Aromatized flavin

Direct hydroxylation of an aromatic ring to yield a hydroxybenzene (a phenol) is difficult and rarely done in the laboratory., but occurs much more frequently in biological pathways. An example is the hydroxylation of p-hydroxyphenyl acetate to give 3,4-dihydroxyphenyl acetate. The reaction is catalyzed by p-hydroxyphenylacctate-3-hydroxylase and requires molecular oxygen plus the coenzyme reduced flavin adenine dinucleotide, abbreviated FADH2. 

Tu, S.-C. (1991). Oxygenated flavin intermediates of bacterial luciferase and flavoprotein aromatic hydroxylases enzymology and chemical models. Adv. Oxygenated Processes 3 115-140. 

A successful case study for asymmetric nitrogen oxidation was reported for a series of (hetero)aromatic tertiary amines. High diastereoselectivity was observed for the enzyme-mediated oxidation of S-(—)-nicotine by isolated CHMOAdneto to give the corresponding ds-N-oxide [215]. The stereoselectivity of this biooxidation was complementary to the product obtained by flavin M O (FM O) from human li ver (trows-selective [216]) as well as unspecific oxidations by FMOs from porcine and guinea pig liver. 

Huvaere, K., and Skibsted, L. H. (2009) Light-Induced Oxidation of Tryptophan and Histidine. Reactivity of Aromatic N-Heterocycles toward Triplet-Excited Flavins, Journal of American and Chemical Society, Vol. 131, (May 2009) pp. 8049-8060, ISSN 0002-7863. 

Zellner G, A Jargon (1997) Evidence for a tungsten-stimulated aldehyde dehydrogenase activity of Desulfovi-brio simplex that oxidizes aliphatic and aromatic aldehydes with flavins as coenzymes. Arch Microbiol 168 480-485. 

Trivially, photo-excitation will drastically enhance the oxidation potential of the flavin chromophore and might give rise to a great variety of reversible chemical reactions, depending on the structure of the environment and/or the pathway of potential e - as well as H -conductivity. It must be emphasized, that the oxidative action of the flavin triplet Tj is by no means confined to 1 e -uptake from suitable aromatic... 

It is a wide-spread belief that such reactions could not be relevant, since they are spin-forbidden. This need not be true. It appears that the reduced flavin is a soft molecule, which resists planarity in the singlet state because of an anti-aromatic number of delocalized 7r-electrons. Hence, the planar conformation of Flre(j might have an unusually low-lying triplet state, which favors the thermal spin relaxation in RX —... 

Most coenzymes have aromatic heterocycles as major constituents. While enzymes possess purely protein structures, coenzymes incorporate non-amino acid moieties, most of them aromatic nitrogen het-erocycles. Coenzymes are essential for the redox biochemical transformations, e.g., nicotinamide adenine dinucleotide (NAD, 13) and flavin adenine dinucleotide (FAD, 14) (Scheme 5). Both are hydrogen transporters through their tautomeric forms that allow hydrogen uptake at the termini of the quinon-oid chain. Thiamine pyrophosphate (15) is a coenzyme that assists the decarboxylation of pyruvic acid, a very important biologic reaction (Scheme 6). 

Hydroxylation Aromatic, allylic, benzylic CYP4S0 or flavin Phenols... 

The oxidation state of thiazolines and oxazolines can be adjusted by additional tailoring enzymes. For instance, oxidation domains (Ox) composed of approximately 250 amino acids utilize the cofactor FMN (flavin mononucleotide) to form aromatic oxazoles and thiazoles from oxazolines and thiazolines, respectively. Such domains are likely utilized in the biosynthesis of the disorazoles, " diazonimides, bleomycin, and epothiolone. The typical domain organization for a synthetase containing an oxidation domain is Cy-A-PCP-Ox however, in myxothiazol biosynthesis one oxidation domain is incorporated into an A domain. Alternatively, NRPSs can utilize NAD(P)H reductase domains to convert thiazolines and oxazolines into thiazolidines and oxazolidines, respectively. For instance, PchC is a reductase domain from the pyochelin biosynthetic pathway that acts in trans to reduce a thiazolyinyl-Y-PCP-bound intermediate to the corresponding thiazolidynyl-Y-PCP. ... 

Since flavin semiquinones are tricyclic heteronuclear aromatic systems, the spin density due to the unpaired electron can be distributed at a number of sites on the isoalloxazine ring. Knowledge of the location and the extent of spin density at these locations on the ring system is important for the determination of sites that may participate... 

Major oxidations are aromatic, aliphatic, alicyclic, heterocyclic, N-oxidation, S-oxidation, dealkylation. Other enzymes also catalyze phase 1 reactions microsomal flavin monooxygenases, amine oxidases, peroxidases, and alcohol dehydrogenase. 

JBC(244)2590,76JBC(251)6994>. The compounds monooxygenated by flavin-dependent enzymes include both electrophilic and nucleophilic species. These compounds can be divided into three groups for the convenience of discussion (i) amines and sulfides, (ii) aromatic compounds with electron releasing substituents, and (iii) aldehydes and ketones (Table 3). 

Flavin coenzymes are usually bound tightly to proteins and cycle between reduced and oxidized states while attached to the same protein molecule. In a free unbound coenzyme the redox potential is determined by the structures of the oxidized and reduced forms of the couple. Both riboflavin and the pyridine nucleotides contain aromatic ring systems that are stabilized by resonance. Part of this resonance stabilization is lost upon reduction. The value of E° depends in part upon the varying amounts of resonance in the oxidized and reduced forms. The structures of the coenzymes have apparently evolved to provide values of E° appropriate for their biological functions. 

The enzyme is organized into two structural domains,201 one of which binds FAD and the other NADP+. Similar single-electron transfers through flavoproteins also occur in many other enzymes. Chorismate mutase, an important enzyme in biosynthesis of aromatic rings (Chapter 25), contains bound FMN. Its function is unclear but involves formation of a neutral flavin radical.276 277... 

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