아데노신삼인산 ATP란 무엇인가?

[문형철]

Metabolites. 2022 May; 12(5): 461.

Published online 2022 May 20. doi: 10.3390/metabo12050461

PMCID: PMC9148104

PMID: 35629965

The Legend of ATP: From Origin of Life to Precision Medicine

Xin-Yi Chu,1,2 Yuan-Yuan Xu,1 Xin-Yu Tong,1 Gang Wang,1 and Hong-Yu Zhang1,*

Silvia Ravera, Academic Editor

Author information Article notes Copyright and License information PMC Disclaimer

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Abstract

Adenosine triphosphate (ATP) may be the most important biological small molecule. Since it was discovered in 1929, ATP has been regarded as life’s energy reservoir. However, this compound means more to life. Its legend starts at the dawn of life and lasts to this day. ATP must be the basic component of ancient ribozymes and may facilitate the origin of structured proteins. In the existing organisms, ATP continues to construct ribonucleic acid (RNA) and work as a protein cofactor.

ATP also functions as a biological hydrotrope, which may keep macromolecules soluble in the primitive environment and can regulate phase separation in modern cells. These functions are involved in the pathogenesis of aging-related diseases and breast cancer, providing clues to discovering anti-aging agents and precision medicine tactics for breast cancer.

아데노신 삼인산(ATP)은 

가장 중요한 생물학적 소분자일 수 있습니다. 

1929년에 발견된 이래 

ATP는 생명의 에너지 저장고로 여겨져 왔습니다. 하지만 이 화합물은 생명에 더 많은 의미를 지니고 있습니다. 이 화합물의 전설은 생명의 태동과 함께 시작되어 오늘날까지 이어지고 있습니다. 

ATP는

ancient 리보효소의 기본 구성 요소임에 틀림없으며

구조화된 단백질의 기원을 촉진할 수 있습니다.

현존하는 유기체에서

ATP는

계속해서 리보핵산(RNA)을 구성하고

단백질 보조 인자로 작용합니다. 

ATP는 

또한 원시 환경에서 거대 분자의 용해성을 유지하고 

현대 세포에서 상 분리를 조절할 수 있는  phase separation in modern cells

생물학적 하이드로트로프 역할을 합니다. 

이러한 기능은 

노화 관련 질병과 유방암의 발병에 관여하여 

노화 방지제 및 유방암에 대한

 정밀 의학 전략을 발견하는 데 단서를 제공합니다.

Keywords: adenosine triphosphate (ATP), origin of life, precision medicine, drug discovery, phase separation, hydrotrope

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1. Introduction

The origin of life is one of the most significant and fundamental issues in science. In this controversial area, numerous “starting points” of life have been proposed. Different from the biological macromolecules that are conventionally concerned, Sharov focuses on small molecules with catalytic functions and proposed a coenzyme world model: the coenzyme-like molecules (CLMs) attached to the oil droplets constitute the earliest system capable of primitive metabolism and evolvable self-reproduction [1,2]. Although such a system has not been proven, coenzymes’ structural simplicity and functional importance make CLMs an attractive starting point for life.

생명의 기원은 

과학에서 가장 중요하고 근본적인 문제 중 하나입니다. 

논란의 여지가 많은 이 분야에서 

수많은 생명의 '출발점'이 제안되었습니다. 

샤로프는 

기존의 생물학적 거대 분자와는 

달리 촉매 기능을 가진 작은 분자에 초점을 맞추고 

코엔자임 세계 모델을 제안했는데, 

기름방울에 붙어 있는 코엔자임 유사 분자(CLM)가 

원시적 대사와 진화 가능한 자기 복제가 가능한 최초의 시스템을 구성한다는 것입니다[1,2]. 

이러한 시스템이 입증되지는 않았지만, 

코엔자임의 구조적 단순성과 기능적 중요성으로 인해 

CLM은 생명체의 매력적인 출발점이 되고 있습니다.

Among the various coenzymes, adenosine triphosphate (ATP) is an especially attractive one. ATP is one of the most abundant components in the modern cell, with a concentration of up to 10 mmol/L [3]. Coinciding with its high concentration, ATP is indeed versatile. As a coenzyme, ATP is bound by hundreds of protein structures and, thus, is involved in many metabolic pathways. Since first isolated from muscle and liver extracts by Karl Lohmann in 1929, ATP was regarded as life’s energy reservoir [4]. ATP is a component of RNA and a substrate for the first step of protein synthesis. Through protein phosphorylation reaction, ATP participates in the signaling of key bioprocesses. ATP can also work as a transmitter in intercellular purinergic signaling [5]. Recently, ATP was found to have a role as a hydrotrope and regulate cellular compartmentalization [6].

From the beginning to the current scene, ATP plays multiple critical roles in the drama of life. In this paper, we will show why ATP is so important to the origin of life and how the critical functions of ATP open up a new area of biomedicine.

다양한 코엔자임 중에서도 

아데노신 삼인산(ATP)은 

특히 매력적인 코엔자임입니다. 

ATP는 

현대 세포에서 가장 풍부한 성분 중 하나로, 

농도가 최대 10mmol/L에 달합니다[3]. 

높은 농도에 걸맞게 

ATP는 

실제로 다재다능합니다. 

조효소인 ATP는 

수백 개의 단백질 구조에 결합되어 있어 

많은 대사 경로에 관여합니다. 

1929년

칼 로만이  Karl Lohmann in 1929

근육과 간 추출물에서 처음 분리한 이래 

ATP는 생명의 에너지 저장고로 여겨져 왔습니다[4]. 

ATP는 

RNA의 구성 요소이자 

단백질 합성의 첫 번째 단계를 위한 기질입니다. 

ATP는 

단백질 인산화 반응을 통해 

주요 생체 과정의 신호 전달에 참여합니다. 

ATP는 또한 

세포 간 퓨린성 신호 전달자로서도 작용할 수 있습니다[5]. 

최근 

ATP는 

하이드로트로프로서의 역할과 

세포 구획화를 조절하는 것으로 밝혀졌습니다 [6].

생명의 시작부터 현재에 이르기까지 

ATP는 생명의 드라마에서 

여러 가지 중요한 역할을 합니다. 

이 논문에서는 

ATP가 생명의 기원에 왜 그렇게 중요한지, 

그리고 ATP의 중요한 기능이 

어떻게 생물 의학의 새로운 영역을 여는지를 보여 드리겠습니다.

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2. Prebiotic Synthesis of ATP

ATP may exist on the primitive Earth. ATP is composed of adenine, a ribose, and a triphosphate group. The prebiotic synthesis of adenine and ribose has been extensively studied and excellently reviewed in a recent work by Yadav et al. [7]. The soluble phosphorus required for the synthesis of triphosphate groups may be provided by the phosphite contained in the extraterrestrial schreibersite or the polyphosphates produced by volcanic activity [8,9], which can be converted to orthophosphate in plausible prebiotic environments [8]. One obstacle to the synthesis of nucleotides is that the condensations of the three components are thermodynamically unfavorable in water [10]. A possible solution to this challenge is adsorbing the reactants on mineral surfaces, and then carrying out the condensations during a drying process. Using such a strategy, Akouche et al. synthesized adenosine monophosphate (AMP) from adenosine, ribose, and potassium dihydrogenophosphate on the amorphous silica at 70 °C [11]. AMP can be further phosphorylated into ADP and ATP in the presence of hydroxyapatite and cyanate at room temperature [12], or by reacting with metaphosphoric acid under the catalysis of metal ions [13,14]. Nickel was found to be the most efficient metal catalyst for ATP synthesis, which may have been brought to the Hadean Earth by meteorites [15]. These reactions do not rely on harsh physical and chemical conditions and thus may be feasible on the primitive Earth.

ATP는 

원시 지구에 존재했을 수 있습니다. 

ATP는 

아데닌, 

리보스, 

삼인산기로 구성됩니다. 

아데닌과 리보스의 프리바이오틱 합성은

 광범위하게 연구되어 왔으며 

최근 Yadav 등의 연구에서 훌륭하게 검토되었습니다[7]. 

https://www.nature.com/articles/s41467-018-07220-y

삼인산염 그룹의 합성에 필요한 

용해성 인은 외계 슈라이버사이트에 포함된 인산염 또는

 화산 활동으로 생성된 다인산염에 의해 제공될 수 있으며[8,9], 

이는 그럴듯한 프리바이오틱 환경에서 

오르토인산염으로 전환될 수 있습니다[8]. 

뉴클레오타이드 합성의 한 가지 장애물은 

세 가지 구성 요소의 응축이 

물에서 열역학적으로 불리하다는 것입니다[10]. 

이 문제에 대한 가능한 해결책은 

광물 표면에 반응물을 흡착한 다음 

건조 공정 중에 응축을 수행하는 것입니다. 

Akouche 등은 

이러한 전략을 사용하여 

70°C의 비정질 실리카에서 

아데노신, 리보스 및 이수소인산칼륨으로부터 

아데노신 모노포스페이트(AMP)를 합성했습니다[11]. 

AMP는 

상온에서 하이드 록시 아파타이트와 시안산염이 있을 때 [12] 또는 

금속 이온의 촉매 작용으로 메타 인산과 반응하여 

ADP 및 ATP로 추가 인산화될 수 있습니다 [13,14]. 

니켈은 

운석에 의해 하데안 지구로 옮겨졌을 수 있는 ATP 합성에

 가장 효율적인 금속 촉매로 밝혀졌습니다 [15]. 

이러한 반응은 

가혹한 물리적, 화학적 조건에 의존하지 않으므로 

원시 지구에서 실현 가능할 수 있습니다.

3. ATP as the Cofactor of Primitive Proteins

Being biological energy currency is the most well-known biological function of ATP, but may not be the first [16,17]. However, even without this function, ATP is still vital to life. Although RNA world theory has been debated since it was proposed in the 1960s [18], it is still one of the most widely accepted hypotheses about the origin of life [19]. This theory proposed a life form in which RNA takes the responsibility of carrying genetic information and catalyzing biochemical reactions. As a basic monomer for RNA polymerization, ATP lays the foundation of the RNA world.

Forty-five years ago, White suggested nucleotide-containing cofactors, such as ATP, nicotinamide adenine dinucleotide (NAD), flavin adenine dinucleotide (FAD), and coenzyme A, were firstly the cofactors of the RNA enzymes; when the protein enzymes replace the RNA ones, these nucleotide-containing cofactors still kept their position [20]. White’ s opinion, as we will discuss below, has a significant inspiration for studies about protein origin and evolution.

생물학적 에너지 현금은

 ATP의 가장 잘 알려진 생물학적 기능이지만, 

최초의 기능은 아닐 수도 있습니다[16,17]. 

그러나 

이 기능이 없어도 

ATP는 여전히 생명에 필수적입니다. 

RNA 세계 이론은 

1960년대에 제안된 이후 많은 논쟁이 있었지만[18], 

여전히 생명의 기원에 대해 가장 널리 받아들여지는 가설 중 하나입니다[19]. 

이 이론은 

RNA가 

유전 정보를 전달하고 

생화학 반응을 촉매하는 역할을 하는 생명체를 제안했습니다. 

RNA 중합을 위한 기본 단량체인 ATP는 

RNA 세계의 기초를 마련합니다. 

45년 전 White는 

ATP, 

니코틴아마이드 아데닌 디뉴클레오티드(NAD), 

플라빈 아데닌 디뉴클레오티드(FAD), 

코엔자임 A와 같은 뉴클레오티드 함유 보조 인자가 

RNA 효소의 보조 인자이며 

단백질 효소가 RNA를 대체하더라도 

이러한 뉴클레오티드 함유 보조 인자는 

여전히 그 위치를 유지한다고 제안했습니다[20]. 

아래에서 설명하겠지만 화이트의 의견은

단백질 기원과 진화에 관한 연구에

중요한 영감을 주었습니다.

In the field of protein origin and evolution, it is generally considered that the sequences and architectures that originated earlier are more widely shared by extant proteins [21,22]. Following this principle, we have pinpointed the early cofactor–protein interactions through analyzing the distribution patterns of cofactors in the protein structure space [23,24]. The cofactor-structure mapping shows a power–law relationship: most cofactors bind only one structure, while a few cofactors can bind tens of structures. ATP was found to be the most preval‎ent cofactor in protein structure space, and, thus, should be one of the earliest cofactors used by proteins. Furthermore, we inferred that the most ancient protein using ATP belongs to P-loop containing nucleoside triphosphate hydrolases (P-loop NTPases, pertaining to c.37 protein fold, defined by the Structural Classification of Proteins (SCOP) database [25]). Other nucleotide-containing cofactors, such as NAD and FAD, were also found in many protein structures, showing their early co-operation with proteins [23]. The corresponding earliest protein architectures belong to NAD-binding Rossmann-fold domains (c.2 fold) and FAD/NAD-binding domain (c.3 fold), respectively [23].

단백질 기원과 진화 분야에서는 

일반적으로 초기에 발생한 서열과 구조가 

현존하는 단백질에서 더 널리 공유되는 것으로 간주됩니다 [21,22]. 

이러한 원리에 따라 

단백질 구조 공간에서 

보조인자의 분포 패턴을 분석하여 

초기 보조인자-단백질 상호작용을 정확히 찾아냈습니다 [23,24]. 

보조 인자-구조 매핑은 cofactor-structure mapping

대부분의 보조 인자가 하나의 구조에만 결합하는 반면, 몇몇 

보조 인자는 수십 개의 구조와 결합할 수 있는 

거듭제곱 법칙 관계를 보여줍니다. 

ATP는 

단백질 구조 공간에서 가장 널리 퍼져 있는 보조인자로 밝혀졌으며, 

따라서 단백질이 가장 먼저 사용한 보조인자 중 하나라고 할 수 있습니다. 

또한 ATP를 사용하는 가장 오래된 단백질은 

뉴클레오사이드 삼인산 가수분해효소(단백질 구조 분류(SCOP) 데이터베이스 [25]에 정의된 c.37 단백질 폴드와 관련된 P-루프 NTPase)를 포함하는 P-루프에 속하는 것으로 추론했습니다. 

NAD 및 FAD와 같은 

다른 뉴클레오티드 함유 보조 인자들도 

많은 단백질 구조에서 발견되어 

단백질과의 초기 협력을 보여줍니다 [23]. 

이에 해당하는 가장 초기의 단백질 구조는 

각각 NAD 결합 로스만 폴드 도메인(c.2배)과 FAD/NAD 결합 도메인(c.3배)에 속합니다 [23].

This result is consistent with the previous sequence- and structure-based protein origin studies. Sobolevsky and Trifonov identified short protein sequence fragments that are conserved among the 131 prokaryotic genomes available at the time [21]. Most of these fragments belong to the Walker A motif [26], which is the ATP binding region of P-loop NTPases. Based on different protein structure classification schemes, Caetano-Anollés’ group built phylogenomic trees for protein structures [22,27,28,29]. P-loop NTPases proteins are located at the roots of these trees, indicating the ancient origin of this structure. Combining the sequence and structure information, Alva et al. identified 40 protein fragments that were inferred to be the remnants of primitive proteins, and one of them is the component of P-loop NTPases [30].

이 결과는 

이전의 서열 및 구조 기반 단백질 기원 연구와 일치합니다. 

소볼레프스키와 트리포노프는 

당시 이용 가능한 131개의 원핵생물 게놈 중에서 보존된 

짧은 단백질 서열 단편을 확인했습니다[21]. 

이러한 단편의 대부분은 

P-루프 NTPases의 ATP 결합 영역인 Walker A 모티프[26]에 속합니다. 

다양한 단백질 구조 분류 체계를 기반으로 Caetano-Anollés의 그룹은 단백질 구조에 대한 계통 발생학 트리를 구축했습니다[22,27,28,29]. P-루프 NTPase 단백질은 이 나무의 뿌리에 위치하여 이 구조의 고대 기원을 나타냅니다. 

Alva 등은 

염기서열과 구조 정보를 결합하여 

원시 단백질의 잔재로 추정되는 40개의 단백질 조각을 확인했으며, 

그 중 하나가 P-루프 NTPase의 구성 요소입니다[30].

4. Why ATP? ATP Facilitated the Origin of Protein

The above findings suggest that primitive proteins bind ATP and keep this feature to this day. A question naturally arises: why was ATP used by the most ancient proteins?

A possible answer resides in the fact that ATP promotes protein folding and folded proteins are more resistant to degradation and more likely to be functional than the unfolded ones. The free energy released during ATP–protein binding is 10~15 kcal/mol, which is close to the free energy of protein folding (10~20 kcal/mol) [31,32]. This energy may help the folding of the primitive proteins [23]. Therefore, it was proposed that the most ancient protein structures may be selected from random peptide sequences by cofactors, such as ATP [23]. Tokuriki and Tawfik presented a similar opinion about protein origin, which suggested that ligand binding selected the primitive protein structures and functions [33]. In support of this idea, ATP was indeed found to facilitate the folding of E. coli glyceraldehyde-3-phosphate dehydrogenase [34].

위의 연구 결과는 

원시 단백질이 

ATP와 결합하여 오늘날까지 이 기능을 유지하고 있음을 시사합니다. 

그렇다면 

왜 가장 오래된 단백질에서 ATP를 사용했을까요? 

한 가지 가능한 대답은 

ATP가 

단백질 접힘을 촉진하고 

접힌 단백질이 펼쳐진 단백질보다 

분해에 더 강하고 

기능적일 가능성이 높다는 사실에 있습니다. 

ATP-단백질 결합 시 방출되는 자유 에너지는 

10~15kcal/mol로 

단백질 폴딩의 자유 에너지(10~20kcal/mol)와 비슷합니다[31,32]. 

이 에너지는 

원시 단백질의 폴딩을 도울 수 있습니다 [23]. 

따라서 

가장 오래된 단백질 구조는 

ATP와 같은 보조 인자에 의해 

무작위 펩타이드 서열에서 선택될 수 있다고 제안되었습니다 [23]. 

토쿠리키와 타우픽은 

단백질 기원에 대해 비슷한 의견을 제시했는데,

 리간드 결합이 원시 단백질 구조와 기능을 선택한다고 제안했습니다 [33]. 

이 아이디어를 뒷받침하기 위해 

ATP는 

실제로 대장균 글리세랄데히드-3-포스페이트 탈수소효소의 폴딩을 

촉진하는 것으로 밝혀졌습니다 [34].

The above hypotheses about protein origin are in accordance with experimental observations. To investigate the occurrence frequency of functional/folded proteins in random sequences, Keefe and Szostak performed an in vitro selection using ATP as the bait. As a result, four families of ATP-binding proteins were selected from 6 × 1012 random sequences [35]. One of the proteins was crystallized and its structure is closest to c.37 fold [28], which is just the most ancient protein architecture inferred by ATP distribution patterns in the protein structure space [23]. Our group carried out in vitro selection for ATP-binding protein with a different random protein library which is composed of only 15 kinds of amino acids [36]. The excluded five amino acids, i.e., Phe, Cys, Met, Tyr, and Trp, were considered to be not abundant in the primitive Earth and, thus, may not exist in the early proteins [37]. The ATP-binding protein we obtained was found to have NTPases activity, which implied another role that ATP played in protein origin and evolution. A major part of modern proteins are enzymes; some of them catalyze energetically uphill reactions. For these reactions, external energy sources are also necessary. The high-energy phosphate bond contained in ATP can meet this demand. Enzymes with ATPase activity enable organisms to use ATP as an energy source to drive more metabolic reactions, laying the metabolic foundation for more complex and delicate life forms.

단백질 기원에 대한 위의 가설은 

실험적 관찰에 따른 것입니다. 

무작위 서열에서 

기능성/접힌 단백질의 발생 빈도를 조사하기 위해 

Keefe와 Szostak은 

ATP를 미끼로 사용하여 시험관 내 선택을 수행했습니다. 

그 결과, 6×1012개의 무작위 서열에서 

4개의 ATP 결합 단백질 군이 선택되었습니다[35]. 

그 중 한 단백질은 결정화되었고 

그 구조는 단백질 구조 공간에서 

ATP 분포 패턴으로 유추한 가장 오래된 단백질 구조인 

c.37배[28]에 가장 가깝습니다[23]. 

우리 그룹은 

15종의 아미노산으로만 구성된 다른 무작위 단백질 라이브러리를 사용하여 

ATP 결합 단백질에 대한 시험관 내 선택을 수행했습니다 [36]. 

제외된 5가지 아미노산, 

즉 Phe, Cys, Met, Tyr, Trp는 

원시 지구에 풍부하지 않아 

초기 단백질에 존재하지 않았을 것으로 추정되는 아미노산입니다 [37]. 

우리가 얻은 ATP 결합 단백질은 

NTPase 활성을 가지고 있는 것으로 밝혀졌으며, 

이는 단백질 기원과 진화에 있어 ATP가 

또 다른 역할을 한다는 것을 암시합니다. 

현대 단백질의 주요 부분은 

효소이며, 

그 중 일부는 에너지적으로 오르막길을 오르는 반응을 촉매합니다. 

이러한 반응에는 

외부 에너지원도 필요합니다. 

ATP에 포함된 고에너지 인산염 결합은 

이러한 요구를 충족시킬 수 있습니다. 

ATPase 활성을 가진 효소는 

유기체가 ATP를 에너지원으로 사용하여 

더 많은 대사 반응을 일으켜 

더 복잡하고 섬세한 생명체를 위한 

대사 기반을 마련할 수 있게 해줍니다.

5. Why ATP? ATP as a Hydrotrope

Other cofactors, e.g., NAD, may also facilitate protein folding [38] or provide energy for biochemical reactions (in the reduced form, NADH) [39]. So, why is ATP the one that binds the most preval‎ent protein structures and is likely the earliest cofactor used by proteins? Recently, a new property of ATP was revealed: high-level ATP can function as a hydrotrope to prevent protein aggregation [6]. Most proteins only maintain activity in the solubilized state; over-aggregation can cause protein precipitation.

We argue that this function is especially significant for the origin of proteins. There is an opinion that many primitive proteins are intrinsically disordered [40], and these proteins are more prone to aggregate or even precipitate than globular ones [41]. Thus, the ATP-like solubilization-facilitating property is crucial to protein origin. RNA-binding protein fused in sarcoma (FUS) is a model intrinsically disordered protein. At the millimolar level, ATP can prevent the aggregation of FUS and even dissolve FUS amyloid fibers in higher concentrations. A recent molecular dynamics study revealed the mechanism underlying these processes: the hydrophobic adenine head of ATP pretended to contact the core of FUS aggregates, while its hydrophilic phosphoric acid tail was exposed to the external solvent, which promoted the dissolution of the aggregates [42]. This property has not been observed for other cofactors, manifesting the irreplaceable role of ATP in the origin of life.

다른 보조 인자(예: NAD)도 

단백질 폴딩을 촉진하거나[38] 

생화학 반응에 에너지를 제공할 수 있습니다(환원된 형태인 NADH)[39]. 

그렇다면 

왜 ATP가 가장 널리 퍼진 단백질 구조와 결합하고 

단백질이 가장 먼저 사용하는 보조 인자일까요? 

최근 ATP의 새로운 특성이 밝혀졌는데, 

바로 높은 수준의 ATP가 

단백질 응집을 방지하는 수화제로서 기능할 수 있다는 것입니다[6]. 

대부분의 단백질은 

용해된 상태에서만 활성을 유지하며, 

과도한 응집은 단백질 침전을 유발할 수 있습니다. 

우리는 이 기능이 

단백질의 기원에 특히 중요하다고 주장합니다. 

많은 원시 단백질이 

본질적으로 무질서하다는 의견이 있으며[40], 

이러한 단백질은 구형 단백질보다 

응집되거나 침전되기 쉽습니다[41]. 

따라서 

ATP와 같은 가용화 촉진 특성은 

단백질 기원에 매우 중요합니다. 

육종에서 융합된 RNA 결합 단백질(FUS)은 

본질적으로 무질서한 단백질의 모델입니다. 

밀리몰 수준에서 ATP는

 FUS의 응집을 방지하고 

더 높은 농도의 FUS 아밀로이드 섬유를 용해할 수도 있습니다. 

최근 분자 역학 연구에 따르면

 이러한 과정의 근간이 되는 메커니즘이 밝혀졌습니다. 

ATP의 소수성 아데닌 머리는 

FUS 응집체의 핵심에 접촉하는 척하고, 

친수성 인산 꼬리는 외부 용매에 노출되어 응집체의 용해를 촉진합니다 [42]. 

이 특성은 다른 보조 인자에서는 관찰되지 않았으며, 

이는 생명의 기원에서 ATP의 대체 불가능한 역할을 나타냅니다.

In modern cells, the hydrotrope function of ATP is still significant. To coordinate the huge amount of contents inside the crowded intracellular space, functionally related proteins can condense through liquid–liquid phase separation (LLPS) [43]. In cytoplasm, the formed LLPS droplets, also called membrane-less organelles, help to maintain the efficiency of molecular machines [44]. However, LLPS is thermodynamically imbalanced. To minimize the system’s free energy, the separated phases tend to further condense. So, without external regulation, the separated phases do not disappear spontaneously, which may generate harmful amyloids [45]. ATP has been proven to prevent the formation of protein LLPS droplets and dissolve previously formed ones [6], and is considered to be a key regulator of cellular LLPS [43,46].

현대 세포에서 

ATP의 수화 기능은 hydrotrope function of ATP

여전히 중요합니다. 

혼잡한 세포 내 공간 내부의 방대한 양의 내용물을 조정하기 위해 

기능적으로 관련된 단백질은 

액-액상 분리(LLPS)를 통해 

응축될 수 있습니다[43]. 

liquid–liquid phase separation (LLPS)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445271/

세포질에서 

멤브레인이 없는 소기관이라고도 불리는 LLPS 방울은 

분자 기계의 효율을 유지하는 데 도움이 됩니다 [44]. 

그러나 

LLPS는 

열역학적으로 불균형합니다. 

시스템의 자유 에너지를 최소화하기 위해 분리된 상은 

더욱 응축되는 경향이 있습니다. 

따라서 

외부 조절 없이는 분리된 상이 자연적으로 사라지지 않아 

유해한 아밀로이드를 생성할 수 있습니다 [45]. 

ATP는 

단백질 LLPS 방울의 형성을 방지하고 

이전에 형성된 방울을 용해하는 것으로 입증되었으며[6], 

세포 LLPS의 주요 조절 인자로 간주됩니다[43,46].

LLPS also exists inside the nucleus and is regulated by ATP. During gene transcription and genome replication, numerous biomolecules agglomerate and form liquid–liquid separated phases, which remodeled the structure of the chromosome to ensure proteins access the genome and perform their tasks in a relatively stable environment [47]. Hormones, such as estrogen, can induce chromatin remodeling and specific gene transcription accompanying intranuclear phase separation. Wright et al. observed an ATP level increase in the nucleus of estrogen-stimulated breast cancer cells and further showed that this intranuclear ATP is required for chromatin remodeling and gene transcription [48]. In a follow-up paper, Wright et al. proposed that, as a hydrotrope, ATP can regulate the production, maintenance, and dissolution of dynamic phase separation in the nucleus [49]. They also suggested that ATP may influence the concentration of Mg2+, and the latter is well known to influence the solubility of chromatin.

LLPS는 

핵 내부에도 존재하며 

ATP에 의해 조절됩니다. 

유전자 전사 및 게놈 복제 과정에서 

수많은 생체 분자가 응집하여 

액-액 분리상을 형성하여 

염색체 구조를 리모델링함으로써 

단백질이 게놈에 접근하고 

비교적 안정적인 환경에서 작업을 수행할 수 있도록 합니다[47]. 

에스트로겐과 같은 호르몬은 

염색질 리모델링과 핵 내 상 분리에 수반되는 

특정 유전자 전사를 유도할 수 있습니다. 

Wright 등은 

에스트로겐 자극 유방암 세포의 핵에서 

ATP 수준이 증가하는 것을 관찰하고 

이 핵 내 ATP가 염색질 리모델링과 유전자 전사에 필요하다는 것을 추가로 보여주었습니다 [48]. 

후속 논문에서 Wright 등은 

ATP가 하이드로트로프로서 핵에서 

동적 상 분리의 생성, 유지 및 용해를 조절할 수 있다고 제안했습니다[49]. 

그들은 또한

 ATP가 마그네슘2+의 농도에 영향을 미칠 수 있으며, 

후자는 염색질의 용해도에 영향을 미치는 것으로 잘 알려져 있다고 제안했습니다.

As shown in the above descriptions, ATP acts as a hydrotrope to participate in fundamental cellular physiological processes through regulating biomolecular condensates. These advances not only explain why ATP remains at high concentrations in cells, but also bring inspirations to biomedicine, especially in combating aging-related diseases and breast cancer.

위의 설명에서 볼 수 있듯이 

ATP는 생체 분자 응축물을 조절하여 

근본적인 세포 생리 과정에 참여하는 

수화 작용을 합니다. 

이러한 발전은 

ATP가 세포에서 고농도로 유지되는 이유를 설명할 뿐만 아니라 

특히 노화 관련 질병과 유방암 퇴치 등 생물 의학에 영감을 불어넣고 있습니다.

6. Implications of ATP in Aging-Related Diseases

Mitochondria, the main source of cellular ATP, has been considered to be related to aging for decades [50]. A common view is that the mitochondrial genome accumulates harmful mutations with age, which damages mitochondrial function, leads to cell energy shortage, and further causes aging pathologies. Consistent with this point of view, a decline in ATP with age has been observed in different animal and human investigations [51] and is related to aging pathologies, such as sarcopenia [52], heart failure [53], and neurodegenerative diseases [54,55,56].

세포 ATP의 주요 공급원인 

미토콘드리아는 

수십 년 동안 노화와 관련이 있는 것으로 여겨져 왔습니다[50]. 

일반적인 견해는 

미토콘드리아 게놈이 나이가 들면서 

유해한 돌연변이를 축적하여 

미토콘드리아 기능을 손상시키고 

세포 에너지 부족으로 이어지며 

나아가 노화 병리를 유발한다는 것입니다. 

이러한 관점에서 볼 때, 

나이가 들면서 ATP가 감소하는 것은 

다양한 동물 및 인간 조사에서 관찰되었으며[51], 

근육 감소증[52], 

심부전[53], 신

경 퇴행성 질환[54,55,56]과 같은 노화 병리와 관련이 있습니다.

The hydrotrope character of ATP is also involved in aging. As mentioned above, ATP is a key regulator of biomolecules. Dysregulation of protein condensates causes harmful protein aggregation, misfolding, and dissolution [44], and the further induced loss of proteostasis is a hallmark of aging [57]. A typical example is the generation of Aβ amyloid deposition, which plays an important role in the pathogenesis of neurodegenerative diseases. ATP can prevent and even dissolve different types of Aβ amyloid aggregation [6,58,59], and may reduce the wrong folding of Aβ [60]. A recent molecular dynamics simulation study found that ATP has the potential to inhibit the aggregation of human islet amyloid polypeptide, which can lead to type II diabetes mellitus [61].

ATP의 하이드로트로프 특성도 

노화에 관여합니다. 

위에서 언급했듯이 

ATP는

 생체 분자의 핵심 조절 인자입니다. 

단백질 응축물의 조절 장애는 

유해한 단백질 응집, 

오접힘 및 용해를 유발하며[44], 

이로 인해 유도된 단백질 정체성의 손실은 노화의 특징입니다[57].

 대표적인 예가 

신경 퇴행성 질환의 발병에 중요한 역할을 하는 

Aβ 아밀로이드 침착의 생성입니다. 

ATP는 

다양한 유형의 Aβ 아밀로이드 응집을 예방하고 

심지어 용해시킬 수 있으며[6,58,59], Aβ의 잘못된 접힘을 줄일 수 있습니다[60]. 

https://pubmed.ncbi.nlm.nih.gov/31830415/

https://pubmed.ncbi.nlm.nih.gov/24625803/

최근 분자 역학 시뮬레이션 연구에 따르면 

ATP는 

인간 섬 아밀로이드 폴리펩타이드의 응집을 억제하여 

제2형 당뇨병을 유발할 수 있는 잠재력이 있는 것으로 나타났습니다 [61].

The association between ATP and the aging-related diseases naturally sparked the idea of treating these diseases by maintaining the normal concentration of ATP. In the discovery of neurodegenerative disease treatment, a “brain energy rescue” strategy has been practiced for several years [62]. A series of compounds capable of elevating ATP cellular, animal, and human experiments have been reported [63,64,65]. A more detailed introduction of these studies could be found in our previous paper [66].

ATP와 노화 관련 질병 사이의 연관성은 

자연스럽게 ATP의 정상 농도를 유지하여 

이러한 질병을 치료하는 아이디어를 촉발시켰습니다. 

신경 퇴행성 질환 치료의 발견에서 

"뇌 에너지 구조" 전략은 

수년 동안 실행되어 왔습니다 [62]. 

세포, 동물 및 인간 실험에서 

ATP를 상승시킬 수 있는 

일련의 화합물이 보고되었습니다 [63,64,65]. 이러한 연구에 대한 자세한 소개는 이전 논문 [66]에서 확인할 수 있습니다.

Moreover, the decrease in cellular NAD, which is another nucleotide-containing cofactor, has been found to be deeply involved in multiple aging-related cellular processes, and restoring NAD level has emerged as a helpful therapy for aging-related diseases [67]. Reduced NAD (NADH) is a central hydride donor in mitochondrial ATP synthesis. A study observed that ATP level decreased following the NAD decline in toxic prion-protein-treated neurons [68], suggesting that ATP is involved in the NAD-related aging mechanism. Thus, we consider that ATP may be partially responsible for NAD-augmentation-based aging prevention.

또한, 또 다른 뉴클레오티드 함유 보조 인자인 

세포 NAD의 감소는 

여러 노화 관련 세포 과정에 깊이 관여하는 것으로 밝혀졌으며, 

NAD 수준을 회복하는 것이 

노화 관련 질환에 유용한 치료법으로 부상하고 있습니다 [67]. 

감소된 NAD(NADH)는 

미토콘드리아 ATP 합성의 중심 수화물 공여체입니다. 

한 연구에 따르면 

독성 프리온 단백질로 처리된 뉴런에서 

NAD가 감소한 후 ATP 수준이 감소하는 것을 관찰했는데[68], 

이는 ATP가 NAD 관련 노화 메커니즘에 관여한다는 것을 시사합니다. 

따라서 

ATP가 

NAD 증강 기반 노화 예방에 부분적으로 관여할 수 있다고 생각합니다.

7. Implications of ATP in Precision Medicine of Breast Cancer

Estrogen is the most important hormone that directly stimulates the growth and development of the breast, and it also plays a vital role in the occurrence and development of estrogen-receptor-positive breast cancer. As mentioned above, ATP can regulate the estrogen-induced production, maintenance, and dissolution of dynamic phase separation in the nucleus [48]. These processes are necessary for the expression‎ of estrogen-regulated genes and important in the proliferation of breast cancer cells. Moreover, Wright et al. found that the concentration of ATP in the nucleus significantly increased 30 min after the hormone stimulation, while the level of ATP in the mitochondria or cytoplasm did not change, suggesting a source of ATP inside the nucleus [48]. Nudix hydrolase 5 (NUDIX5, also called NUDT5) has been identified as a key factor in the production of ATP in the nucleus, which can use intranuclear ADP-ribose (ADPR) as the substrate to synthesize ATP in the presence of diphosphate [48]. Further studies on NUDT5 showed that both the intranuclear ATP level increase and the estrogen-regulated gene transcription depended on the activity of NUDT5. These findings revealed that ATP functions as an estrogen coactivator by mediating phase separation in the nucleus [49,69].

에스트로겐은 

유방의 성장과 발달을 직접 자극하는 가장 중요한 호르몬이며, 

에스트로겐 수용체 양성 유방암의 발생과 발달에도 

중요한 역할을 합니다. 

위에서 언급했듯이 

ATP는 

핵에서 에스트로겐에 의한 동적 상 분리의 생성, 

유지 및 용해를 조절할 수 있습니다 [48]. 

이러한 과정은 

에스트로겐 조절 유전자의 발현에 필요하며 

유방암 세포의 증식에 중요합니다. 

또한 Wright 등은 

호르몬 자극 30분 후 핵 내 

ATP 농도가 유의하게 증가한 반면 

미토콘드리아나 세포질 내 ATP 수준은 변하지 않아 

핵 내부의 ATP 공급원을 시사한다는 사실을 발견했습니다 [48]. 

누딕스 가수분해효소 5(NUDIX5, NUDT5라고도 함)는 

핵 내에서 ATP를 생성하는 핵심 인자로 확인되었으며, 

이는 핵 내 ADP-리보스(ADPR)를 기질로 사용하여 이인산염이 있을 때 ATP를 합성할 수 있습니다 [48]. 

NUDT5에 대한 추가 연구에 따르면 핵 내 ATP 수준 증가와 에스트로겐 조절 유전자 전사가 모두 NUDT5의 활성에 의존하는 것으로 나타났습니다. 이러한 연구 결과는 ATP가 핵에서 상 분리를 매개하여 에스트로겐 보조 활성제로서 기능한다는 것을 밝혀냈습니다 [49,69].

This ATP new function brings a novel strategy for estrogen-related disease treatment, that is, suppressing the activity of estrogen by decreasing the concentration of ATP, which may be achieved by inhibiting NUDT5. Page et al. discovered a series of NUDT5 inhibitors and proved that these compounds can repress the nuclear ATP production, and further restrain hormone signal transduction and cell proliferation in breast cancer cells [70]. However, these inhibitors have not yet entered clinical trials, which means that they cannot be clinically used in the near future. To accelerate the development of drugs based on this new concept, we resorted to a drug-repositioning strategy. Through bioinformatic analysis, molecular simulation, and cell-level experiments, seven approved drugs were identified as potential NUDT5 inhibitors and were proved to have a cytotoxic effect on estrogen-receptor-positive breast cancer cell line MCF7 [71]. These drugs are of apparent interest for further eval‎uation.

이 ATP의 새로운 기능은 

에스트로겐 관련 질병 치료를 위한 새로운 전략, 

즉 ATP의 농도를 낮추어 

에스트로겐의 활성을 억제하는 것으로, 

이는 NUDT5를 억제함으로써 달성할 수 있습니다. 

Page 등은 일련의 NUDT5 억제제를 발견하고 

이러한 화합물이 핵 ATP 생성을 억제하고 

유방암 세포에서 호르몬 신호 전달과 세포 증식을 

더욱 억제할 수 있음을 증명했습니다[70]. 

그러나 이러한 억제제는 아직 임상 시험에 들어가지 않았기 때문에 가까운 장래에 임상적으로 사용할 수 없습니다. 이 새로운 개념에 기반한 약물 개발을 가속화하기 위해 우리는 약물 재배치 전략에 의지했습니다. 생물정보학적 분석, 분자 시뮬레이션, 세포 수준 실험을 통해 7개의 승인된 약물이 잠재적인 NUDT5 억제제로 확인되었으며, 에스트로겐 수용체 양성 유방암 세포주 MCF7에 세포 독성 효과가 있는 것으로 입증되었습니다[71]. 이러한 약물은 추가 평가가 필요한 것으로 보입니다.

In recent years, precision medicine has attracted much attention in the area of cancer therapy. Biomarkers are key components for precision medicine, which help to classify patients according to different expectations for prognosis, treatment response, and disease susceptibility [72]. Prognostic biomarkers can provide information about overall cancer outcomes to facilitate cancer diagnosis [73]. For estrogen-receptor-positive breast cancer, there remains a lack of commonly accepted prognostic biomarkers. Our group found that estrogen-receptor-positive breast cancer patients with low-level NUDT5 expression‎ had significantly longer survival times compared with high-NUDT5-level counterparts [74]. In comparison, this phenomenon cannot be observed in estrogen-receptor-negative breast cancer patients. Together, all these results exhibited the potential of NUDT5 as a drug target and a prognostic biomarker in precision medicine of breast cancer.

최근 몇 년 동안 정밀 의학은 

암 치료 분야에서 많은 주목을 받고 있습니다. 

바이오마커는 

예후, 치료 반응 및 질병 감수성에 대한 

다양한 기대치에 따라 환자를 분류하는 데 

도움이 되는 정밀 의학의 핵심 요소입니다 [72]. 

예후 바이오마커는 암 진단을 용이하게 하기 위해 전반적인 암 결과에 대한 정보를 제공할 수 있습니다[73]. 에스트로겐 수용체 양성 유방암의 경우, 아직까지 일반적으로 인정되는 예후 바이오마커가 부족합니다. 우리 연구팀은 NUDT5 발현이 낮은 에스트로겐 수용체 양성 유방암 환자의 생존 기간이 높은 환자에 비해 현저히 길다는 사실을 발견했습니다 [74]. 이에 비해 에스트로겐 수용체 음성 유방암 환자에서는 이러한 현상이 관찰되지 않았습니다. 이 모든 결과를 종합하면 유방암 정밀 의학에서 약물 표적 및 예후 바이오마커로서 NUDT5의 잠재력을 확인할 수 있습니다.

8. Summary and Outlook

ATP takes a significant part in the origin of life. ATP constituted the ancient ribozymes and facilitated the generation of the earliest proteins. The energy contained in its phosphate bond may drive the prebiotic metabolic reactions. The amphiphilic structure makes the molecule an effective hydrotrope, which helps to maintain the solubility of primitive biomolecular condensates. The legend of ATP continues to this day. In modern organisms, ATP helps to delay the inevitable destiny of life—aging, and may contribute to precision medicine by inspiring the discovery of therapeutic drugs and prognostic biomarkers for breast cancer.

ATP는 

생명의 기원에서 중요한 역할을 합니다. 

ATP는 고대 리보효소를 구성하고 

초기 단백질의 생성을 촉진했습니다. 

인산염 결합에 포함된 에너지는 

프리바이오틱스 대사 반응을 주도할 수 있습니다. 

양친매성 구조는 

분자를 효과적인 하이드로트로프로 만들어 

원시 생체 분자 응축물의 용해도를 유지하는 데 도움이 됩니다. 

ATP의 전설은 

오늘날까지도 계속되고 있습니다. 

현대 유기체에서 ATP는 

피할 수 없는 생명 노화의 운명을 늦추는 데 도움이 되며, 

유방암 치료제와 예후 바이오마커를 발견하는 데 

영감을 주어 정밀 의학에 기여할 수 있습니다.

The primary progress introduced in the current paper indicates the potential of ATP in precision medicine. However, from now, the understanding of ATP as a hydrotrope is still insufficient. Most of the knowledge on this function was obtained from in vitro and cellular studies. The local environment regulation in live cells is more complicated. Take the estrogen-receptor-regulated transcription as an example, multiple regulators are recruited and arranged by scaffold molecules, such as SRA RNA, to form functional transcription complexes [75]. This process is a key part of the pathogenesis of breast cancer. Understanding how ATP is involved in such processes could be a challenging topic. Whether the desired effect can be achieved in living organisms needs much more research effort.

이번 논문에서 소개한 주요 연구 성과는 

정밀 의학에서 ATP의 잠재력을 보여줍니다. 

그러나 아직까지 

수화 효소로서의 ATP에 대한 이해는 

부족합니다. 

이 기능에 대한 대부분의 지식은 체외 및 세포 연구에서 얻은 것입니다. 살아있는 세포의 국소 환경 조절은 더 복잡합니다. 에스트로겐 수용체 조절 전사를 예로 들면, 여러 조절 인자가 SRA RNA와 같은 스캐폴드 분자에 의해 모집되고 배열되어 기능적 전사 복합체를 형성합니다[75]. 이 과정은 유방암 발병의 핵심적인 부분입니다. 이러한 과정에 ATP가 어떻게 관여하는지 이해하는 것은 어려운 주제일 수 있습니다. 생물체에서 원하는 효과를 얻을 수 있는지 여부는 훨씬 더 많은 연구 노력이 필요합니다.

Moreover, most functions of ATP are very fundamental, which means activating or inhibiting related targets may cause preval‎ent perturbation. During the protein synthesis, ATP not only is utilized as the energy reservoir and substrate of tRNA aminoacylation, but also as a regulator. In bacteria, the activity of ribosome RNA promoters is correlated with the concentration of initiating NTP and, on most occasions, of ATP [76]. In this way, ribosome biogenesis and protein synthesis are physiologically connected with cellular energy status. However, an excess of ATP will arrest too much Mg2+, and inhibits ribosome biogenesis and cell growth, because Mg2+ is necessary to maintain ribosome structure [77]. How to accurately control the effect of ATP could be a challenge. Therefore, it seems that there is a long way to the finale of the legend of ATP.

또한 ATP의 대부분의 기능은 

매우 기본적이기 때문에 관련 표적을 활성화하거나 억제하면 

만연한 교란을 일으킬 수 있습니다. 

단백질 합성 과정에서 ATP는 

에너지 저장소이자 

tRNA 아미노아실화의 기질로 활용될 뿐만 아니라 

조절제로도 사용됩니다. 

박테리아에서 리보솜 RNA 프로모터의 활성은

 개시 NTP의 농도와 대부분의 경우 

ATP의 농도와 상관관계가 있습니다 [76]. 

이러한 방식으로 리보솜 생성과 

단백질 합성은 생리적으로 

세포 에너지 상태와 연결되어 있습니다. 

그러나 리보솜 구조를 유지하려면 

Mg2+가 필요하기 때문에 ATP가 너무 많으면 

Mg2+가 과도하게 축적되어 리

보솜 생성과 세포 성장을 억제합니다 [77]. 

ATP의 효과를 정확하게 제어하는 방법은 어려울 수 있습니다. 

따라서 ATP의 전설의 피날레는 아직 갈 길이 먼 것 같습니다.

Acknowledgments

The authors wish to thank the anonymous reviewers whose constructive comments were helpful to strengthen the presentation of this study.

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Funding Statement

This research was funded by National Natural Science Foundation of China, grant number 31870837; Scientific Research Grant of Ningbo University, grant number 215-432000282; and Ningbo Top Talent Project, grant number 215-432094250.

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Author Contributions

Writing—original draft preparation, X.-Y.C., Y.-Y.X., X.-Y.T. and G.W.; writing—review and editing, X.-Y.C. and H.-Y.Z.; supervision, H.-Y.Z.; funding acquisition, X.-Y.C. and H.-Y.Z. All authors have read and agreed to the published version of the manuscript.

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Conflicts of Interest

The authors declare no conflict of interest.

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Footnotes

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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