Rise of the Rival-对手的崛起

yusheen

在2010年2月19日的Science杂志上，刊登了两篇中国科学家对代谢途径中的蛋白乙酰化的研究报告。正如蛋白的乙酰化对基因的表达调控起重要的作用一样，细胞中的代谢途径的中酶的活性也受到乙酰化水平的影响。杂志的编辑刊发了评论文章，把细胞中的乙酰化看作是和磷酸化同等重要的分子开关。评论文章的题目是Rise of the Rival。我觉得作者的观点和视角独特，很有新颖性和启发性。现把其文章刊登在此，并尝试着进行了中文翻译，也一并放在这里，仅供参考。限于水平，中文翻译不太准确的地方请见谅，有兴趣的同行可阅读原文。请批评纠正，共同提高。7 ]3 ^. n: \) A1 T1 W

& _- g& a( h: I& `( ]8 }Perspectives" S6 I7 s6 P+ t1 p

$ B. B* V$ p6 F6 a& mCell Biology:
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' L$ V* U" P" z- T/ X5 vRise of the Rival' r& s* P) J/ ~  f7 Z9 v

3 L  k3 Z* z* y0 O" jAmanda Norvell1 and Steven B. McMahon2
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1 Department of Biology, College of New Jersey, Ewing, NJ 08628, USA.9 t+ X' A4 f- ]9 a

8 C1 \* |' _9 e; i# a8 r. r3 @4 H2 Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
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E-mail: steven.mcmahon@jci.tju.edu
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* e. r5 v- A! I5 s; J2 J' eLike protein phosphorylation, the posttranslational addition of acetyl groups to lysine residues of eukaryotic and prokaryotic proteins has been known for decades (1). The discovery that eukaryotic enzymes implicated in transcriptional regulation can acetylate or deacetylate lysines in chromatin-associated proteins (histones) raised the possibility that dynamic changes in lysine acetylation might provide an important regulatory switch in complex cellular processes (2, 3). A decade ago, Kouzarides made the bold prediction that acetylation might "rival phosphorylation" as a regulator of cell function (4). With proteomics, thousands of mammalian proteins with acetylated lysines have indeed been identified (5, 6), and one of the surprising findings has been that, along with chromatin proteins, metabolic enzymes are highly represented among acetylation substrates. This suggested that changes in acetylation status might alter enzymatic activity to allow the cell to respond to changes in metabolic demands by adjusting flux through critical nodes in the relevant pathways. Reports by Zhao et al. and Wang et al. on pages 1000 and 1004 of this issue, respectively, now validate this hypothesis in the prokaryote Salmonella enterica and in human liver cells (7, 8).
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0 c; m5 \" n/ F2 r1 Q; XThese two studies report a number of fundamental similarities betwen bacteria and humans. The first is the sheer pervasiveness of lysine acetylation on metabolic enzymes. Zhao et al. found that 90% of the S. enterica proteins involved in central metabolism are acetylated, and Wang et al. likewise found acetylation of essentially every enzyme involved in glycolysis, fatty acid and glycogen metabolism, and the tricarboxylic acid (TCA) and urea cycles (see the figure). Both groups also found that changing the carbon source available to either the prokaryotic or eukaryotic cells altered the total profile of acetylated metabolic enzymes.
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Zhao et al. and Wang et al. conducted elegant biochemical studies on a handful of enzymes from S. enterica and humans and showed that acetylation has multiple effects, increasing the activity of some metabolic enzymes while inhibiting the activity of others. Furthermore, the effects of acetylation appear to be coordinated to simultaneously shunt metabolic flux down specific pathways and away from others. Remarkably, this flux can be reversed by changes in metabolic state or carbon source availability. However, not all aspects of this process are conserved. In S. enterica, the changes in metabolic enzyme acetylation result in part from changes in the relative expression of the major acetylase and deacetylase, a feature that has not been widely observed for eukaryotic counterparts. Indeed, only a few cases exist in which we understand the mechanisms regulating mammalian acetylases and deacetylases (9). When Zhao et al. compared proteins acetylated in human liver cells to those identified in earlier studies, they found 70% overlap with the acetylated proteins identified in mouse liver but only 14% overlap with the acetylated proteins found in a human leukemia cell line, which suggests that acetylation patterns vary widely between cell lineages.
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- Q+ j; I0 `( ]! WIn protein phosphorylation, adenosine triphosphate (ATP) serves as the major phosphoryl group donor. Lysine acetylation relies on acetyl–coenzyme A (CoA) as the acetyl group donor. Like ATP, acetyl-CoA lies at the core of a number of critical cellular pathways, and its intracellular concentration is therefore a potential readout of the processes involved. Changes in the availability of acetyl-CoA could directly affect the acetylation status of critical substrates, as observed for the core histone proteins H2A, H2B, H3, and H4 (10). Thus, a model emerges in which changes in cellular pools of acetyl-CoA, which fluctuate in response to a myriad of metabolic pathways, could provide the rheostat by which the acetylation status, and hence the activity, of metabolic enzymes can be modulated. , W) G" |' \% i. \

& `: q& F$ @  n  ]Understanding the control of lysine acetylation, as well as the effect of altered protein acetylation on specific cellular pathways, has clear implications for human disease. (Verinostat, a deacetylase inhibitor, received approval by the U.S. Food and Drug Administration in 2006 as a treatment for cutaneous T cell lymphoma.) Given the renewed appreciation of cancer as a partly metabolic disease (11), the studies by Zhao et al. and Wang et al. raise the question of how much the success of deacetylase inhibtors depends on their ability to change transcriptional profiles versus reprogramming cancer cell metabolism. Beyond cancer, as we learn more about the role of acetylation in regulating flux through metabolic pathways, drugs that modulate acetylation might be of benefit to patients with specific metabolic disorders. And as the proteomic data on protein acetylation are mined further, and the methodology is refined, we should come to understand whether there are cellular processes—beyond those linked to chromatin or metabolism—where dynamic lysine acetylation plays a global regulatory role.
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The importance of phosphorylation is broadly accepted, but the importance of pathways related to dynamic protein acetylation has received little recognition since the 1964 Nobel Prize in Physiology or Medicine to Konrad Bloch and Feodor Lynen for their discoveries linking acetyl-CoA to fatty acid metabolism. Although dynamic protein phosphorylation unquestionably provides a major regulatory switch in cells, it is now clear from studies like those of Zhao et al. and Wang et al. that lysine acetylation is an equally important and evolutionarily conserved control mechanism (7, 8). Phosphorylation appears indeed to have found its "rival" in lysine acetylation.
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References 0 a7 l% n9 I- t- [, T
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1. V. G. Allfrey, R. Faulkner, A. E. Mirsky, Proc. Natl. Acad. Sci. U.S.A. 51, 786 (1964).
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2. J. E. Brownell et al., Cell 84, 843 (1996).
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3. J. Taunton, C. A. Hassig, S. L. Schreiber, Science 272, 408 (1996).! {8 w+ s9 p! `1 G4 _1 v& I$ u
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4. T. Kouzarides, EMBO J. 19, 1176 (2000).6 E) v1 o1 p3 E8 `

6 e7 [. i% h! j( _! c5. C. Choudhary et al., Science 325, 834 (2009).0 ^. m9 g% K- q- Z9 O
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6. S. C. Kim et al., Mol. Cell 23, 607 (2006).
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$ o' p5 R* |+ L7. S. Zhao et al., Science 327, 1000 (2010).
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8. Q. Wang, Y. Zhang, C. Yang, H. Xiong, Y. Lin, Science 327, 1004 (2010).
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$ c. y5 D) `3 }( M- }0 C9. H. S. Mellert, S. B. McMahon, Trends Biochem. Sci. 34, 571 (2009).
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0 x# @5 H$ \; d" K5 b1 [  l10. K. E. Wellen et al., Science 324, 1076 (2009).+ l$ Q# z) e& \2 ^6 m+ B& `+ P; Q
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11. C. B. Thompson, N. Engl. J. Med. 360, 813 (2009).
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参考译文：+ I- p: n9 L/ C2 r
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如同蛋白质的磷酸化一样，真核和原核蛋白质的赖氨酸残基上进行乙酰基团的添加所进行的翻译后修饰是众所周知的事实，这一事实被人们认识已几十年了（1）。真核细胞转录调控所涉及的酶可以在染色质相关蛋白（组蛋白）的赖氨酸上发生乙酰化或去乙酰化。这一发现提供了这样一种可能性，即赖氨酸乙酰化的动态变化是复杂的的细胞过程的一个重要的调节开关（2，3）。十年前，Kouzarides 作出大胆的预测，乙酰化可能是“磷酸化的竞争对手”来调节细胞功能（4）。随着蛋白质组学的发展，鉴定到数千种具有赖氨酸乙酰化的哺乳动物蛋白质（5，6），其中一个令人惊讶的发现是，参与代谢的酶类也和染色质蛋白质一样，极高程度地出现在乙酰化的底物中。这表明，乙酰化状态的变化可能改变酶的活性，使细胞对代谢需求的转变作出反应，通过调整有关的途径的关键节点的流量来调整。这一期1000页上赵等的报告和1004页上王等的报告。，分别通过原核沙门氏菌和人类肝细胞的研究证实了这一假说（7，8）。 1 N8 J! d8 P8 p, q# m3 G

( g( Y+ a/ e6 y8 [这两项研究报告了细菌和人类在代谢机制上的许多相似点。第一篇文章报道了代谢酶在赖氨酸残基上乙酰化的普遍性。赵等发现90%沙门氏菌参与中心代谢相关的蛋白质被乙酰化，王等同样发现参与糖酵解、脂肪酸和糖元代谢、三羧酸（TCA）和尿素循环的每一种酶都基本上发生了乙酰化（见图）。这两个研究小组还发现，无论是原核细胞还是真核细胞，可供利用的碳源的改变可以改变乙酰化的代谢酶的总表达谱。9 o7 n. T" J$ x7 ]0 E# C% `/ p3 `

" S/ N  @6 J0 c) D5 Y; x; m赵等和王等分别对沙门氏菌和人的许多酶进行了精细的生化研究，结果表明，乙酰化具有多个效能，能够增加一些代谢酶的活性，同时抑制了其他代谢酶的活性。此外，乙酰化的效应似乎是协调自动分流代谢流到一些特定途径而远离其些代谢途径。值得注意的是，这中代谢流可因新陈代谢状态或和可利用的碳源的变化发生可逆性反转。然而，这一过程的所有方面并不是保守的。在沙门氏菌中，代谢酶乙酰化的的变化可以导致主要的乙酰基转移酶和去乙酰基转移酶相对表达的部分变化，这一特点尚未在真核细胞中得到广泛的观察。的确，只有少数情况是存在有助于我们理解调节哺乳动物乙酰化酶和脱乙酰酶的机制（9）。当赵等人将人肝细胞乙酰化的蛋白和以前研究鉴定的蛋白质进行比较时，他们发现有70％的蛋白是和小鼠肝中确定的乙酰化蛋白是重叠的，只有14％乙酰化蛋白是和人的白血病细胞系的乙酰化蛋白重叠。这表明乙酰化的模式在不同细胞谱系之间的变化具有很大的差异。 1 }+ {- P& _7 W, _4 m) J& q
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在蛋白磷酸化中，三磷酸腺苷（ATP）是主要的磷酰基团的供体。赖氨酸的乙酰化依赖于乙酰辅酶A（CoA）作为乙酰基的供体。如ATP一样，乙酰辅酶A处于许多关键的细胞通路的核心地位，因此其在细胞内的浓度是许多生化过程的潜在的数值示读器。可利用的乙酰辅酶A的变化可以直接影响到关键底物的乙酰化状态，如观察到的核心组蛋白H2A，H2B，H3的，和H4的情况（10）。因此，一个模型日益显现，在这一模型乙酰辅酶A代谢库中是变化的，其在对许多代谢途径的响应中发生波动， 这一波动充当了一个可调制变阻器，通过这一变阻器许多代谢相关的酶的而在回答众多的代谢途径，可以提供其中的乙酰化状态，因此，代谢酶的乙酰状态以致其活性都受到调节。 ) Y- D# ^3 S. C8 _

7 `- y/ @# _( W理解赖氨酸乙酰化的控制，以及蛋白的乙酰化的改变对特定细胞代谢途径的效应，对于理解人类疾病具有深远的意义（例如Verinostat是一种一去乙酰酶抑制剂，在2006年获得美国食品和药物管理局的批准，作为治疗皮肤T细胞淋巴瘤的药物）。鉴于癌症部分是由于代谢性疾病引起的全新认识（11），赵等人和王等人的研究提出了这样一个问题，在多大程度上去乙酰化酶抑制剂是成功依赖于其具改变转录表达谱的能力，而不是使癌细胞代谢的重新编程。撇开癌症不谈，我们已了解到乙酰化作用在调控代谢途径的代谢流的作用，调节乙酰化的药物也许对具有某种特定的代谢紊乱患的病人有益。正如蛋白乙酰化的蛋白组学数据有待深入挖掘一样，这种研究的方法是精妙的，我们应该能够理解有一种除了联系染色质之外一个细胞过程或代谢的存在，在这一过程和代谢中赖氨酸乙酰化的动态变化发挥这全局性的调控作用。
+ z8 K# ^# X  q+ V. Q1 ?) n2 ~6 \  U6 X    磷酸化的重要性已得到广泛接受，但是自1964年诺贝尔生理学或医学奖授予发现了乙酰辅酶A的脂肪酸代谢的联系的Konrad Bloch和Feodor Lynen以来，与蛋白乙酰化动态变化相关的代谢途径的重要性很少被人们所认知。
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3 a0 J; z0 ]0 U  O尽管动态蛋白磷酸化毫无疑问提供了一个主要的细胞内调节开关，现在从赵等人和王等人的研究中也已很清楚地看到赖氨酸的乙酰基化也是同等重要的，在进化上是一种保守的控制机制（7，8）。磷酸化似乎确实在赖氨酸的乙酰化中发现了其功能调节的“对手”。
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References / `- R( T8 |( k5 t% ~9 g8 l

+ O6 m  v& j  L1. V. G. Allfrey, R. Faulkner, A. E. Mirsky, Proc. Natl. Acad. Sci. U.S.A. 51, 786 (1964).
2 D9 F0 z) s3 H! a2 q# J2 E( U4 |9 t6 m% S3 y
2. J. E. Brownell et al., Cell 84, 843 (1996).
8 m$ B. x& s* G4 z# k; g. f/ y
8 z; G& w. J- V) E0 \% [0 t) y3. J. Taunton, C. A. Hassig, S. L. Schreiber, Science 272, 408 (1996).
2 A6 N3 N+ T1 e6 ]+ N' v2 J. _6 ^# `) I3 e3 B1 ~* h
4. T. Kouzarides, EMBO J. 19, 1176 (2000).
! u* i8 r! V8 i7 J- v4 Q0 u6 E! I6 g% @$ y2 G$ t
5. C. Choudhary et al., Science 325, 834 (2009).9 |) d6 S: ]3 m4 B. Z% |6 t' ]- \" ]

$ m# U9 k) L( P. h6. S. C. Kim et al., Mol. Cell 23, 607 (2006).
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, e/ ]4 u  A  T8 ~& _: u7. S. Zhao et al., Science 327, 1000 (2010).) p, J) a3 ?" Z5 z: J2 U

& h! L$ V" R; h* {& R8. Q. Wang, Y. Zhang, C. Yang, H. Xiong, Y. Lin, Science 327, 1004 (2010).
/ J6 m, o: e+ @( ~* F; R- R4 _0 w& |2 {* L
9. H. S. Mellert, S. B. McMahon, Trends Biochem. Sci. 34, 571 (2009). 4 B/ |3 `9 D- ?

' Q1 a6 x" Z3 z; ?. C5 A10. K. E. Wellen et al., Science 324, 1076 (2009).
( n1 k5 e4 ~& u' j  s& x* W2 K$ {; C2 T* U7 @% o! b, J
11. C. B. Thompson, N. Engl. J. Med. 360, 813 (2009).

yusheen

在这个评论中，有两个地方很难翻，原文中翻的不准确，仔细揣摩，似乎这样翻更好，让各位见笑了。
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1. Thus, a model emerges in which changes in cellular pools of acetyl-CoA, which fluctuate in response to a myriad of metabolic pathways, could provide the rheostat by which the acetylation status, and hence the activity, of metabolic enzymes can be modulated.
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一个模型日益显现，在这一模型乙酰辅酶A代谢库中是变化的，其在对许多代谢途径的响应中发生波动， 这一波动充当了一个可调制变阻器，通过这一变阻器许多代谢相关的酶的乙酰状态以致其活性都受到调节。
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2. The studies by Zhao et al. and Wang et al. raise the question of how much the success of deacetylase inhibtors depends on their ability to change transcriptional profiles versus reprogramming cancer cell metabolism.
- o$ q% u2 X5 _. H赵等人和王等人的研究提出了这样一个问题，去乙酰化酶抑制剂对癌症抑制的成功有多少程度是依赖于其具有改变转录表达谱的能力，又有多大程度是由于其使癌细胞代谢重编程的呢？

linxingxing

very good!!