Flavoenzymes metabolism

Salicylate is an intermediate in the metabolism of PAHs including naphthalene and phen-anthrene, and its degradation involves oxidation to catechol. The hydroxylase (monooxygenase) has been extensively studied (references in White-Stevens and Kamin 1972) and in the presence of an analog that does not serve as a substrate, NADH is oxidized with the production of H2O2 (White-Stevens and Kamin 1972). This uncoupling is characteristic of flavoenzymes and is exemplified also by the chlorophenol hydroxylase from an Azotobacter sp. that is noted later. 

The acyl-Co A dehydrogenases are a family of mitochondrial flavoenzymes involved in fatty acid and branched chain amino-acid metabolism. In addition to long chain acyl-Co A dehydrogenases (LCADs), there are short/ branched chain acyl-CoA dehydrogenase (SBCAD) that act on 2-methyl branched chain acyl-CoA substrates of varying chain lengths. 

Dihydroorotate dehydrogenase (DHOD), dihydropyrimidine dehydrogenase (DPD), and dihydrouridine synthase (DUS), flavoenzymes involved in various stages of pyrimidine metabolism, catalyze very similar C-C oxidation/reduction reactions. These enzymes share common active site residues and structural homology. They have all been implicated as potential drug targets due to their important physiological roles. 

Bruce A. Palfey did his undergraduate work at Pennsylvania State University where he majored in biochemistry. After few years as a technician, he earned an M.S. in chemistry at Drexel University and then a Ph.D. in biological chemistry at the University of Michigan working jointly in the laboratories of Professors David Ballou and Vincent Massey. After postdoctoral work in the laboratories of Vincent Massey and David Ballou, he became a lecturer at the University of Michigan and, in 2003, an Assistant Professor. Research in his laboratory is focused on flavoenzymes in pyrimidine metabolism. 

Karplus, P., M. Daniels, and J. Herriott. Atomic Structure of Ferredoxin-NADP Reductase Prototype for a Structurally Novel Flavoenzyme Family. Science 251, 60-66 (1991). [The structure of a key enzyme involved in nitrogen and sulfur metabolism, as well as in photosynthesis.]... 

Release of iron from ferritin is a reductive process which can be accomplished in vitro with a variety of agents (thioglycolate, dithionite, ascorbate) [20,21]. Superoxide and reduced flavins [22-24] are efficient reductants that may serve this purpose in vivo. Xanthine oxidase and other flavoenzymes that generate superoxide may play a dual role in the redox metabolism of iron. 

Riboflavin, commonly known as vitamin B2, is metabolized inside cells to flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), two very important enzyme cofactors. These molecules possess rather unique and versatile chemical properties, which confer on them the ability to be among the most important redox cofactors found in a broad range of enzymes. In this chapter we provide a brief description of riboflavin metabolism and chemistry, overview the different flavoenzymes engaged in fatty acid p-oxidation and their respective roles. We also highlight recent studies shedding light on the cellular processes and biological effects of riboflavin supplementation in the context of metabolic disease. 

In this section we provide a short overview of the mitochondrial p-oxidation process and focus more specifically on the several flavoenzymes that participate in the pathway, as their adequate function and folding strongly relies on riboflavin metabolism to assure flavin biosynthesis. 

Gianazza and co-workers have carried a series of elegant proteomic studies aimed at establishing correlations between flavin metabolism and mitochondrial flavoenzyme dysfunction (Gianazza et al. 2006). A detailed investigation was carried out on muscle mitochondria from a patient with profound muscle weakness associated with MADD. The patient received riboflavin supplementation treatment (200 mg/day) in combination with carnitine treatment (2g/day) which resulted in a substantial improvement, as assessed by biochemical parameters. Prior the therapeutic riboflavin supplementation, the activity of different fatty acid (5-oxidation enzymes, respiratory complexes, the ratio between acyl/free carnitine and the levels of intracellular lipids were altered in respect to controls. These data led the authors to evaluate the FAD and FMN concentrations in whole muscle, and the results evidenced a lower amount of available FAD upon riboflavin therapy the flavin levels were restored to, at least, control levels. 

Riboflavin, also called vitamin B2, is stmcturally composed of an isoafloxazine ring with a ribityl side chain at the nitrogen at position 10. This vitamin functions metabol-icafly as the essoitial component of two flavin coenzymes, flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), complexed with proteins, which act as intmnediaries in transfers of electrons in biological oxidation-reduction reactions. Both FAD and FMN function as coenzymes for flavoproteins of flavoenzymes. Flavoproteins are essoitial for the metabolism of carbohydrates, amino acids, and lipids and for pyridoxine and folate conversion to their respective coenzyme forms. 

There are several metabolic interrelationships between riboflavin and vitamin Bg. The conversion of pyridoxine or pyridoxamine phosphates to pyri-doxal phosphate is catalyzed by a flavoenzyme (pyri-doxaminephosphate oxidase EC 1.4.3.5), so that a deficiency of riboflavin may, at certain key sites, result in a secondary deficiency in Bg-dependent pathways. More evidence is needed to clarify the extent and importance of these interactions. 

Ross NS and Hansen TPB (1992) Riboflavin deficiency is associated with selective preservation of critical flavoenzyme-dependent metabolic pathways. Biofactors 3 185-190. 

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