1.4.5.8- Tetrahydroxynaphthalene

Ku et al. [434] demonstrated that microreactors can also be used for tandem reactions. A microreactor containing beads functionalized with polyketide synthase [1,3,6,8-tetrahydroxynaphthalene synthase (THNS)] was coupled to one that contained soybean peroxidase (SBP). THNS was immobilized using the Ni-NTA method... 

Streptomycetes also produce a variety of fused ring aromatic polyketides, the carbon skeletons of some of which closely parallel those of their fimgal counterparts. However, with very few exceptions, such as the melanin spore pigment precursor 1,3,6,8-tetrahydroxynaphthalene (10, Scheme 5) of Alternaria alternate and Streptomyces griseus, fimgi and streptomycetes have not been found to produce identical fiised ring structures. 

CHS-related enzymes are also found in microorganisms and appear to be responsible for the formation of the pentaketide 1,3,6,8-tetrahydroxynaphthalene (10) in Streptomyces griseusP While flavonoids are widely distributed in plants, chlorflavonin (72) has been isolated from the frmgus Aspergillus candicusP although nothing is currently known of the nature of the associated synthase. 

Figure 9 Type III PKS biosynthesis In myxobacteria. Biosynthesis of flaviolin (20) catalyzed by a type III PKS (CHS) from Sorangium cellulosum So ce56. The primary product released from the CHS, 1,3,6,8-tetrahydroxynaphthalene (26), Is spontaneously oxidized to form 20. Neither 26 nor 20 has been Identified In the myxobacterial strain. Indicating that the CHS-encodIng gene Is silent under the tested conditions. Activation of the type III PKS-encodIng gene by heterologous expression In Pseudomonas putida led to the formation of the red pigment 20 In the P. putida CHS strain (see picture).

Several fungicides inhibit 1,3,6,8-tetrahydroxynaphthalene reductase (MBI-Rs) (Table 20.2). These inhibitors have been used since the 1970s, such as pentachlor-obenzyl alcohol (PCBA) (6), tricyclazole (7) (Eli Lilly, 1975), pyroquilon (8) (Ciba, Pflzer, 1985) and fthalide (9) (Kureha, 1971), without any resistance problems and retain considerable economical importance, mainly in Northeast Asia. They are not discussed in more detail here. 

Table 20.2 Structures of inhibitors of 1,3,6,8-tetrahydroxynaphthalene reductase in DHN melanin biosynthesis.

Enzymatic syntheses within the microfluidic platform were also reported. The construction and novel compound synthesis from a synthetic metabolic pathway consisting of a type III poly-ketide synthase (PKS) known as 1,3,6,8-tetrahydroxynaphthalene synthase (THNS) from Streptomyces coelicolor and soybean peroxidase (SBP) in a microreactor were performed (Fig. 5) [11]. THNS immobilized to Ni-NTA agarose... 

Enzymatic syntheses within the microfluidic platform were also reported. The construction and novel compound synthesis from a synthetic metabolic pathway consisting of a type HI polyketide synthase (PKS) known as 1,3,6,8-tetrahydroxynaphthalene synthase (THNS) from Streptomyces coelicolor and soybean peroxidase (SBP) in a microreactor were performed (Fig. 5) [11]. THNS immobilized to Ni-NTA agarose beads was prepacked into a microfluidic channel, while SBP was covalently attached to the walls of a second microfluidic channel precoated with a reactive poly(maleic anhydride) derivative. The result was a tandem, two-step hiochip that enabled synthesis of novel polyketide derivatives. The first microchan-nel, consisting of THNS, resulted in the conversion of malonyl-CoA to flaviolin in yields of up to 40% with a residence time of 6 min. This conversion is similar to that obtained in several-milliliter batch reactions after 2 h. Linking this microchannel to the SBP microchannel results in biflaviolin synthesis. During the course of this work, we discovered that the substrate specificity of THNS could be manipulated by simply changing the reaction pH. As a result, the starter acyl-CoA specificity can be broadened to yield a series of truncated pyrone products. When combined with variations in the ratio of acyl-CoA and... 

Geminal dihalides have also been applied for the construction of 1,3-dioxanes and congeners. For example, bromochloromethane readily reacted with tetrahydroxynaphthalenes to afford the tetracycle 218 in good yield (Equation 82). Bisdioxane 218 was subsequently used for the synthesis of alkannin and shikonin <1998AGE839, 2000SC1023>. 

Figure 11 Diverse pathways for tetrahydroxynaphthalene biosynthesis in fungi and bacteria...

Oxidation. 1,2,5,6-Tetrahydroxynaphthalenes are oxidized to the amphiquinones in high yield."... 

The strucmral and kinetic data on chalcone synthase and related PKS Ills have been used to develop a model that explains how these enzymes control loading, condensation, and cyclization reactions in one active site. The attention of readers is drawn to an excellent review by Austin and Noel in which the structure and mechanism of plant and bacterial PKS III homologs have been compared and contrasted. Several noteworthy points from their analyses include a discussion on the bacterial PKS III enzymes that contain multiple cysteine residues in their active sites, such as tetrahydroxynaphthalene synthase and DpgA, a PKS III involved in dihydroxyphenylglycine synthesis, and the possibility that some bacterial PKS III enzymes may use AGP as the substrate carrier. 

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