Menaquinone synthesis

K2 Menaquinone Synthesis by gram positieve intestinal bacteria (menaquinone) because the intestinal flora has not yet been fuUy developed (see Chapter 41, Section VIII)... 

Dhiman RK, Mahapatra S, Slayden RA, Boyne ME, Lenaerts A, Hinshaw JC, Angala SK, Chat-teijee D, Biswas K, Narayanasamy P et al (2009) Menaquinone synthesis is critical for maintairung mycobacterial viability during exponential growth and recovery from non-replicating persistence. Mol Microbiol 72 85-97... 

Myers, C.R. and Myers, J.M. (2004) Shewanella oneidemis MR-1 restores menaquinone synthesis to a menaquinone-negative mutant. Appl. Environ. Microbiol. 70(9), 5415-5425. 

Oxidation may take place by a modified tricarboxylic acid cycle in which the production of CO2 is coupled to the synthesis of NADPH and reduced ferredoxin, and the dehydrogenation of succinate to fumarate is coupled to the synthesis of reduced menaquinone. This pathway is used, for example, by Desulfuromonas acetoxidans and in modified form by... 

The K vitamins include vitamin Ki, phylloquinone or phytonadione, and vitamin K2 which is a group of compounds, the menaquinones. Menadione, vitamin K3, is a precursor of menaquinone-4. Vitamin K is present in alfalfa and fish livers. Other dietary sources include green vegetables, soybean oil and eggs. A normal diet together with the bacterial synthesis of vitamin K in the gut are usually sufficient to prevent deficiencies in healthy adults. 

Vitamin K activity is associated with several quinones, including phylloquinone (vitamin Kj), menadione (vitamin K3), and a variety of menaquinones (vitamin K2). These quinones promote the synthesis of proteins that are involved in the coagulation of blood. These proteins include prothrombin, factor VII (proconvertin), factor IX (plasma thromboplastin), and factor X (Stuart factor). A detailed discussion of blood coagulation is found in Chapter 22. The vitamin K quinones are obtained from three major sources. Vitamin K is present in vari-... 

In the original investigation of the Pd- or Ni-catalyzed alkenyl-benzyl and benzyl-alkenyl coupling reactions168, both Pd- and Ni-phosphine catalysts were shown to be effective. In some Ni-catalyzed reactions, however, double-bond migration to produce styrene derivatives was observed as a side reaction169. Nonetheless, both Pd- and Ni-catalyzed procedures have been successfully applied to the synthesis of various coenzymes Q , where n is < 10, and related menaquinones (Scheme 63)171,172. 

SCHEME 63. Synthesis of coenzyme Q (n lO) and menaquinone-3 via Pd- or Ni-catalyzed alkenyl-benzyl coupling with alkenylalanes... 

FIGURE 19-33 Bacterial respiratory chain, (a) Shown here are the respiratory carriers of the inner membrane of E. coli. Eubacteria contain a minimal form of Complex I, containing all the prosthetic groups normally associated with the mitochondrial complex but only 14 polypeptides. This plasma membrane complex transfers electrons from NADH to ubiquinone or to (b) menaquinone, the bacterial equivalent of ubiquinone, while pumping protons outward and creating an electrochemical potential that drives ATP synthesis. 

V). The centers resemble PSII of chloroplasts and have a high midpoint electrode potential E° of 0.46 V. The initial electron acceptor is the Mg2+-free bacteriopheophytin (see Fig. 23-20) whose midpoint potential is -0.7 V. Electrons flow from reduced bacteriopheophytin to menaquinone or ubiquinone or both via a cytochrome bct complex, similar to that of mitochondria, then back to the reaction center P870. This is primarily a cyclic process coupled to ATP synthesis. Needed reducing equivalents can be formed by ATP-driven reverse electron transport involving electrons removed from succinate. Similarly, the purple sulfur bacteria can use electrons from H2S. 

Streptocarpus (Gesneriaceae), e.g. catalponone (compare Figure 4.56), and this can be transformed to deoxylapachol and then menaquinone-1 (Figure 4.58). Lawsone is formed by an oxidative sequence in which hydroxyl replaces the carboxyl. A further interesting elaboration is the synthesis of an anthraquinone skeleton by effectively cycliz-ing a dimethylallyl substituent on to the naph-thaquinone system. Rather little is known about how this process is achieved but many examples are known from the results of labelling studies. 

Various approaches to the synthesis of menaquinones have been made, in which the aromatic component is activated to encourage nucleophilic attack upon a receptive prenyl fragment. Thus alkylation of the potassium salt of 2-methyl-1,4-naphthoquinol (236) or 4-methoxy-3-methyl-l-naphthol (237) with geranyl bromide (244) gave menaqui none-2 (246) in 20 and 45% yield, respectively, after oxidation. Hydrogenolysis of the dimethyl ether (238) of 1 -oxymenaquinol-2 [from... 

The quinone ring is derived from isochorismic acid, formed by isomerization of chorismic acid, an intermediate in the shikirnic acid pathway for synthesis of the aromatic amino acids. The first intermediate unique to menaquinone formation is o-succinyl benzoate, which is formed by a thiamin pyrophosphate-dependent condensation between 2-oxoglutarate and chorismic acid. The reaction catalyzed by o-succinylbenzoate synthetase is a complex one, involving initially the formation of the succinic semialdehyde-thiamin diphosphate complex by decarboxylation of 2-oxoglutarate, then addition of the succinyl moiety to isochorismate, followed by removal of the pyruvoyl side chain and the hydroxyl group of isochorismate. 

The determination of vitamin K requirements is complicated by the intestinal bacterial synthesis of menaquinones and the extent to which these are absorbed and utilized (Section 5.1). Prolonged use of antibiotics leads to impaired blood clotting, but simple dietary restriction of vitamin K results in prolonged prothrombin time and increased circulating preprothrombin so it is apparent that bacterial synthesis is inadequate to meet requirements in the absence of a dietary intake of phylloquinone. Preprothrombin is elevated at intakes between 40 to 60 /xg per day, but not at intakes above 80 /rg per day (Suttie etal., 1988). 

Thijssen HH, Drittij-Reijnders MJ, and Fischer MA (1996) Phylloquinone and menaquinone-4 distribution in rats synthesis rather than uptake determines mena-quinone-4 organ concentmtions. Journal of Nutrition 126, 537-43. 

The method could be applied to the synthesis of many natural benzo- and naphthoquinones. The masked quinone (146), which may serve as a general precursor to the menaquinones, was prepared and isoprenylated by a similar series of reactions. 

Schematised electron transfer pathway across a Gram-negative bacterial ceU membrane (with lactate as the primary electron donor), coupled with H translocation and ATP synthesis, adopted and simplified from ref. 137. MQ and MQHj are menaquinone and -hydroquinone, respectively CymA is a tetrameric and MtrC a decameric cytochrome-c type haemoprotein. See also the text and Eqnation (4.41)). Peptidoglycan (or murein), serving a structural role in the cell membrane, is a block copolymer built up from acetylhexoses and oligopeptides.

An easy synthesis of prenyl naphthoquinones, e.g. menaquinone-2 (205 n = 2), was achieved by coupling the appropriate prenyl halide with an organo-copper derivative of the electrochemically derived quinone bisacetal (216). Menaquinone-2 and phylloquinone (204) were also obtained in good yields by reaction of 2-methyl-1,4-naphthoquinone (205 n =0) with geranyl and phytyl halides in the presence of metal dust. A one-step method for the preparation of vitamin K analogues uses cyclodextrin inclusion catalysts.Thus reaction of the diol (217) with allyl bromide in the presence of oxygen and/3-cyclodextrin at pH 9 afforded the menaquinone analogue (218). 

Vitamin K activity is associated with at least two distinct natural substances, designated as vitamin K, and vitamin Kj. Vitamin K or phylloquinone (phytonadione) is 2-methyl-3-phytyl-l,4-naphthoquinone it is found in plants and is the only natural vitamin K available for therapeutic use. Vitamin K is actually a series of compounds (the mena-quinones) in which the phytyl side chain of phylloquinone has been replaced by a side chain built up of 2 to 13 prenyl units. Considerable synthesis of menaquinones occurs in Gram-positive bacteria indeed, intestinal flora synthesize the large amounts of vitamin K contained in human and animal feces. In animals menaquinone-4 can be synthesized from the vitamin precursor menadione (2-methyl-l,4-naphtho-quinone), or vitamin Kj. Depending on the bioassay system used, menadione is at least as active on a molar basis as phylloquinone. 

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