MetaCyc Pathway: superpathway of phylloquinol biosynthesis
Inferred from experiment

Pathway diagram: superpathway of phylloquinol biosynthesis

If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Synonyms: superpathway of phylloquinone biosynthesis

Superclasses: BiosynthesisCofactors, Prosthetic Groups, Electron Carriers BiosynthesisQuinol and Quinone BiosynthesisPhylloquinol Biosynthesis

Some taxa known to possess this pathway include : Arabidopsis thaliana col, Catharanthus roseus, Galium mollugo, Synechococcus elongatus, Synechococcus sp. PCC 7002, Synechocystis sp. PCC 6803

Expected Taxonomic Range: Cyanobacteria, Viridiplantae

General Background

Phylloquinone (vitamin K1, 2-methyl-3-phytyl-1,4-naphthoquinone) acts as the electron transfer cofactor A1 of photosystem I (PS I) in higher plants and cyanobacteria. In non-photosynthetic microbes the very similar compound a menaquinone plays an essential role in several anaerobic electron transport systems [Sharma96]. The chemical structure of menaquinone (vitamin K2) exhibits a partly unsaturated side chain consisting most often 7 prenyl units, whereas phylloquinone consists of a mostly saturated phytyl side chain of 4 units [Shimada05].

The biosynthesis of phylloquinone was studied in detail in the cyanobacterium Synechocystis sp. PCC 6803 and the genes encoding enzymes of this pathway were identified by comparison with genes encoding enzymes of the menaquinone biosynthetic pathway in Escherichia coli (see menaquinol-8 biosynthesis) [Sharma96]. With the isolation and functional confirmation of the homolog genes in Synechocystis encoding for 1,4-dihydroxy-2-naphthoate phytyltransferase, naphthoyl-CoA synthase [Johnson00], 2-phytyl-1,4-naphthoquinone methyltransferase [Sakuragi02], 2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexene-1-carboxylate synthase and O-succinylbenzoate synthase [Johnson03], most of the enzymatic steps of the phylloquinone bisoynthesis have been determined and proven to be highly identical with those in the menaquinone biosynthesis.

The biosynthesis of certain components of the multienzyme complex PS I (such as phylloquinone) in cyanobacteria and plants have been found to follow analogous routes, including corresponding enzymatic activities [Heide82] [Kolkmann87, Simantiras89, Simantiras91], reflecting the phylogenetic origin of PS I in photosynthetic microbes.

About This Pathway

The enzymatic steps involved in the biosynthesis of phylloquinone in cyanobacteria and plants are almost identical to the biosynthetic route leading to the microbial complement menaquinone. The discernible step between phylloquinone and menaquinone biosynthesis is the prenylation of 2-carboxy-1,4-naphthoquinol (DHNA). The DHNA phytyltransferase catalyzes the attachment of a C-20 phytyl side chain leading to demethylphylloquinone [Shimada05], whereas microbial DHNA prenyltransferases attache a multiprenyl side chain, forming demethylmenaquinones. The length of the side chain varies among different species.

It has been found that phylloquinone is not absolutely required for efficient electron transfer in PS I [Johnson00]. At least in Synechocystis sp. PCC 6803, benzoquinones such as plastoquinone-9, which usually act as secondary electron acceptors in PS II [Johnson01a, Sakuragi05], can efficiently replace phylloquinone in the A1-site of PS I as a one-electron cofactor. However, as shown in both Arabidopsis and Synechocystis sp. PCC 6803 mutants, the deficiency of phylloquinone causes distortions in the thylakoid structure of chloroplasts, decreases the content of PS I, and affects the functionality of PS II [Shimada05].

It has been demonstrated that the final step of the pathway, a transmethylation reaction to form phylloquinol, depends on the oxidation state of the penultimate substrate. This led to the discovery that one more reaction was inserted in between demethylphylloquinone and the final product phylloquinol. This reaction was catalyzed by type II NAD(P)H dehydrogenases in both Arabidopsis thaliana and the cyanobacterium Synechocystis sp. PCC 6803 encoded by NDC1 and ndbB, respectively, which resulted in the formation of the reduced demethylphylloquinol [Fatihi15]. Only this reduced (quinol) substrate was able to accept the electrons from the electrophilic S-adenosyl-L-methionine for the subsequent transmethylation step of the phylloquinol biosynthesis to yield phylloquinol [Fatihi15]. In general, the intermediates of the phylloquinol biosynthesis including in-feeding pathways such as 1,4-dihydroxy-2-naphthoate biosynthesis are depicted in their dihydroxy conformation, for example see 2-carboxy-1,4-naphthoquinol and 1,4-dihydroxy-2-naphthoyl-CoA, although the latter has been shown to be used in vitro in its diketo form [Widhalm09]. However, the study on the dehydrogenases of Arabidopsis and Synechocystis provide evidence that demethylphylloquinone and probably any other preceding intermediates occur in their diketo instead of the dihydroxy form [Basset15].

Subpathways: geranylgeranyl diphosphate biosynthesis, phytyl diphosphate biosynthesis, 1,4-dihydroxy-2-naphthoate biosynthesis, phylloquinol biosynthesis

Created 18-Mar-2008 by Caspi R, SRI International
Revised 04-Aug-2015 by Foerster H, Boyce Thompson Institute


Basset15: Basset GJ (2015). personal communication 2015.

Collins81: Collins MD, Jones D (1981). "Distribution of isoprenoid quinone structural types in bacteria and their taxonomic implication." Microbiol Rev 45(2);316-54. PMID: 7022156

Fatihi15: Fatihi A, Latimer S, Schmollinger S, Block A, Dussault PH, Vermaas WF, Merchant SS, Basset GJ (2015). "A Dedicated Type II NADPH Dehydrogenase Performs the Penultimate Step in the Biosynthesis of Vitamin K1 in Synechocystis and Arabidopsis." Plant Cell 27(6);1730-41. PMID: 26023160

Fujimoto12: Fujimoto N., Kosaka T., Yamada M. (2012). "Menaquinone as Well as Ubiquinone as a Crucial Component in the Escherichia coli Respiratory Chain." Chapter 10 in Chemical Biology, edited by D Ekinci, ISBN 978-953-51-0049-2.

Heide82: Heide L, Kolkmann R, Arendt S, Leistner E (1982). "Enzymic synthesis of o-succinylbenzoyl-CoA in cell-free extracts of anthraquinone producing Galium mollugo L. cell suspension cultures." Plant Cell Reports, 1, 180-182.

Johnson00: Johnson TW, Shen G, Zybailov B, Kolling D, Reategui R, Beauparlant S, Vassiliev IR, Bryant DA, Jones AD, Golbeck JH, Chitnis PR (2000). "Recruitment of a foreign quinone into the A(1) site of photosystem I. I. Genetic and physiological characterization of phylloquinone biosynthetic pathway mutants in Synechocystis sp. pcc 6803." J Biol Chem 275(12);8523-30. PMID: 10722690

Johnson01a: Johnson TW, Zybailov B, Jones AD, Bittl R, Zech S, Stehlik D, Golbeck JH, Chitnis PR (2001). "Recruitment of a foreign quinone into the A1 site of photosystem I. In vivo replacement of plastoquinone-9 by media-supplemented naphthoquinones in phylloquinone biosynthetic pathway mutants of Synechocystis sp. PCC 6803." J Biol Chem 276(43);39512-21. PMID: 11470786

Johnson03: Johnson TW, Naithani S, Steward Jr C, Zybailov B, Jones AD, Golbeck JH, Chitnis PR (2003). "The menD and menE homologs code for 2-succinyl-6-hydroxyl-2, 4-cyclohexadiene-1-carboxylate synthase and O-succinylbenzoic acid-CoA synthase in the phylloquinone biosynthetic pathway of Synechocystis sp. PCC 6803." Biochimica et Biophysica Acta, 1557, 67-76.

Kolkmann87: Kolkmann R, Leistner E (1987). "4-2'-(carboxyphenyl)-4-oxobutyryl coenzyme A ester, an intermediate in vitamin K (menaquinone) biosynthesis." Z. Naturforsch., 42c, 1207-1214.

Sakuragi02: Sakuragi Y, Zybailov B, Shen G, Jones AD, Chitnis PR, van der Est A, Bittl R, Zech S, Stehlik D, Golbeck JH, Bryant DA (2002). "Insertional inactivation of the menG gene, encoding 2-phytyl-1,4-naphthoquinone methyltransferase of Synechocystis sp. PCC 6803, results in the incorporation of 2-phytyl-1,4-naphthoquinone into the A(1) site and alteration of the equilibrium constant between A(1) and F(X) in photosystem I." Biochemistry 41(1);394-405. PMID: 11772039

Sakuragi05: Sakuragi Y, Zybailov B, Shen G, Bryant DA, Golbeck JH, Diner BA, Karygina I, Pushkar Y, Stehlik D (2005). "Recruitment of a foreign quinone into the A1 site of photosystem I. Characterization of a menB rubA double deletion mutant in Synechococcus sp. PCC 7002 devoid of FX, FA, and FB and containing plastoquinone or exchanged 9,10-anthraquinone." J Biol Chem 280(13);12371-81. PMID: 15681848

Sharma96: Sharma V, Hudspeth ME, Meganathan R (1996). "Menaquinone (vitamin K2) biosynthesis: localization and characterization of the menE gene from Escherichia coli." Gene 1996;168(1);43-8. PMID: 8626063

Shimada01: Shimada H, Shida Y, Nemoto N, Oshima T, Yamagishi A (2001). "Quinone profiles of Thermoplasma acidophilum HO-62." J Bacteriol 183(4);1462-5. PMID: 11157962

Shimada05: Shimada H, Ohno R, Shibata M, Ikegami I, Onai K, Ohto MA, Takamiya K (2005). "Inactivation and deficiency of core proteins of photosystems I and II caused by genetical phylloquinone and plastoquinone deficiency but retained lamellar structure in a T-DNA mutant of Arabidopsis.." Plant J 41(4);627-37. PMID: 15686525

Simantiras89: Simantiras M, Leistner E (1989). "Formation of o-succinylbenzoic acid from iso-chorismic acid in protein extracts from anthraquinone-producing plant cell suspension cultures." Phytochemistry, 28, 1381-1382.

Simantiras91: Simantiras M, Leistner E (1991). "Cell free synthesis of O-succinylbenzoic acid in protein extracts from anthraquinone and phylloquinone (vitamin K1) producing plant cell suspension cultures. Occurrence of intermediates between isochorismic and O-succinylbenzoic acid." Z. Naturforsch., 46c, 364-370.

Widhalm09: Widhalm JR, van Oostende C, Furt F, Basset GJ (2009). "A dedicated thioesterase of the Hotdog-fold family is required for the biosynthesis of the naphthoquinone ring of vitamin K1." Proc Natl Acad Sci U S A 106(14);5599-603. PMID: 19321747

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Almquist75: Almquist HJ (1975). "The early history of vitamin K." Am J Clin Nutr 28(6);656-9. PMID: 805522

Austin06: Austin JR, Frost E, Vidi PA, Kessler F, Staehelin LA (2006). "Plastoglobules are lipoprotein subcompartments of the chloroplast that are permanently coupled to thylakoid membranes and contain biosynthetic enzymes." Plant Cell 18(7);1693-703. PMID: 16731586

Bhasin03: Bhasin M, Billinsky JL, Palmer DR (2003). "Steady-state kinetics and molecular evolution of Escherichia coli MenD [(1R,6R)-2-succinyl-6-hydroxy-2,4-cyclohexadiene-1-carboxylate synthase], an anomalous thiamin diphosphate-dependent decarboxylase-carboligase." Biochemistry 42(46);13496-504. PMID: 14621995

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

BRENDA14: BRENDA team (2014). Imported from BRENDA version existing on Aug 2014.

Caldelari01: Caldelari D, Sternberg H, Rodriguez-Concepcion M, Gruissem W, Yalovsky S (2001). "Efficient prenylation by a plant geranylgeranyltransferase-I requires a functional CaaL box motif and a proximal polybasic domain." Plant Physiol 126(4);1416-29. PMID: 11500541

Carrie08: Carrie C, Murcha MW, Kuehn K, Duncan O, Barthet M, Smith PM, Eubel H, Meyer E, Day DA, Millar AH, Whelan J (2008). "Type II NAD(P)H dehydrogenases are targeted to mitochondria and chloroplasts or peroxisomes in Arabidopsis thaliana." FEBS Lett 582(20);3073-9. PMID: 18703057

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

Chen13a: 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

Chen93b: Chen A, Poulter CD (1993). "Purification and characterization of farnesyl diphosphate/geranylgeranyl diphosphate synthase. A thermostable bifunctional enzyme from Methanobacterium thermoautotrophicum." J Biol Chem 268(15);11002-7. PMID: 8388380

Chiba13: Chiba R, Minami A, Gomi K, Oikawa H (2013). "Identification of ophiobolin F synthase by a genome mining approach: a sesterterpene synthase from Aspergillus clavatus." Org Lett 15(3);594-7. PMID: 23324037

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

Dam35: Dam, H. (1935). "The antihaemorrhagic vitamin of the chick: occurrence and chemical nature." Nature 135:652-653.

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

Dillon04: Dillon SC, Bateman A (2004). "The Hotdog fold: wrapping up a superfamily of thioesterases and dehydratases." BMC Bioinformatics 5;109. PMID: 15307895

Dogbo87: Dogbo, O., Camara, B. (1987). "Purification of isopentenyl pyrophosphate isomerase and geranylgeranyl pyrophosphate synthase from Capsicum chromoplasts by affinity chromatography." Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism 920(2):140-148.

Fang11a: Fang M, Macova A, Hanson KL, Kos J, Palmer DR (2011). "Using substrate analogues to probe the kinetic mechanism and active site of Escherichia coli MenD." Biochemistry 50(40);8712-21. PMID: 21928762

Gross06a: Gross J, Cho WK, Lezhneva L, Falk J, Krupinska K, Shinozaki K, Seki M, Herrmann RG, Meurer J (2006). "A plant locus essential for phylloquinone (vitamin K1) biosynthesis originated from a fusion of four eubacterial genes." J Biol Chem 281(25);17189-96. PMID: 16617180

Heide81: Heide L, Leistner E (1981). "Enzymatic synthesis of the coenzyme A ester of o-succinylbenzoic acid, an intermediate in menaquinone (vitamin K2) biosynthesis." FEBS Lett 128(2);201-4. PMID: 7262311

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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