Biosynthesis of menaquinone

Meganathan, R., Biosynthesis of menaquinone (vitamin Kj) and ubiquinone (coenzyme Q) a perspective on enzymatic mechanism. Vitamins Hormones, 61, 173, 2001. 

Quinones.—Four menaquinone (139) homologues from Sarcina lutea have been identified as dihydromenaquinones-6, -7, -8, and -9. A novel quinone from bulbs and leaves of Iris is thought to be related to plastoquinone-9 (140) but to have a modified ring methylation pattern.No chemical data were reported. The distribution of ubiquinone (141) homologues in a number of Gram-negative bacteria has been surveyed.The biosynthesis of menaquinones and related quinones has been reviewed. The molecular structure and electronic properties of ubiquinone have been studied by semi-empirical molecular orbital theory. 

Biosynthesis of menaquinone (vitamin K2) and ubiquinone (coenzyme Q) 01MI12. 

The biosynthesis of menaquinone is outlined in Fig. 44. Isomerization of chorismate to isochorismate followed by condensation with a-ketogluta-rate and aromatization gives o-succinylbenzoic acid. Conversion of 238 to the CoA thio ester, followed by cyclization, prenylation and methylation completes the biosynthesis. The biosynthesis of the prenyl side chain follows the alternative terpene biosynthetic pathway described for ubiquinone. 

The biosynthesis of menaquinones in E. coli (Fig. 5) starts with the conversion of isochorismic acid and a-ketoglutaric acid in the presence of thiamine pyrophosphate [105-107] to 2-succinyl-6-hydroxy-2,4-cyclohexadiene-1-carboxylic acid (SHCHC) catalyzed by SHCHC synthase, and a-ketoglutarate decarboxylase, both encoded by the menD gene [104,108,109]. SHCHC is converted to o-succinylbenzoic acid by dehydration, catalyzed by a protein encoded by menC (Table 1) [110]. Palaniappan et al., [111] showed for the first time the biosynthesis of menaquinones via o-succinyl benzoic acid in B. subtilis including the activity of the enzymes. 

The only known function of PhQ in cyanobacteria and plants is to function as an electron transfer cofactor in PS I. In spite of its importance in cyanobacteria, the biosynthetic route of PhQ was not previously elucidated. Many prokaryotes contain the metabolic pathway for the biosynthesis of menaquinone (MQ), a PhQ-Hke molecule (Figure 119.1). In certain bacteria, MQ is used during fumarate reduction in anaerobic respiration. - In green sulfur bacteria and in heliobacteria, MQ may function as a loosely bound secondary electron acceptor in the photosynthetic reaction center. The genes encoding enzymes involved in the conversion of chorismate to MQ were cloned in a variety of organisms. MQ differs from PhQ only in the tail portion of the molecule an unsaturated C-40 side chain is present, rather than a mostly saturated C-20 phytyl side chain. Therefore, the synthesis of the naphthalene rings in PhQ and MQ involves similar steps in both pathways. 

FIGURE 119.2 Proposed biosynthetic pathway of phylloquinone in Synechocystis sp. PCC 6803. The genes responsible for the biosynthesis of menaquinone were initially described in E. colt. The homologs of these genes were identified in the genome sequence of Synechocystis sp. PCC 6803, and menA, menB, menD, menE, and menG were confirmed by experiment. 

The shikimate pathway is the major route in the biosynthesis of ubiquinone, menaquinone, phyloquinone, plastoquinone, and various colored naphthoquinones. The early steps of this process are common with the steps involved in the biosynthesis of phenols, flavonoids, and aromatic amino acids. Shikimic acid is formed in several steps from precursors of carbohydrate metabolism. The key intermediate in quinone biosynthesis via the shikimate pathway is the chorismate. In the case of ubiquinones, the chorismate is converted to para-hydoxybenzoate and then, depending on the organism, the process continues with prenylation, decarboxylation, three hydroxy-lations, and three methylation steps. - ... 

In normal individuals phytonadione and the menaquinones have no activity while in vitamin K deficiency the vitamin promotes the hepatic biosynthesis of factor II (prothrombin), factor VII, factor IX and factor X. Vitamin K functions as an essential cofactor for the enzymatic activation of precursors of these vitamin K dependent clotting factors. The quinone structure of the active form of vitamin K, i.e. reduced vitamin K or hydroquinone. 

OSB, and 1,4-dihydroxynaphthoic acid, or its diketo tautomer, have been implicated in the biosynthesis of a wide range of plant naphthoquinones and anthraquinones. There are parallels with the later stages of the menaquinone sequence shown in Figure 4.55, or differences according to the plant species concerned. Some of these pathways are illustrated in Figure 4.58. Replacement of the carboxyl function by an isoprenyl substituent is found to proceed via a disubstituted intermediate in Catalpa (Bignoniaceae) and... 

The shikimate biosynthetic pathway occurs in bacteria, plants, and fungi (including yeasts) and is a major entry into the biosynthesis of primary and secondary metabolites, for example aromatic amino acids, menaquinones, vitamins, and antibiotics [1], Starting from erythrose-4-phosphate (E4P) and phosphoenol-pyruvate... 

Vitamin K is a dietary component essential for the normal biosynthesis of several factors required for clotting of blood. Vitamin Ki (phylloqui-none, phytonadione) is a 2-methyl-3-phytyl-1,4-naphthoquinone, and is the only natural vitamin available for therapeutic use. Vitamin K2 represents a series of compounds (the menaquinones, MK) in which the phytyl side-... 

Oligomerization of isoprenoids under elimination of pyrophosphate affords the precursors for the biosynthesis of monoterpenes, sesquiterpenes, diterpenes, triterpenes, and tetra-terpenes (93). Long-chain oligomer pyrophosphates also supply the side chains of vitamin E (99, a-tocopherol. Fig. 11), heme a (18), chlorophyll (17, Fig. 2), and the quinone type cofactors, including vitamin K (menaquinone, 98) and coenzyme QIO (ubiquinone, 97). The quinone moieties are derived from hydroxybenzoate that is synthesized from tyrosine in animals or from chorismate in microorganisms (53, 54). 

Figure 11 Biosynthesis of isoprenoid type cofactors. 18, Heme a 39, pyridoxal 5 -phosphate 43, 1-deoxy-D-xylulose 5-phosphate 46, thiamine pyrophosphate 83, acetyl-CoA 84, (S)-3-hydroxy-3-methylglutaryl-CoA 85, mevalonate 86, isopentenyl diphosphate (IPP) 87, dimethylallyl diphosphate (DMAPP) 88, pyruvate 89, D-glyceraldehyde 3-phosphate 90, 2C-methyl-D-erythritol 4-phosphate 91, 2C-methyl-erythritol 2,4-cyclodiphosphate 92, 1-hydroxy-2-methyl-2-( )-butenyl 4-diphosphate 93, polyprenyl diphosphate 94, cholecalciferol 95, fS-carotene 96, retinol 97, ubiquinone 98, menaquinone 99, a-tocopherol.

The chemistry of the cofactors has provided a fertile area of overlap between organic chemistry and biochemistry, and the organic chemistry of the cofactors is now a thoroughly studied area. In contrast, the chemistry of cofactor biosynthesis is stiU relatively underdeveloped. In this review the biosynthesis of nicotinamide adenine dinucleotide, riboflavin, folate, molyb-dopterin, thiamin, biotin, Upoic acid, pantothenic acid, coenzyme A, S-adenosylmethionine, pyridoxal phosphate, ubiquinone and menaquinone in E. coli will be described with a focus on unsolved mechanistic problems. 

Even though E. coli is a very well-studied bacterium, many interesting mechanistic problems in cofactor biosynthesis in this organism remain unsolved. The mechanisms for the formation of the nicotinamide ring of NAD, the pyridine ring of pyridoxal, the pterin system of molybdopterin, and the thiazole and pyrimidine rings of thiamin are unknown. The sulfur transfer chemistry involved in the biosynthesis of lipoic acid, biotin, thiamin and molybdopterin is not yet understood. The formation of the isopentenylpyrophosphate precursor to the prenyl side chain of ubiquinone and menaquinone does not occur by the mevalonate pathway. None of the enzymes involved in this alternative terpene biosynthetic pathway have been characterized. The aim of this review is to focus attention on these unsolved mechanistic problems. 

Meganathan R (1996) Biosynthesis of the isoprenoid quinones menaquinone (vitamin K2) and ubiquinone (coenzyme Q). In Neidhardt FC, Curtiss III R, Ingraham JL, Lin ECC, Low KB, Magasanik B, Reznikoff WS, Riley M, Schaechter M, Umbarger HE (eds) Escherichia coli and Salmonella typhimurium Cellular and Molecular Biology. Vol 1. ASM, Washington DC, p 642... 

Besides the siderophores, the menaquinone pathway also involves isochorismate synthase (review [100]). Menaquinone (vitamin K2) is an electron carrier involved in anaerobic ATP-generating redox reactions. It also plays a role in the anaerobic biosynthesis of pyrimidines, porphyrins and succinyl CoA [101-104]. Menaquinone is detectable in E. call. The accumulation of menaquinone (MK8) is significantly stimulated in the absence of oxygen. 

Biosynthesis. The asymmetric incorporation of 4-(2 -carboxyphenyl-4-oxobu-tyrate [o-succinylbenzoate (211)] into phylloquinone by Zea mays has been reported. The incorporation of (211), via its coenzyme A thioester, into l,4-dihydroxy-2-naphthoic acid (212) and menaquinone has been studied in cell-free extracts of Mycobacterium phlei and Micrococcus luteus. The biosynthesis and metabolism of menaquinone-4 in the crab has been described. A soluble enzyme complex capable of converting 2-octaprenylphenol (213) into... 

CjiHioOs, Mr 222.20, mp. 135-137 °C. An intermediate in the biosynthesis of 1,4-dihydroxynaphthalene-2-carboxylic acid, which in turn is a precursor of alizarin(e), menaquinone (vitamin K3), and vitamin K] (phylloquinone). The biosynthesis proceeds from isochorismic acid and 2-oxoglutaric acid. 

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