B-vitamins and NAD metabolism, or when vitamin B3's bioavailability is not enough

B 族维生素和 NAD 代谢，或当维生素 B3 的生物利用度不足时

• 批准号: BB/N001842/1
• 负责人: Fiona Furlong
• 金额: $ 44.62万
• 依托单位: Queen's University Belfast
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN001842%2F1
• 关键词: vitamins; NAD; metabolism; when; vitamin

The dietary vitamin B3, which encompasses nicotinamide, nicotinic acid and nicotinamide riboside, is precursor to the coenzyme nicotinamide adenine dinucleotide (NAD+), its phosphorylated parent (NADP+) and their respective reduced forms (NADH and NADPH). Once converted intracellularly to NAD(P)+, it is used as a co-substrate in two types of intracellular modifications, which control numerous essential signalling events (adenosine diphosphate ribosylation and deacetylation), and is a cofactor for over 400 redox enzymes, thus controlling metabolism. Critically, the NAD(P)(H)-cofactor family can promote mitochondrial dysfunction and cellular impairment if present in sub-optimal intracellular concentrations.Vitamin B3, and other B-vitamins such as thiamine (vitamin B1), riboflavin (vitamin B2) and pyridoxine (vitamin B6) are extracted in their coenzyme forms from food stuff. During digestion, the coenzymes are catabolised to the free circulating vitamins, which are then passively or actively transported across membranes, and salvaged intracellularly to their respective cofactors. Mammals are entirely reliant on a dietary source of vitamin B1 and heavily dependent on the dietary supply of vitamin B3, B2, and B6. Of note, acute deficiencies in vitamin B1 and vitamin B3 effect identical organs, with identical outcomes if left untreated: dementia and death. Conditions such as diabetes and obesity, alcoholism, high fat diet and conditions where therapy impacts nutrition can compromise suitable absorption of these vitamins.The bulk of intracellular NAD+ is regenerated via the effective salvage of nicotinic acid and nicotinamide (vitamin B3), while de novo NAD+ is obtained from tryptophan. Crucially, these salvage and de novo pathways depend on the functional forms of vitamin B1, B2 and B6 to generate NAD+ via a phosphoriboside pyrophosphate intermediate. Nicotinamide Riboside (NR) is the only form of vitamin B3 from which NAD+ can be generated in a vitamin B1, B2 and B6 independent manner and even though NR is a minor component of vitamin B3, the salvage pathway using NR for the production of NAD+ is expressed in most eukaryotes. While major strides have been made in the field of NAD+ biology and NAD+ metabolism, the role of this later pathway and the importance of the interplay between the bioavailability of vitamin B1, B2 and B6 and the pool of NAD(P)(H)-cofactors remain poorly explored. Using our synthetic expertise in nucleotide and stable isotope labelling chemistry, we will generate isotopically labelled vitamin B1 and B3 derivatives. These entities will be used to determine the profile of the vitamin B3 metabolome quantified by mass spectroscopy, under vitamin B1, B2 and B6 depletion conditions, in genetically engineered yeast strains and mammalian (murine and human) hepatocytes. In mammalian cells, these metabolic profiles will be correlated to mitochondrial functions. With this information, we will be able to prioritise the mechanisms cells use to best maintain the NAD(P)(H) pool in time of shortage of vitamin B1, B2 or B6. We predict that the pathway, by which NR is converted to NAD+, provides the means to rapidly yet transiently elevate mitochondrial and cytosolic NAD(P)(H) levels to kick start mitochondrial functions. If demonstrated, this knowledge will help identify new, physiologically relevant, vitamin-B combinations that could better restore mitochondrial function through enhanced bioavailability, in cells and organs where metabolism has been compromised by imbalanced micronutrition. This knowledge will be particularly important in terms of understanding the impacts of a global or partial vitamin B deficiency and vitamin B supplementation on organ functions in relation to malnutrition and over-nutrition.

膳食维生素 B3 包含烟酰胺、烟酸和烟酰胺核苷，是辅酶烟酰胺腺嘌呤二核苷酸 (NAD+)、其磷酸化母体 (NADP+) 及其各自的还原形式（NADH 和 NADPH）的前体。一旦在细胞内转化为 NAD(P)+，它就被用作两种细胞内修饰的共底物，控制许多重要的信号转导事件（腺苷二磷酸核糖基化和脱乙酰化），并且是 400 多种氧化还原酶的辅助因子，从而控制新陈代谢。至关重要的是，NAD(P)(H)-辅因子家族如果以次优的细胞内浓度存在，会促进线粒体功能障碍和细胞损伤。维生素 B3 和其他 B 族维生素，如硫胺素（维生素 B1）、核黄素（维生素 B2）和吡哆醇（维生素 B6）以辅酶形式提取 来自食品。在消化过程中，辅酶分解代谢为游离循环维生素，然后被动或主动跨膜转运，并在细胞内回收为各自的辅因子。哺乳动物完全依赖维生素 B1 的膳食来源，并且严重依赖维生素 B3、B2 和 B6 的膳食供应。值得注意的是，维生素 B1 和维生素 B3 的严重缺乏会影响相同的器官，如果不及时治疗，会产生相同的结果：痴呆和死亡。糖尿病和肥胖、酗酒、高脂肪饮食以及治疗影响营养等情况会影响这些维生素的适当吸收。大部分细胞内 NAD+ 是通过烟酸和烟酰胺（维生素 B3）的有效回收来再生的，而 NAD+ 是从色氨酸中获得的。至关重要的是，这些挽救和从头途径依赖于维生素 B1、B2 和 B6 的功能形式，通过磷酸核苷焦磷酸中间体生成 NAD+。烟酰胺核苷 (NR) 是维生素 B3 的唯一形式，可以以独立于维生素 B1、B2 和 B6 的方式生成 NAD+，尽管 NR 是维生素 B3 的次要成分，但使用 NR 生成 NAD+ 的补救途径在大多数真核生物中都有表达。虽然 NAD+ 生物学和 NAD+ 代谢领域已经取得了重大进展，但这一后续途径的作用以及维生素 B1、B2 和 B6 的生物利用度与 NAD(P)(H) 辅因子库之间相互作用的重要性仍然鲜有研究。利用我们在核苷酸和稳定同位素标记化学方面的合成专业知识，我们将生成同位素标记的维生素 B1 和 B3 衍生物。这些实体将用于确定在维生素 B1、B2 和 B6 消耗条件下、基因工程酵母菌株和哺乳动物（鼠类和人类）肝细胞中通过质谱定量的维生素 B3 代谢组的概况。在哺乳动物细胞中，这些代谢特征将与线粒体功能相关。有了这些信息，我们将能够优先考虑细胞使用的机制，以便在维生素 B1、B2 或 B6 短缺时最好地维持 NAD(P)(H) 池。我们预测，NR 转化为 NAD+ 的途径提供了快速而短暂地升高线粒体和胞质 NAD(P)(H) 水平以启动线粒体功能的方法。如果得到证实，这一知识将有助于识别新的、生理相关的维生素 B 组合，通过增强生物利用度，在新陈代谢因微量营养不平衡而受到损害的细胞和器官中更好地恢复线粒体功能。这些知识对于了解整体或部分维生素 B 缺乏以及维生素 B 补充对营养不良和营养过剩相关器官功能的影响尤其重要。

项目成果

Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle.

• DOI: 10.1016/j.cmet.2016.07.005
• 发表时间: 2016-08-09
• 期刊: Cell metabolism
• 影响因子: 29
• 作者: Frederick DW;Loro E;Liu L;Davila A Jr;Chellappa K;Silverman IM;Quinn WJ 3rd;Gosai SJ;Tichy ED;Davis JG;Mourkioti F;Gregory BD;Dellinger RW;Redpath P;Migaud ME;Nakamaru-Ogiso E;Rabinowitz JD;Khurana TS;Baur JA
• 通讯作者: Baur JA

Nicotinamide Riboside Is a Major NAD+ Precursor Vitamin in Cow Milk.

• DOI: 10.3945/jn.116.230078
• 发表时间: 2016-05
• 期刊: The Journal of nutrition
• 作者: Samuel A. J. Trammell;Liping Yu;P. Redpath;M. Migaud;C. Brenner

HDAC6 Degradation Inhibits the Growth of High-Grade Serous Ovarian Cancer Cells.

• DOI: 10.3390/cancers12123734
• 发表时间: 2020-12-11
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Ali A;Zhang F;Maguire A;Byrne T;Weiner-Gorzel K;Bridgett S;O'Toole S;O'Leary J;Beggan C;Fitzpatrick P;McCann A;Furlong F
• 通讯作者: Furlong F

Nicotinamide riboside is uniquely and orally bioavailable in mice and humans.

• DOI: 10.1038/ncomms12948
• 发表时间: 2016-10-10
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Trammell, Samuel A. J.;Schmidt, Mark S.;Weidemann, Benjamin J.;Redpath, Philip;Jaksch, Frank;Dellinger, Ryan W.;Li, Zhonggang;Abel, E. Dale;Migaud, Marie E.;Brenner, Charles
• 通讯作者: Brenner, Charles

Nicotinamide riboside kinases display redundancy in mediating nicotinamide mononucleotide and nicotinamide riboside metabolism in skeletal muscle cells.

• DOI: 10.1016/j.molmet.2017.05.011
• 发表时间: 2017-08
• 期刊: Molecular metabolism
• 影响因子: 8.1
• 作者: Fletcher RS;Ratajczak J;Doig CL;Oakey LA;Callingham R;Da Silva Xavier G;Garten A;Elhassan YS;Redpath P;Migaud ME;Philp A;Brenner C;Canto C;Lavery GG
• 通讯作者: Lavery GG