Pinto John T, Cooper Arthur J L
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY.
Adv Nutr. 2014 Mar 1;5(2):144-63. doi: 10.3945/an.113.005181.
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.
黄素依赖性单加氧酶和氧化还原酶位于胆固醇和维生素D生物合成与代谢的关键分支点。这些黄素蛋白作为 obligatory 中间体，从NAD(P)H接受2个电子，随后将1个电子转移到线粒体基质（I型）和（微粒体）内质网（II型）内的多种细胞色素P450（CYP）血红素蛋白。这些系统中的电子转移模式在黄素辅基部分的数量和形式上略有不同。在I型线粒体系统中，FAD - 肾上腺皮质铁氧化还原蛋白还原酶在电子转移至CYP血红素蛋白之前与肾上腺皮质铁氧化还原蛋白相互作用。在微粒体II型系统中，一种双黄素（FAD/FMN）依赖性细胞色素P450氧化还原酶[NAD(P)H - 细胞色素P450还原酶（CPR）]将电子捐赠给多种血红素加氧酶。两种黄素酶复合物与所有CYP酶都具有功能共性，对于维持胆固醇和维生素D代谢物的平衡至关重要。核黄素可用性不足、细胞内FAD与FMN比例失衡以及影响黄素结合域和/或与客户蛋白相互作用的突变会导致骨骼和中枢神经系统内出现明显的结构改变，类似于导致胆固醇、类固醇激素、维生素D及其代谢物的生物合成途径中的疾病（先天性缺陷）。胚胎发育期间核黄素缺乏的研究表明存在与这些途径中黄素酶基因改变相关的先天性畸形。总体而言，深入了解核黄素在这些途径中的作用可能对针对胆固醇和维生素D代谢的靶向治疗设计至关重要。
