Third Faculty of Medicine, Charles University , Prague, Czech Republic .
Antioxid Redox Signal. 2019 Jan 20;30(3):415-442. doi: 10.1089/ars.2017.7255. Epub 2018 Jun 18.
Hexokinases are key enzymes that are responsible for the first reaction of glycolysis, but they also moonlight other cellular processes, including mitochondrial redox signaling regulation. Modulation of hexokinase activity and spatiotemporal location by reactive oxygen and nitrogen species as well as other gasotransmitters serves as the basis for a unique, underexplored method of tight and flexible regulation of these fundamental enzymes. Recent Advances: Redox modifications of thiols serve as a molecular code that enables the precise and complex regulation of hexokinases. Redox regulation of hexokinases is also used by multiple parasites to cause widespread and severe diseases, including malaria, Chagas disease, and sleeping sickness. Redox-active molecules affect each other, and the moonlighting activity of hexokinases provides another feedback loop that affects the cellular redox status and is hijacked in malignantly transformed cells.
Several compounds affect the redox status of hexokinases in vivo. These include the dehydroascorbic acid (oxidized form of vitamin C), pyrrolidinium porrolidine-1-carbodithioate (contraceptive), peroxynitrite (product of ethanol metabolism), alloxan (a glucose analog), and isobenzothiazolinone ebselen. However, very limited information is available regarding which amino acid residues in hexokinases are affected by redox signaling. Except in cases of monogenic diabetes, direct evidence is absent for disease phenotypes that are associated with variations within motifs that are susceptible to redox signaling.
Further studies should address the propensity of hexokinases and their disease-associated variants to participate in redox regulation. Robust and straightforward proteomic methods are needed to understand the context and consequences of hexokinase-mediated redox regulation in health and disease.
己糖激酶是糖酵解的第一个反应的关键酶，但它们也在其他细胞过程中发挥作用，包括线粒体氧化还原信号调节。活性氧和氮物种以及其他气体递质对己糖激酶活性和时空定位的调节是这些基本酶紧密和灵活调节的独特但未被充分探索的方法的基础。
巯基的氧化还原修饰作为一种分子密码，能够精确而复杂地调节己糖激酶。多种寄生虫也利用己糖激酶的氧化还原调节来引起广泛而严重的疾病，包括疟疾、恰加斯病和昏睡病。氧化还原活性分子相互影响，而己糖激酶的兼职活动提供了另一个反馈回路，影响细胞的氧化还原状态，并在恶性转化细胞中被劫持。
有几种化合物在体内影响己糖激酶的氧化还原状态。这些包括脱氢抗坏血酸（维生素 C 的氧化形式）、吡咯烷酮 1-四氢噻吩甲二硫代氨基甲酸酯（避孕药）、过氧亚硝酸根（乙醇代谢产物）、别嘌醇（葡萄糖类似物）和异苯并噻唑啉酮依布硒啉。然而，关于哪些氨基酸残基受到氧化还原信号的影响，我们所掌握的信息非常有限。除了单基因糖尿病的情况外，直接证据缺失，无法证明与易受氧化还原信号影响的基序变异相关的疾病表型。
进一步的研究应该解决己糖激酶及其与疾病相关的变体参与氧化还原调节的倾向。需要稳健和直接的蛋白质组学方法来了解健康和疾病中己糖激酶介导的氧化还原调节的背景和后果。
