], 11 [Shah80, Collins80], 12 [Shah80], and 13 [Shah80] isoprene units have been reported in bacteria.
About This Pathway
The best characterized menaquinone biosynthetic pathway is that of Escherichia coli K-12 that synthesizes menaquinone-8 (MK-8). MK-8 is not unique to E. coli, and is found in many different bacterial species.
A study of the quinones of halophilic archaebacteria found that MK-8 was the major quinone in most species included in the study, including Haloferax volcanii, Halococcus morrhuae, Halobacterium salinarum, Halorubrum saccharovorum and Halorubrum trapanicum [Mullakhanbhai72, Kushwaha74, Collins81a].
MK-8 is very common in facultatively anaerobic Gram negative bacteria, such as the enterobacteria. In addition to Escherichia coli K-12 it has been documented in Citrobacter freundii, Enterobacter aerogenes, Pectobacterium carotovorum, Proteus mirabilis, Proteus vulgaris [Whistance69] and Serratia marcescens [Bezborodov69], as well as the non-eneterobacteria Aeromonas hydrophila, Aeromonas caviae [Whistance69] and Salinivibrio costicola [Collins81a]. MK-8 has not been discovered in obligate anaerobes so far
Some aerobic Gram-negative bacteria that contain MK-8 as their major quinone include the gliding bacterium Myxococcus fulvus [Kleinig74], and several members of the Deinococcus-Thermus phylum, including Thermus aquaticus and Thermus thermophilus [Collins80, Collins81], Deinococcus radiophilus and Deinococcus radiodurans [Yamada77].
Even though most Gram-positive bacteria contain menaquinone-7 as their major quinone, a few are known to make MK-8 instead, including Virgibacillus pantothenticus [Hess79], Bacillus thuringiensis [Hess79], Lactobacillus mali [Collins80], Nesterenkonia halobia [Collins81a], certain Micrococcus luteus strains [Watanuki72, Yamada76], and Planococcus citreus [Yamada76].
Collins80: Collins MD, Shah HN, Minnikin DE (1980). "A note on the separation of natural mixtures of bacterial menaquinones using reverse phase thin-layer chromatography." J Appl Bacteriol 48(2);277-82. PMID: 7462123
Goble13: Goble AM, Toro R, Li X, Ornelas A, Fan H, Eswaramoorthy S, Patskovsky Y, Hillerich B, Seidel R, Sali A, Shoichet BK, Almo SC, Swaminathan S, Tanner ME, Raushel FM (2013). "Deamination of 6-aminodeoxyfutalosine in menaquinone biosynthesis by distantly related enzymes." Biochemistry 52(37);6525-36. PMID: 23972005
Hiratsuka08: Hiratsuka T, Furihata K, Ishikawa J, Yamashita H, Itoh N, Seto H, Dairi T (2008). "An alternative menaquinone biosynthetic pathway operating in microorganisms." Science 321(5896);1670-3. PMID: 18801996
Hollander77: Hollander R, Wolf G, Mannheim W (1977). "Lipoquinones of some bacteria and mycoplasmas, with considerations on their functional significance." Antonie Van Leeuwenhoek 43(2);177-85. PMID: 413478
Kleinig74: Kleinig H, Reichenbach H, Theobald N, Achenbach H (1974). "Flexibacter elegans and Myxococcus fulvus: aerobic Gram-negative bacteria containing menaquinones as the only isoprenoid quinones." Arch Microbiol 101(1);91-3. PMID: 4216336
Li11: Li X, Apel D, Gaynor EC, Tanner ME (2011). "5'-methylthioadenosine nucleosidase is implicated in playing a key role in a modified futalosine pathway for menaquinone biosynthesis in Campylobacter jejuni." J Biol Chem 286(22);19392-8. PMID: 21489995
Whistance69: Whistance GR, Dillon JF, Threlfall DR (1969). "The nature, intergeneric distribution and biosynthesis of isoprenoid quinones and phenols in gram-negative bacteria." Biochem J 111(4);461-72. PMID: 4886765
Yamada76: Yamada, Y., Inouye, G., Tahara, Y., Kondo, K. (1976). "The menaquinone system in the classification of aerobic gram-positive cocci in the genera Micrococcus, Staphylococcus, Planococcus and Sporosarcina." J. Gen. Appl. Microbiol. 22:227-236.
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Baba06: Baba T, Ara T, Hasegawa M, Takai Y, Okumura Y, Baba M, Datsenko KA, Tomita M, Wanner BL, Mori H (2006). "Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection." Mol Syst Biol 2;2006.0008. PMID: 16738554
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Bhattacharyya97: Bhattacharyya DK, Kwon O, Meganathan R (1997). "Vitamin K2 (menaquinone) biosynthesis in Escherichia coli: evidence for the presence of an essential histidine residue in o-succinylbenzoyl coenzyme A synthetase." J Bacteriol 1997;179(19);6061-5. PMID: 9324253
Buss01: Buss K, Muller R, Dahm C, Gaitatzis N, Skrzypczak-Pietraszek E, Lohmann S, Gassen M, Leistner E (2001). "Clustering of isochorismate synthase genes menF and entC and channeling of isochorismate in Escherichia coli." Biochim Biophys Acta 1522(3);151-7. PMID: 11779629
Butland05: Butland G, Peregrin-Alvarez JM, Li J, Yang W, Yang X, Canadien V, Starostine A, Richards D, Beattie B, Krogan N, Davey M, Parkinson J, Greenblatt J, Emili A (2005). "Interaction network containing conserved and essential protein complexes in Escherichia coli." Nature 433(7025);531-7. PMID: 15690043
Chang12a: Chang KM, Chen SH, Kuo CJ, Chang CK, Guo RT, Yang JM, Liang PH (2012). "Roles of amino acids in the Escherichia coli octaprenyl diphosphate synthase active site probed by structure-guided site-directed mutagenesis." Biochemistry 51(16);3412-9. PMID: 22471615
Chen11a: Chen M, Jiang M, Sun Y, Guo ZF, Guo Z (2011). "Stabilization of the second oxyanion intermediate by 1,4-dihydroxy-2-naphthoyl-coenzyme A synthase of the menaquinone pathway: spectroscopic evidence of the involvement of a conserved aspartic acid." Biochemistry 50(26);5893-904. PMID: 21627110
Chen13: Chen M, Ma X, Chen X, Jiang M, Song H, Guo Z (2013). "Identification of a Hotdog Fold Thioesterase Involved in the Biosynthesis of Menaquinone in Escherichia coli." J Bacteriol 195(12);2768-75. PMID: 23564174
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Cui10: Cui TZ, Kaino T, Kawamukai M (2010). "A subunit of decaprenyl diphosphate synthase stabilizes octaprenyl diphosphate synthase in Escherichia coli by forming a high-molecular weight complex." FEBS Lett 584(4);652-6. PMID: 20051244
Dahm98: Dahm C, Muller R, Schulte G, Schmidt K, Leistner E (1998). "The role of isochorismate hydroxymutase genes entC and menF in enterobactin and menaquinone biosynthesis in Escherichia coli." Biochim Biophys Acta 1425(2);377-86. PMID: 9795253
Daruwala96: Daruwala R, Kwon O, Meganathan R, Hudspeth ME (1996). "A new isochorismate synthase specifically involved in menaquinone (vitamin K2) biosynthesis encoded by the menF gene." FEMS Microbiol Lett 1996;140(2-3);159-63. PMID: 8764478
Daruwala97: Daruwala R, Bhattacharyya DK, Kwon O, Meganathan R (1997). "Menaquinone (vitamin K2) biosynthesis: overexpression, purification, and characterization of a new isochorismate synthase from Escherichia coli." J Bacteriol 1997;179(10);3133-8. PMID: 9150206
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