Nicotianamine

Nicotianamine is a secondary metabolite ​synthesized by​ plants that plays a central role in maintaining metal ion homeostasis^[1]. Nicotianamine can form stable chelates with various metal ions, ​for example, iron, zinc, copper, and manganese, thereby promoting their transport and distribution within plants^[2]. Nicotianamine is essential for metal nutrition and metal homeostasis in flowering plants, and its deficiency leads to growth abnormalities and imbalances in metal ion distribution^[3]. Additionally, Nicotianamine exhibits inhibitory activity against angiotensin-converting enzyme (ACE), with IC₅₀ values of 76nM (against rhACE2) and 59nM (against rhACE)^[4].

In vitro, treatment of Caco-2 cells with Nicotianamine (10μM) together with an iron-containing solution significantly increased cellular ferritin synthesis levels, enhancing iron bioavailability^[5]. When supplemented (100 μM) into airway mucosal secretions (AMS) and used to pretreat Pseudomonas aeruginosa (PAO1) and ΔPA4834 mutant strain for 16 hours, Nicotianamine maintained the growth capacity of both PAO1 and the ΔPA4834 mutant in AMS and significantly improved bacterial iron acquisition efficiency^[6].

In vivo, oral administration of a Nicotianamine (33mM) and ferrous iron (3.3mM) chelate via gastric gavage to 8-week-old ICR mice significantly promoted iron absorption in the proximal jejunum and increased iron content in the kidneys and spleen within 5 hours^[7]. In ovo injection of Nicotianamine (1.6mM) into 17-day-old chicken embryos significantly elevated serum iron concentration in the chickens and suppressed the expression of iron homeostasis genes such as DcytB and DMT1 in the duodenum^[8].

References:
[1] Bouazaoui M, Mari S, Czernic P, et al. Synthesis and biological activity of nicotianamine and analogues. Adv Exp Med Biol. 2009;611:555-7.
[2] Trampczynska A, Küpper H, Meyer-Klaucke W, et al. Nicotianamine forms complexes with Zn(II) in vivo. Metallomics. 2010 Jan;2(1):57-66.
[3] Clemens S, Deinlein U, Ahmadi H, et al. Nicotianamine is a major player in plant Zn homeostasis. Biometals. 2013 Aug;26(4):623-32.
[4] Takahashi S, Yoshiya T, Yoshizawa-Kumagaye K, et al. Nicotianamine is a novel angiotensin-converting enzyme 2 inhibitor in soybean. Biomed Res. 2015;36(3):219-24.
[5] Zheng L, Cheng Z, Ai C, et al. Nicotianamine, a novel enhancer of rice iron bioavailability to humans. PLoS One. 2010 Apr 16;5(4):e10190.
[6] Gi M, Lee KM, Kim SC, et al. A novel siderophore system is essential for the growth of Pseudomonas aeruginosa in airway mucus. Sci Rep. 2015 Oct 8;5:14644.
[7] Murata Y, Yoshida M, Sakamoto N, et al. Iron uptake mediated by the plant-derived chelator nicotianamine in the small intestine. J Biol Chem. 2021 Jan-Jun;296:100195.
[8] Beasley JT, Johnson AAT, Kolba N, et al. Nicotianamine-chelated iron positively affects iron status, intestinal morphology and microbial populations in vivo (Gallus gallus). Sci Rep. 2020 Feb 10;10(1):2297.

Nicotianamine是一种由植物产生的、在维持金属离子平衡中起核心作用的次生代谢物质^[1]。Nicotianamine能够与铁、锌、铜、锰等多种金属离子形成稳定的螯合物，从而促进这些微量元素在植物体内的运输和分布^[2]。Nicotianamine对于开花植物的金属营养和金属稳态至关重要，其缺乏会导致植物出现生长异常和金属离子分布失衡^[3]。Nicotianamine还表现出对血管紧张素转换酶（ACE）的抑制活性，其IC₅₀值分别为76nM（针对rhACE2）和59nM（针对rhACE）^[4]。

在体外，Nicotianamine（10μM）与含铁溶液共同处理Caco-2细胞，显著提升细胞铁蛋白合成水平，促进细胞铁的生物利用度^[5]。Nicotianamine（100μM）补充于气道黏液分泌物（AMS）中，预处理Pseudomonas aeruginosa（PAO1）及其ΔPA4834突变株16小时，Nicotianamine可维持PAO1和ΔPA4834突变株在AMS中的生长能力，并显著提升细菌对铁的获取效率^[6]。

在体内，Nicotianamine（33mM；200μL）与亚铁离子（3.3mM；200μL）的螯合物通过胃管灌胃给予8周龄ICR小鼠，显著促进了近端空肠对铁的吸收，并在5小时内提升了肾脏和脾脏中的铁含量^[7]。Nicotianamine（1.6mM）通过卵内注射方式给予孵化17天的鸡胚，显著提高了鸡只血液血清铁浓度，并下调了十二指肠中DcytB和DMT1等铁稳态基因的表达^[8]。