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MetaCyc Pathway: demethylmenaquinol-8 biosynthesis II
Inferred from experiment

Enzyme View:

Pathway diagram: demethylmenaquinol-8 biosynthesis II

This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Synonyms: demethylmenaquinone-8 biosynthesis II

Superclasses: BiosynthesisCofactors, Prosthetic Groups, Electron Carriers BiosynthesisQuinol and Quinone BiosynthesisDemethylmenaquinol BiosynthesisDemethylmenaquinol-8 Biosynthesis

Some taxa known to possess this pathway include : Chlamydia muridarum, Chlamydia trachomatis, Chlamydophila abortus, Chlamydophila caviae, Chlamydophila felis, Leptospira borgpetersenii, Leptospira interrogans, Streptomyces coelicolor, Streptomyces coelicolor A3(2), Thermus thermophilus, Thermus thermophilus HB8

Expected Taxonomic Range: Archaea, Bacteria

General Background

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 [Meganathan01]. 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, Li11a, 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

Most bacteria appear to synthesize menaquinone from chorismate by seven enzymes in a well characterized route (see superpathway of menaquinol-8 biosynthesis I). Recently an alternative pathway for the biosynthesis of menaquinone from chorismate has been identified in some bacteria, including Streptomyces coelicolor and Thermus thermophilus [Hiratsuka08]. Initial analysis of sequenced genomes suggested that the pathway may be present in a variety of organisms, including the bacterial pathogens Campylobacter jejuni and Helicobacter pylori, and members of the genera Deltaproteobacteria, Epsilonproteobacteria, Firmicutes, Acidobacteria , Actinobacteria , Planctomycetes, Chlamydiae , Spirochaetes , Chloroflexi , Deinococcus, Thermus and Aquifex, as well as some Archaebacterial genera, including both Euryarchaeota and Crenarchaeota [Dairi09]. Further analysis revealed that the pathway in Campylobacter jejuni and Helicobacter pylori is somewhat different [Li11a] (see demethylmenaquinol-8 biosynthesis III).

The pathway, which branches at chorismate, follows a different route, including the intermediate futalosine, an unusual nucleoside derivative consisting of inosine and o-substituted benzoate moieties. Several genes that encode enzymes in this pathway have been identified by mutagenesis [Hiratsuka08], and the enzymes responsible for the steps leading from chorismate to 1,4-dihydroxy-6-naphthoate are known, although so far only one of them, futalosine hydrolase, has been characterized [Hiratsuka09]. Several genes of Streptomyces coelicolor have been implicated in the steps of the later part of the pathway, leading from 1,4-dihydroxy-6-naphthoate to demethylmenaquinone-8. Even though their roles have not been verified yet, their sequence suggests prenylation, decarboxylation and methylation, similar to the conventional pathway [Dairi09].

Superpathways: superpathway of menaquinol-8 biosynthesis II

Variants: demethylmenaquinol-8 biosynthesis I, demethylmenaquinol-8 biosynthesis III, superpathway of demethylmenaquinol-8 biosynthesis

Created 29-May-2009 by Caspi R, SRI International


Cawthorne67: Cawthorne MA, Jeffries LR, Harris M, Price SA, Diplock AT, Green J (1967). "Menaquinone-4 and -5 in a bacterium." Biochem J 104(2);35contd-36c. PMID: 6048777

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

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

Dairi09: Dairi T (2009). "An alternative menaquinone biosynthetic pathway operating in microorganisms: an attractive target for drug discovery to pathogenic Helicobacter and Chlamydia strains." J Antibiot (Tokyo) 62(7);347-52. PMID: 19557031

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

Doisy40: Doisy EA, Binkley SB, Thayer SA, McKee RW (1940). "Vitamin K." Science 91(2351);58-62. PMID: 17783315

Dunphy71: Dunphy PJ, Phillips PG, Brodie AF (1971). "Separation and identification of menaquinones from microorganisms." J Lipid Res 12(4);442-9. PMID: 5005959

Farrand73: Farrand SK, Taber HW (1973). "Physiological effects of menaquinone deficiency in Bacillus subtilis." J Bacteriol 115(3);1035-44. PMID: 4353869

Farrand74: Farrand SK, Taber HW (1974). "Changes in menaquinone concentration during growth and early sporulation in Bacillus subtilis." J Bacteriol 117(1);324-6. PMID: 4202999

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

Hiratsuka09: Hiratsuka T, Itoh N, Seto H, Dairi T (2009). "Enzymatic properties of futalosine hydrolase, an enzyme essential to a newly identified menaquinone biosynthetic pathway." Biosci Biotechnol Biochem 73(5);1137-41. PMID: 19420717

Hollander76: Hollander R (1976). "Correlation of the function of demethylmenaquinone in bacterial electron transport with its redox potential." FEBS Lett 72(1);98-100. PMID: 187454

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

Isler58: Isler, O, Ruegg, R., Chopard-dit-Jean, L. H., Winterstein, A., Wiss, O. (1958). "Synthese und Isolierung von Vitamin K und Isoprenologen Verbindungen." Helv. Chim. Acta 41:786-807.

Li11a: 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

Maroc70: Maroc J, Azerad R, Kamen MD, Le Gall J (1970). "Menaquinone (MK-6) in the sulfate-reducing obligate anaerobe, Desulfovibrio." Biochim Biophys Acta 197(1);87-9. PMID: 5412037

Meganathan01: Meganathan R (2001). "Biosynthesis of menaquinone (vitamin K2) and ubiquinone (coenzyme Q): a perspective on enzymatic mechanisms." Vitam Horm 61;173-218. PMID: 11153266

Shah80: Shah HN, Collins MD (1980). "Fatty acid and isoprenoid quinone composition in the classification of Bacteroides melaninogenicus and related taxa." J Appl Bacteriol 48(1);75-87. PMID: 6102980

Weber70: Weber MM, Matschiner JT, Peck HD (1970). "Menaquinone-6 in the strict anaerobes Desulfovibrio vulgaris and Desulfovibrio gigas." Biochem Biophys Res Commun 38(2);197-204. PMID: 5418698

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

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

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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
Page generated by Pathway Tools version 19.5 (software by SRI International) on Mon May 2, 2016, biocyc14.