细胞质NADK对叶酸依赖的核酸合成有条件必要
Kyle M Flickinger1,2, Carlos A Mellado Fritz1,2, Kimberly S Huggler1,2
1Morgridge Institute for Research, Madison, WI, USA.
Nature metabolism
|May 2, 2025
概括
尼古丁胺胺氨基二核酸激酶 (NADK) 在低叶酸条件下对癌细胞生长至关重要,它通过支持二叶酸还原酶 (DHFR) 的NADPH生产来支持癌细胞生长. 这揭示了对于理解癌症代谢至关重要的条件依赖.
科学领域:
- 生物化学 生物化学
- 细胞生物学 细胞生物学
- 代谢途径 代谢途径
背景情况:
- 尼古丁胺胺氨基二核酸激酶 (NADK) 将NAD+酸化为NADP+,产生NADPH,这是减少代谢的关键辅因子.
- 癌细胞利用细胞质 (NADK) 和线粒体 (NADK2) 异构体,这些异构体通常在标准介质中不可或缺.
- 克里斯普尔屏幕显示,在类似于人体血的介质中,在NADK被删除后,有条件的生长缺陷.
研究的目的:
- 为了研究NADK在癌细胞中的条件基本性.
- 阐明与NADK功能相关的特定代谢途径和营养依赖性.
- 了解NADK在叶酸代谢和NADPH生产中的作用.
主要方法:
- 在多个癌症细胞系中进行CRISPR查.
- 在常规和人体等离子体媒介中进行细胞生长测试.
- 代谢分析侧重于叶酸代谢和辅助因子的可用性.
主要成果:
- 在低叶酸条件下,NADK删除特别损害了癌细胞的生长.
- 纳迪克是细胞质NADPH生产所需的,这对于二叶酸减少酶 (DHFR) 活性至关重要.
- 足够的DHFR活性,由NADPH驱动,对于在营养压力下依赖叶酸的核酸合成至关重要.
- 叶酸的可用性决定了DHFR是否依赖NADPH或像NADH这样的替代捐赠者.
结论:
- NADK的条件基本性与叶酸的可用性有关.
- 通过NADPH的产生,NADK在维持叶酸代谢中起着至关重要的作用,特别是在营养有限的条件下.
- 向NADK可能是针对特定依赖叶酸的癌症的策略.
相关概念视频
01:29Role of Reduced Coenzymes NADH and FADH₂
10.9K
The energy released from the breakdown of the chemical bonds within nutrients can be stored either through the reduction of electron carriers or in the bonds of adenosine triphosphate (ATP). In living systems, a small class of compounds functions as mobile electron carriers, molecules that bind to and shuttle high-energy electrons between compounds in pathways. The principal electron carriers that will be considered originate from the B vitamin group and are derivatives of nucleotides; they are...
10.9K
02:27Nonsense-mediated mRNA Decay
10.3K
The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
10.3K
01:28ATP and Macromolecule Synthesis
5.1K
Biological macromolecules are organic compounds, predominantly composed of carbon atoms. The carbon atoms are covalently bonded with hydrogen, oxygen, nitrogen, and other minor elements. There are four major biological macromolecule classes: carbohydrates, lipids, proteins, and nucleic acids.
Most macromolecules are composed of single subunits, or building blocks, called monomers. The monomers combine with each other using covalent bonds to form larger molecules known as polymers.
Conversion of...
Most macromolecules are composed of single subunits, or building blocks, called monomers. The monomers combine with each other using covalent bonds to form larger molecules known as polymers.
Conversion of...
5.1K
01:48ATP Synthase: Mechanism
13.6K
In animals, the mitochondrial F1F0 ATP synthase is the key protein that synthesizes ATP molecules through a complex catalytic mechanism. While the nuclear genome encodes the majority of ATP synthase subunits, the mitochondrial genome encodes some of the enzyme's most critical components. The formation of this multi-subunit enzyme is a complex multi-step process regulated at the level of transcription, translation, and assembly. Defects in one or more of these steps can result in decreased...
13.6K
02:53Ribosomal RNA Synthesis
12.9K
Ribosome synthesis is a highly complex and coordinated process involving more than 200 assembly factors. The synthesis and processing of ribosomal components occurs not only in the nucleolus but also in the nucleoplasm and the cytoplasm of eukaryotic cells.
Ribosome biogenesis begins with the synthesis of 5S and 45S pre-rRNAs by distinct RNA polymerases. The primary transcripts are extensively processed and modified before they are bound and folded by ribosomal proteins and assembly factors,...
Ribosome biogenesis begins with the synthesis of 5S and 45S pre-rRNAs by distinct RNA polymerases. The primary transcripts are extensively processed and modified before they are bound and folded by ribosomal proteins and assembly factors,...
12.9K
01:19Allosteric Proteins-ATCase
5.6K
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
5.6K