di Salvo Martino Luigi, Contestabile Roberto, Safo Martin K
Dipartimento di Scienze Biochimiche A. Rossi Fanelli, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza Università di Roma, Piazzale Aldo Moro 5, 00185, Roma, Italy.
Biochim Biophys Acta. 2011 Nov;1814(11):1597-608. doi: 10.1016/j.bbapap.2010.12.006. Epub 2010 Dec 20.
Vitamin B(6) is a generic term referring to pyridoxine, pyridoxamine, pyridoxal and their related phosphorylated forms. Pyridoxal 5'-phosphate is the catalytically active form of vitamin B(6), and acts as cofactor in more than 140 different enzyme reactions. In animals, pyridoxal 5'-phosphate is recycled from food and from degraded B(6)-enzymes in a "salvage pathway", which essentially involves two ubiquitous enzymes: an ATP-dependent pyridoxal kinase and an FMN-dependent pyridoxine 5'-phosphate oxidase. Once it is made, pyridoxal 5'-phosphate is targeted to the dozens of different apo-B(6) enzymes that are being synthesized in the cell. The mechanism and regulation of the salvage pathway and the mechanism of addition of pyridoxal 5'-phosphate to the apo-B(6)-enzymes are poorly understood and represent a very challenging research field. Pyridoxal kinase and pyridoxine 5'-phosphate oxidase play kinetic roles in regulating the level of pyridoxal 5'-phosphate formation. Deficiency of pyridoxal 5'-phosphate due to inborn defects of these enzymes seems to be involved in several neurological pathologies. In addition, inhibition of pyridoxal kinase activity by several pharmaceutical and natural compounds is known to lead to pyridoxal 5'-phosphate deficiency. Understanding the exact role of vitamin B(6) in these pathologies requires a better knowledge on the metabolism and homeostasis of the vitamin. This article summarizes the current knowledge on structural, kinetic and regulation features of the two enzymes involved in the PLP salvage pathway. We also discuss the proposal that newly formed PLP may be transferred from either enzyme to apo-B(6)-enzymes by direct channeling, an efficient, exclusive, and protected means of delivery of the highly reactive PLP. This new perspective may lead to novel and interesting findings, as well as serve as a model system for the study of macromolecular channeling. This article is part of a Special Issue entitled: Pyridoxal Phosphate Enzymology.
维生素B6是一个通用术语，指的是吡哆醇、吡哆胺、吡哆醛及其相关的磷酸化形式。磷酸吡哆醛是维生素B6的催化活性形式，在140多种不同的酶反应中作为辅因子发挥作用。在动物体内，磷酸吡哆醛通过一条“补救途径”从食物和降解的B6-酶中循环利用，该途径主要涉及两种普遍存在的酶：一种依赖ATP的吡哆醛激酶和一种依赖FMN的磷酸吡哆醇5'-氧化酶。一旦合成，磷酸吡哆醛就会靶向细胞中正在合成的数十种不同的脱辅基B6-酶。补救途径的机制和调节以及磷酸吡哆醛添加到脱辅基B6-酶中的机制尚不清楚，是一个极具挑战性的研究领域。吡哆醛激酶和磷酸吡哆醇5'-氧化酶在调节磷酸吡哆醛形成水平方面发挥动力学作用。由于这些酶的先天性缺陷导致的磷酸吡哆醛缺乏似乎与几种神经病理学有关。此外，已知几种药物和天然化合物对吡哆醛激酶活性的抑制会导致磷酸吡哆醛缺乏。了解维生素B6在这些病理学中的确切作用需要更好地了解该维生素的代谢和稳态。本文总结了目前关于参与PLP补救途径的两种酶的结构、动力学和调节特征的知识。我们还讨论了新形成的PLP可能通过直接通道化从任一酶转移到脱辅基B6-酶的提议，这是一种高效、专一且受保护的高反应性PLP递送方式。这种新观点可能会带来新颖有趣的发现，并作为研究大分子通道化的模型系统。本文是名为《磷酸吡哆醛酶学》的特刊的一部分。
