Benzene ring, biosynthesis

Snznki H, Y Ohnishi, Y Fnrnsho, S Saknda, S Horinonchi (2006b) Novel benzene ring biosynthesis from C3 and C4 primary metabolites by two enzymes. J Biol Chem 281 36944-36951. 

This is a very large group of alkaloids whose basic structure contains a pyrrole ring fused to a benzene ring. Biosynthesis of pure indoles involves the amino acid tryptophan as precursor, while that of a major subgroup of the indoles, including the Catharanthus and Rauwolfia alkaloids, involves a second precursor— the monoterpene iridoid loganin. 

Substitution of a trifluoromethyl group in the 3-position of the benzene ring and alkylation of the 4-amino group, as in norflurazon (16) (69FRP1575643), turns the pyridazin-3-ones into inhibitors of carotenoid biosynthesis. A similar substitution pattern occurs in fluridone (17) (74GEP2537753). The long-established l,2,4-triazol-3-ylamine, known as amitrole, and... 

For the biosynthesis of inositols and of the benzene rings of aromatic a-amino acids nature employs nucleophilic centers at C-6 of a D-glucose-derived hexos-5-ulose phosphate [5] and at C-7 of a 3,7-dideoxyhept-2,6-diulosonic acid [6], respectively, ions 1 and 2... 

Synthesis of podophyllotoxin (3.86) in cell culture of Linum album results in yields comparable to those of the most efficient tissue cultures of Podophyllum hexandrum. In order to further improve L. album cultures, Seidel et al. (2002) investigated the biosynthesis of podophyllotoxin (3.86). They fed a number of labeled compounds that to L. album cell cultures to identify which of these compounds could be used as precursors to podophyllotoxin. They determined that the substitution pattern on the benzene ring is critical. The substitution has to be either 3-methoxy, 4-hydroxy, as in ferulic acid (3.33), or, alternatively, 3,4-methylenedioxycinnamic acid (3.90) can serve as precursor. The precursor of podophyllotoxin in L. album appears to be deoxypodophyllotoxin (3.83), based on the higher level of isotope incorporation in the latter compound. This means that 7-hydroxymatairesinol, the precursors of 5-methoxypodophyllotoxin in L. flavum (Xia et al., 2000), is not a precursor of podophyllotoxin in L. album. 

The Palauan deep-water (500 m) marine actinomycete Salinispora pacifica has yielded cyanosporasides A (1731) and B (1732), which feature a chlorine on an unactivated benzene ring (1658). The authors suggest a novel biosynthesis from an enediyne precursor. Related to the previously known nosto-cyclophanes (1) are the new carbamidocyclophanes A-E, of which A (1733), B (1734), C (1735), and D (1736) are chlorinated, being isolated from the Vietnamese cyanobacterium Nostoc sp. (1659). These compounds exhibit cytotoxicity against MCF-7 (breast) and FI (amniotic epithelial) human cancer cells. 

Hanefeld U, Floss HG, Laatsch H (1994) Biosynthesis of the Marine Antibiotic Pentabro-mopseudilin. 1. The Benzene Ring. J Org Chem 59 3604... 

In the next chapter you will see how hydroxylation of benzene rings plays an important part in the biosynthesis of alkaloids and other aromatic natural products. 

MK biosynthesis by the OSB pathway has been elucidated on the basis of isotopic tracer experiments, isolation of mutants blocked in the various steps, isolation and identification of intermediates accumulated by the mutants, and by enzyme assays. Early isotopic tracer experiments with various bacteria established that methionine and prenyl PPi contribute to the methyl and prenyl substituents of the naphthoquinone. The early isotopic tracer studies and other work have been reviewed by Bentley and Meganathan. " In 1964, Cox and Gibson observed that [G- " C] shikimate was incorporated into both MK and ubiquinone by E. coli, thus providing the first evidence for the involvement of the shikimate pathway." Chemical degradation of the labeled isolated menaquinone (MK-8) showed that essentially all of the radioactivity was retained in the phthalic anhydride. It was concluded that the benzene ring of the naphthoquinone (sic) portion of vitamin K2 arises from shikimate in E. coli The authors further suggested that shikimate was first converted to chorismate before incorporation into MK. A more complete chemical degradation of the MK derived from... 

Echinulin.— Most convincing evidence has been obtained that (126) is an intermediate in the biosynthesis of echinulin (127) in Aspergillus amstelodami Possible mechanisms for introduction of the isoprene units on to the benzene ring of echinulin (127) and neoechinulin (128) are circumscribed by the results of feeding... 

The principle of SNIF-NMR is based on the fact that the natural biosynthesis of any organic compound generates a unique isotope distribution at different tire molecular positions for that compound. These isotopic fingerprints are determined by the nature of the precursors, the chemical or biochemical synthesis mechanisms, the evolution of the environmental conditions, and even the physiological status of the precursor plant. Synthetic benzaldehyde lias an almost perfectly random distribution of deuterium on the benzene ring, and... 

As examples of the non-ansamycin macrocyclic lactams, stubomycin (hitachimycin) was first isolated as an antitumor antibiotic [4-8]. Ikarugamycin [9], capsimycin [10], rapamycin and demethoxy-rapamycin [11-13] are other examples. Through the investigation of the biosynthesis of stubomycin (hitachimycin), it was found that the benzene ring of the P-phenylalanine moiety was involved as a chromophore outside of the macrocyclic moiety [5,14]. 

The biosynthesis of bufotenine has not been entirely elucidated experimentally. Some biochemical observations, however, prompted Witkop (141) even at early stages of investigation to make the accepted (157) suggestion of the possibility of direct hydroxylation of the benzene ring in tryptophan prior to any reaction on the pyrrole part of the molecule. Since the hydroxyamino acid was found not only in toad secretions but later also in the mushrooms, it may be the precursor of serotonin and hence A/ -dimethyl derivative, bufotenine. 5-Hydroxytryptophan was first found... 

Tenellin.—Results of a study on the biosynthesis of tenellin (10), previously reported in a preliminary communication, are now available in a full paper. " New information is that tyrosine is a less efficient precursor than phenylalanine, which indicates that benzene-ring hydroxylation occurs after the phenylalanine has undergone further modification. It is to be noted that incorporation of phenylalanine into tenellin (10) (benzene ring plus carbons 4,5, and 6) involves an intramolecular rearrangement of the phenylalanine skeleton. ... 

In its biosynthesis the 2-pyrrolecarbonyl unit originates from proline, the spiroketal from acetate/propa-noate, and the substituted benzene ring from shikimic acid. 

The m-CyN unit is derived from the shikimate pathway and possesses a Cj group and an amino group meta-disposed on a benzene ring. For example, some of the alkaloids described in this chapter are established to be derived from 3-amino-5-hydroxybenzoic acid, and other isomers are also involved in the biosynthesis of various alkaloids. 

As implied above, there are two kinds of ansamycins, one that possesses a benzene ring and another that possesses a naphthalene ring in the structure these are known as the benzenoid and naphthalenoid ansamycins, respectively. The m-CyN unit is involved in the biosyntheses of the chromo-phores of both these ansamycins, and the polyketide biosynthetic pathway is also concerned in the biosynthesis of the ansa chains of both types of ansamycin and a part of the chromophore of the naphthalenoid ansamycins. 

A noteworthy example of electrophilic aromatic substitution in nature, as mentioned in the introduction, is biosynthesis of the thyroid hormone thyroxine, where iodine is incorporated into benzene rings that are derived from tyrosine. 

Reactions of the Benzene Ring of Phenols 953 THE CHEMISTRY OF... Polyketide Anticancer Antibiotic Biosynthesis 954... 

Aromatic biosynthesis, aromatizatioa biosynthesis of compounds containing the benzene ring system. The most important mechanisms are 1. the shi-kimate/chorismate pathway, in which the aromatic amino acids, L-phenylalanine, L-tyrosine and L-trypto-phan, 4-hydroxybenzoic acid (precursor of ubiquinone), 4-aminobenzoie acid (precursor of folic acid) and the phenylpropanes, including components of lignin, cinnamic acid derivatives and flavonoids are synthesized and 2. the polyketide pathway (see Polyke-tides) in which acetate molecules are condensed and aromatic compounds (e.g. 6-methylsalicylic acid) are synthesized via poly-fl-keto acids. Biosynthesis of flavonoids (e.g. anthocyanidins) can occur by either pathway. 

These alkaloids have their nitrogen atoms in typical six-membered rings, which in the case of pyridine is a benzene ring. The precursors are generally ornithine and nicotinic acid although lobeline has a unique biosynthesis (see below). 

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