Cholesterogenesis To Steroidogenesis: Role Of B2 In The Biosynthesis Of D

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  1. High_Prob

    High_Prob Member

    Mar 23, 2016
    Cholesterogenesis to Steroidogenesis: Role of B2 in the Biosynthesis of D

    From Cholesterogenesis to Steroidogenesis: Role of Riboflavin and Flavoenzymes in the Biosynthesis of Vitamin D

    From Cholesterogenesis to Steroidogenesis: Role of Riboflavin and Flavoenzymes in the Biosynthesis of Vitamin D1,2

    John T. Pinto* and Arthur J. L. Cooper
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    Flavin-dependent monooxygenases and oxidoreductases are located at critical branch points in the biosynthesis and metabolism of cholesterol and vitamin D. These flavoproteins function as obligatory intermediates that accept 2 electrons from NAD(P)H with subsequent 1-electron transfers to a variety of cytochrome P450 (CYP) heme proteins within the mitochondria matrix (type I) and the (microsomal) endoplasmic reticulum (type II). The mode of electron transfer in these systems differs slightly in the number and form of the flavin prosthetic moiety. In the type I mitochondrial system, FAD-adrenodoxin reductase interfaces with adrenodoxin before electron transfer to CYP heme proteins. In the microsomal type II system, a diflavin (FAD/FMN)-dependent cytochrome P450 oxidoreductase [NAD(P)H-cytochrome P450 reductase (CPR)] donates electrons to a multitude of heme oxygenases. Both flavoenzyme complexes exhibit a commonality of function with all CYP enzymes and are crucial for maintaining a balance of cholesterol and vitamin D metabolites. Deficits in riboflavin availability, imbalances in the intracellular ratio of FAD to FMN, and mutations that affect flavin binding domains and/or interactions with client proteins result in marked structural alterations within the skeletal and central nervous systems similar to those of disorders (inborn errors) in the biosynthetic pathways that lead to cholesterol, steroid hormones, and vitamin D and their metabolites. Studies of riboflavin deficiency during embryonic development demonstrate congenital malformations similar to those associated with genetic alterations of the flavoenzymes in these pathways. Overall, a deeper understanding of the role of riboflavin in these pathways may prove essential to targeted therapeutic designs aimed at cholesterol and vitamin D metabolism.

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    Riboflavin [7,8-dimethyl-(N-10-ribityl) isoalloxazine] or vitamin B-2 is synthesized by plants and bacteria and used by animal cells to form the flavin nucleotide coenzymes. Flavin nucleotides are essential for cell growth and development, and a deficiency of riboflavin can lead to clinical abnormalities that range from hemolytic anemia to growth retardation and neurologic dysfunctions. Marginal riboflavin deficiency as well as development of frank deficiency states can result from digestive and malabsorptive disorders that may involve intestinal resection or bypass, drug interactions, and alcohol abuse. In addition, rare congenital defects of riboflavin transport can cause persistent riboflavin deficiency. It is important to note that physical and clinical symptoms of riboflavin deficiency are not unique to riboflavin. Due to interactions of B vitamins and their interdependency, the classical signs of glossitis, angular stomatitis, cheilosis, and dermatitis may be observed in deficiencies of other B vitamins as well. A comprehensive review of riboflavin metabolism, including its antioxidant activities, involvement in cell signaling, role as a coenzyme, and clinical aspects of deficiency, has recently been published (1).

    Flavoenzymes are capable of conducting electron transfer reactions. The underlying mechanisms that govern these reactions are based predominantly on the ability of the heterocyclic isoalloxazine ring of FMN and FAD to accept 1 or 2 electrons. Diagrammatic representations of riboflavin and its coenzymic nucleotide forms are shown in Fig. 1. The flavin nucleotides function with their client proteins as mediators between 1-electron acceptor/donor and 2-electron acceptor/donor activities that catalyze oxidation-reduction reactions involved primarily in energy, carbohydrate, lipid, and amino acid metabolism. In consideration of the major metabolic pathways that flavoenzymes influence, nutritional deficiencies of riboflavin impact primarily on lipid metabolism. Flavin coenzymes serve an eclectic array of proteins that function as electron transferases, dehydrogenases, oxidoreductases, monooxygenases, hydroxylases, and oxidases for reactions that desaturate essential FAs, form phospho- and ether lipids, and synthesize sphingosine, cholesterol, and steroids (1). Individuals who experience even marginal degrees of riboflavin deficiency can experience skin dyscrasias characteristic of those observed during essential FA deficiencies. Also, riboflavin deficiency can lead to a rapid and marked decrease in hepatic mitochondrial FA oxidation. Needle biopsies of the liver indicate fatty metamorphosis and those of muscle reveal vacuolar myopathy with lipid accumulation.

    FIGURE 1

    Structures of flavin coenzymes. The isoalloxazine ring is shown relative to riboflavin and its nucleotide coenzymes, riboflavin 5′-phosphate (FMN) and FAD. The shaded area depicts the region of the isoalloxazine ring that is involved in the direct ...
    Flavins also assist in the catalytic activation and degradation of other vitamins. For example, flavoenzymes affect de novo biosynthesis of ascorbic acid (2, 3), control the conversion of pyridoxine and vitamin K to their physiologically active forms (47), protect vitamins from oxidative degradation (810), and function conjointly with other vitamin-dependent enzymes, e.g., pyruvate dehydrogenase complex and respiratory chain complexes (11). Such interactions are the basis for the interdependency among vitamins and an underlying cause of secondary vitamin deficiencies. This interconnection ultimately results in the overlapping clinical signs and multiple sequelae that occur during vitamin deficiencies. In view of these interactions, the availability of riboflavin, its conversion to FMN and FAD, and their association with flavoenzymes can markedly affect the metabolism of folate, pyridoxine, vitamin K, niacin, and ascorbate. In light of these interactions, this review will address the critical role of flavoproteins in controlling cholesterogenesis and steroidogenesis and in regulating the biosynthesis and transformations of metabolites from these pathways into vitamin D.

    Metabolically active vitamin D can be obtained from diet-derived, lipid-soluble phyto- and zoosterol prohormones, namely vitamin D2 [9,10-seco(5Z,7E)-5,7,10(19),21-ergostatetraene-3β-ol; ergocalciferol] and vitamin D3 [9,10-seco(5Z,7E)-5,7,10(19)-cholestatriene-3β-ol; cholecalciferol], respectively. In addition to its availability from diet and supplements, cholecalciferol can be synthesized by dermal keratinocytes after cutaneous exposure to UV radiation (UV-B, 270–300 nm). The nonenzymatic reaction involves a photolytic fission of the 9,10-carbon bond within the B ring of the sterol ring system, resulting in a seco (ring opened)-steroid. This results in conversion of provitamin D3 (7-dehydrocholesterol) to a previtamin D3 (6-s-cis form), which undergoes a thermally induced E/Z isomerization to form 6-s-trans, cholecalciferol (12). Both ergocalciferol and cholecalciferol must be converted into physiologically active vitamin D metabolites through 2 separate ring hydroxylations with subsequent formation of 1α,25-dihydroxyvitamin D [1α,25(OH)2D]3. Current investigations in healthy individuals with negligible UV-B exposure suggest that ergocalciferol and cholecalciferol are equipotent in their capacity to be 25-hydroxylated to form 25-hydroxyvitamin D [25(OH)D], the major circulating form of vitamin D (13, 14). For this review we will assume that the 25-hydroxylations of ergocalciferol and cholecalciferol to form their respective 25(OH)D2 and 25(OH)D3 metabolites as well as the 1α-hydroxylations of the latter 2 metabolites to form 1α,25(OH)2D derivatives, the active principal of the vitamin D hormone, are comparable.
  2. Wilfrid

    Wilfrid Member

    Nov 26, 2012
    Very interesting. Thanks.