几十年来,维生素B6缺乏与人脑疾病的认知障碍有关。尽管如此,将维生素B6与这些病理联系起来的分子机制仍然知之甚少,补充维生素B6是否能改善认知功能尚不清楚。吡哆醛5'-磷酸磷酸酶(PDXP),一种控制吡哆醛5'-磷酸(PLP)水平的酶,维生素B6的共酶活性形式可能代表维生素B6相关病理的替代治疗切入点。然而,缺乏用于测试这一概念的药物PDXP抑制剂。我们现在确定了PDXP和小鼠海马中PLP水平的年龄依赖性下降,这为PDXP抑制剂的开发提供了理论基础。使用小分子筛选的组合,蛋白质晶体学,和生物层干涉测量,我们发现,可视化,并分析7,8-二羟基黄酮(7,8-DHF)作为直接和有效的PDXP抑制剂。7,8-DHF以低微摩尔亲和力和亚微摩尔效力结合并可逆地抑制PDXP。在小鼠海马神经元中,7,8-DHF以PDXP依赖的方式增加PLP。这些发现验证了PDXP作为一个药物靶标。值得注意的是,7,8-DHF是脑紊乱模型中研究良好的分子,尽管它的作用机制正在积极辩论。我们发现7,8-DHF作为PDXP抑制剂,为围绕7,8-DHF介导的大脑效应的争议提供了新的机制见解。
维生素B6是优化大脑功能的重要营养素,与记忆受损有关的缺陷,学习和情绪在各种精神障碍。在老年人中,维生素B6缺乏也与记忆力下降和痴呆有关。虽然这已经知道多年了,维生素B6在这些疾病中的确切作用以及补充剂是否可用于治疗或预防这些疾病尚不清楚.这部分是因为维生素B6实际上是少数非常相似和可互换分子的总称。其中只有一种是“生物活性的”,这意味着它在细胞中具有生物学作用。然而,缺乏旨在仅增加维生素B6生物活性形式的治疗策略。以前的工作表明,破坏一种叫做吡哆醛磷酸酶的基因,它可以分解维生素B6,改善小鼠的记忆力和学习能力。为了研究这些作用是否可以被类似药物的化合物模仿,布伦纳,Zink,Witzinger等人。使用几种生化和结构生物学方法来搜索与吡哆醛磷酸酶结合并抑制的分子。实验表明,一种名为7,8-二羟基黄酮的分子-以前被发现可以改善患有脑部疾病的实验动物的记忆力和学习能力-与吡哆醛磷酸酶结合并抑制其活性。这导致参与记忆和学习的小鼠脑细胞中生物活性维生素B6水平增加。Brenner等人的发现。建议抑制吡哆醛磷酸酶以增加大脑中的维生素B6水平可以与补充剂一起使用。将7,8-二羟基黄酮鉴定为有希望的候选药物是发现更有效的吡哆醛磷酸酶抑制剂的第一步。这些将是有用的实验工具,可以直接研究增加大脑中生物活性维生素B6的水平是否可以帮助那些患有与记忆障碍相关的精神健康状况的人。学习和心情。
Vitamin B6 deficiency has been linked to cognitive impairment in human brain disorders for decades. Still, the molecular mechanisms linking vitamin B6 to these pathologies remain poorly understood, and whether vitamin B6 supplementation improves cognition is unclear as well. Pyridoxal 5\'-phosphate phosphatase (PDXP), an enzyme that controls levels of pyridoxal 5\'-phosphate (PLP), the co-enzymatically active form of vitamin B6, may represent an alternative therapeutic entry point into vitamin B6-associated pathologies. However, pharmacological PDXP inhibitors to test this concept are lacking. We now identify a PDXP and age-dependent decline of PLP levels in the murine hippocampus that provides a rationale for the development of PDXP inhibitors. Using a combination of small-molecule screening, protein crystallography, and biolayer interferometry, we discover, visualize, and analyze 7,8-dihydroxyflavone (7,8-DHF) as a direct and potent PDXP inhibitor. 7,8-DHF binds and reversibly inhibits PDXP with low micromolar affinity and sub-micromolar potency. In mouse hippocampal neurons, 7,8-DHF increases PLP in a PDXP-dependent manner. These findings validate PDXP as a druggable target. Of note, 7,8-DHF is a well-studied molecule in brain disorder models, although its mechanism of action is actively debated. Our discovery of 7,8-DHF as a PDXP inhibitor offers novel mechanistic insights into the controversy surrounding 7,8-DHF-mediated effects in the brain.
Vitamin B6 is an important nutrient for optimal brain function, with deficiencies linked to impaired memory, learning and mood in various mental disorders. In older people, vitamin B6 deficiency is also associated with declining memory and dementia. Although this has been known for years, the precise role of vitamin B6 in these disorders and whether supplements can be used to treat or prevent them remained unclear. This is partly because vitamin B6 is actually an umbrella term for a small number of very similar and interchangeable molecules. Only one of these is ‘bioactive’, meaning it has a biological role in cells. However, therapeutic strategies aimed at increasing only the bioactive form of vitamin B6 are lacking. Previous work showed that disrupting the gene for an enzyme called pyridoxal phosphatase, which breaks down vitamin B6, improves memory and learning in mice. To investigate whether these effects could be mimicked by drug-like compounds, Brenner, Zink, Witzinger et al. used several biochemical and structural biology approaches to search for molecules that bind to and inhibit pyridoxal phosphatase. The experiments showed that a molecule called 7,8-dihydroxyflavone – which was previously found to improve memory and learning in laboratory animals with brain disorders – binds to pyridoxal phosphatase and inhibits its activity. This led to increased bioactive vitamin B6 levels in mouse brain cells involved in memory and learning. The findings of Brenner et al. suggest that inhibiting pyridoxal phosphatase to increase vitamin B6 levels in the brain could be used together with supplements. The identification of 7,8-dihydroxyflavone as a promising candidate drug is a first step in the discovery of more efficient pyridoxal phosphatase inhibitors. These will be useful experimental tools to directly study whether increasing the levels of bioactive vitamin B6 in the brain may help those with mental health conditions associated with impaired memory, learning and mood.