Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA.
Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA; Department of Internal Medicine, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA; Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA.
Cell. 2014 Sep 11;158(6):1324-1334. doi: 10.1016/j.cell.2014.07.040.
The P7C3 class of aminopropyl carbazole chemicals fosters the survival of neurons in a variety of rodent models of neurodegeneration or nerve cell injury. To uncover its mechanism of action, an active derivative of P7C3 was modified to contain both a benzophenone for photocrosslinking and an alkyne for CLICK chemistry. This derivative was found to bind nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme involved in the conversion of nicotinamide into nicotinamide adenine dinucleotide (NAD). Administration of active P7C3 chemicals to cells treated with doxorubicin, which induces NAD depletion, led to a rebound in intracellular levels of NAD and concomitant protection from doxorubicin-mediated toxicity. Active P7C3 variants likewise enhanced the activity of the purified NAMPT enzyme, providing further evidence that they act by increasing NAD levels through its NAMPT-mediated salvage.
P7C3 类氨基丙基咔唑类化学物质促进了多种神经退行性或神经细胞损伤的啮齿动物模型中神经元的存活。为了揭示其作用机制，对 P7C3 的一种活性衍生物进行了修饰，使其同时包含用于光交联的二苯甲酮和用于 CLICK 化学的炔烃。发现该衍生物与烟酰胺磷酸核糖转移酶（NAMPT）结合，NAMPT 是将烟酰胺转化为烟酰胺腺嘌呤二核苷酸（NAD）的限速酶。用阿霉素（一种诱导 NAD 耗竭的药物）处理细胞后，用活性 P7C3 化学物质处理，可导致细胞内 NAD 水平反弹，并伴随对阿霉素介导的毒性的保护。活性 P7C3 变体同样增强了纯化的 NAMPT 酶的活性，进一步证明它们通过 NAMPT 介导的补救作用增加 NAD 水平来发挥作用。
