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FIGURE 1.5 MACROMOLECULAR ASSEMBLY. Many macromolecular components of cells assemble spontaneously from constituent
图 1.5 大分子组装细胞中的许多大分子成分都是自发组装而成的。

a 『lopodium assembled from protein subunits, and the plasma membrane formed from lipids and proteins.
way include chromatin, consisting of nuclear DNA packaged by associated proteins; ribosomes, assembled from RNA and proteins; cytoskeletal polymers, assembled from protein subunits; and membranes formed from lipids and proteins.
其中包括由相关蛋白质包装的核 DNA 组成的染色质、由 RNA 和蛋白质组装而成的核糖体、由蛋白质亚基组装而成的细胞骨架聚合物,以及由脂质和蛋白质形成的膜。
  1. Membranes grow by expansion of preexisting membranes (Fig. 1.6). Cellular membranes composed of lipids and proteins grow only by expansion of preexisting lipid bilayers rather than forming de novo. Thus membrane-bounded organelles, such as mitochondria and endoplasmic reticulum, multiply by growth and division of preexisting organelles and are inherited maternally from stockpiles stored in the egg. The endoplasmic reticulum (ER) plays a central role in membrane biogenesis as the site of phospholipid synthesis. Through a series of vesicle budding and fusion events, membrane made in the ER provides material for the Golgi apparatus, which, in turn, provides lipids and proteins for lysosomes and the plasma membrane.
    膜通过扩展原有膜而生长(图 1.6)。由脂质和蛋白质组成的细胞膜只能通过扩展原有的脂质双分子层而生长,而不是从头开始形成。因此,线粒体和内质网等以膜为界的细胞器是通过原有细胞器的生长和分裂来繁殖的,并从卵子中储存的细胞器中遗传给母体。内质网(ER)作为磷脂合成的场所,在膜的生物生成过程中发挥着核心作用。通过一系列囊泡萌发和融合过程,内质网中生成的膜为高尔基体提供材料,而高尔基体又为溶酶体和质膜提供脂质和蛋白质。
  2. Signal-receptor interactions target cellular constituents to their correct locations (Fig. 1.6). Specific recognition signals incorporated into the structures of proteins and nucleic acids route these molecules to their proper cellular compartments. Receptors recognize these signals and guide each molecule to its appropriate compartment. For example, proteins destined for the nucleus contain short amino acid sequences that bind receptors to facilitate their passage through nuclear pores into the nucleus.
    信号与受体的相互作用将细胞成分定位到正确的位置(图 1.6)。蛋白质和核酸结构中的特定识别信号会将这些分子引导到适当的细胞区。受体可识别这些信号,并将每种分子引导至适当的区室。例如,要进入细胞核的蛋白质含有与受体结合的短氨基酸序列,可帮助它们通过核孔进入细胞核。

    Similarly, a peptide signal sequence first targets lysosomal proteins into the lumen of the ER. Subsequently, the Golgi apparatus adds a sugar-phosphate group recognized by receptors that secondarily target these proteins to lysosomes.
    同样,肽信号序列首先将溶酶体蛋白质定向到 ER 腔内。随后,高尔基体会添加一个糖磷酸基团,该基团可被受体识别,从而将这些蛋白质二次定向到溶酶体。
  3. Cellular constituents move by diffusion, pumps, and motors (Fig. 1.7). Most small molecules move through the cytoplasm or membrane channels by diffusion. However, energy provided by ATP hydrolysis or electrochemical gradients is required for molecular pumps to drive molecules across membranes against concentration gradients. Similarly, motor proteins use energy from ATP hydrolysis to move organelles and other cargo along microtubules or actin filaments. In a more complicated example, protein molecules destined for mitochondria diffuse from their site of synthesis in the cytoplasm to a mitochondrion (Fig. 1.6), where they bind to a receptor. Energyrequiring reactions then transport the protein into the mitochondrion.
    细胞成分通过扩散、泵和马达移动(图 1.7)。大多数小分子通过扩散作用在细胞质或膜通道中移动。然而,分子泵需要 ATP 水解或电化学梯度提供的能量来驱动分子逆浓度梯度穿过膜。同样,运动蛋白也利用 ATP 水解产生的能量沿微管或肌动蛋白丝移动细胞器和其他货物。一个更复杂的例子是,要运往线粒体的蛋白质分子从它们在细胞质中合成的部位扩散到线粒体(图 1.6),并在那里与受体结合。然后,需要能量的反应将蛋白质运送到线粒体中。
  4. Receptors and signaling mechanisms allow cells to adapt to environmental conditions (Fig. 1.8). Environmental stimuli modify cellular behavior. Faced with an unpredictable environment, cells must decide which genes to express, which way to move, and whether to proliferate, differentiate into a specialized cell, or die. Some of these choices are programmed genetically or epigenetically, but minute-to-minute decisions generally involve the reception of chemical or physical stimuli from outside the cell and
    受体和信号机制使细胞能够适应环境条件(图 1.8)。环境刺激改变细胞行为。面对不可预知的环境,细胞必须决定表达哪些基因、向哪个方向移动,以及是增殖、分化为特化细胞还是死亡。其中有些选择是通过基因或表观遗传学编程的,但每分钟的决定一般都涉及接收来自细胞外的化学或物理刺激,以及
B. Protein targeting from ER-associated ribosomes
B.来自 ER 相关核糖体的蛋白质靶向
FIGURE 1.6 PROTEIN TARGETING. Signals built into the amino acid sequences of proteins target them to all compartments of the eukaryotic cell. A, Proteins synthesized on free ribosomes can be used locally in the cytoplasm or guided by different signals to the nucleus, mitochondria, or peroxisomes. B, Other signals target proteins for insertion into the membrane or lumen of the endoplasmic reticulum (ER). From there, a series of vesicular budding and fusion reactions carry the membrane proteins and lumen proteins to the Golgi apparatus, Iysosomes, or plasma membrane. mRNA, messenger RNA. processing of these stimuli to change the behavior of the cell. Cells have an elaborate repertoire of receptors for a multitude of stimuli, including nutrients, growth factors, hormones, neurotransmitters, and toxins. Stimulation of receptors activates diverse signal-transducing mechanisms that amplify the message and generate a wide range of cellular responses. These include changes in the electrical potential of the plasma membrane, gene expression, and enzyme activity. Basic signal transduction mechanisms are ancient, but receptors and output systems have diversified by gene duplication and divergence during evolution.
图 1.6 蛋白质靶向。蛋白质氨基酸序列中的信号可将其定向到真核细胞的所有区室。A:在游离核糖体上合成的蛋白质可在细胞质中就地使用,也可在不同信号的引导下进入细胞核、线粒体或过氧物酶体。B,其他信号将蛋白质引向内质网(ER)的膜或腔。从那里,一系列囊泡出芽和融合反应将膜蛋白和腔蛋白带到高尔基体、溶酶体或质膜。细胞对多种刺激物(包括营养物质、生长因子、激素、神经递质和毒素)都有一套复杂的受体。受体受到刺激后会激活各种信号转导机制,从而放大信息并产生各种细胞反应。这些反应包括质膜电位、基因表达和酶活性的变化。基本的信号转导机制由来已久,但受体和输出系统在进化过程中通过基因复制和分化实现了多样化。
  1. Molecular feedback mechanisms control molecular composition, growth, and differentiation (Fig. 1.9). Living cells are dynamic, constantly fine-tuning their composition in response to external stimuli, nutrient
    分子反馈机制控制着分子组成、生长和分化(图 1.9)。活细胞是动态的,它们会根据外部刺激、营养物质和环境变化不断调整自身的组成。
FIGURE 1.7 MOLECULAR MOVEMENTS BY DIFFUSION, PUMPS, AND MOTORS. Diffusion: Molecules up to the size of globular proteins diffuse in the cytoplasm. Concentration gradients can provide a direction to diffusion, such as the diffusion of from a region of high concentration inside the endoplasmic reticulum through a membrane channel to a region of low concentration in the cytoplasm. Pumps: Adenosine triphosphate (ATP)-driven protein pumps transport ions up concentration gradients. Motors: ATP-driven motors move organelles and other large cargo along microtubules and actin 『aments. ADP, adenosine diphosphate.
图 1.7 通过扩散、泵和马达进行的分子运动。扩散:球状蛋白质大小的分子在细胞质中扩散。浓度梯度可为扩散提供方向,如 从内质网内的高浓度区域通过膜通道扩散到细胞质中的低浓度区域。泵:三磷酸腺苷(ATP)驱动的蛋白质泵将离子沿浓度梯度向上输送。马达:ATP驱动的马达沿着微管和肌动蛋白『结构』移动细胞器和其他大型货物。ADP,二磷酸腺苷。
FIGURE 1.8 RECEPTORS AND SIGNALS. Activation of cellular metabolism by an extracellular ligand, such as a hormone. In this example, binding of the hormone triggers a series of linked biochemical reactions monophosphate [cAMP]) and a cascade of three activated proteins to regulate a metabolic enzyme. The response to a single ligand is multiplied at steps B, C, and E, leading to thousands of activated enzymes. GTP, guanosine triphosphate.
图 1.8 受体和信号细胞外配体(如激素)激活细胞新陈代谢。在这个例子中,荷尔蒙 的结合引发了一系列相关的生化反应 monophosphate [cAMP])和由三种活化蛋白组成的级联反应,从而调节一种代谢酶。对单个配体的反应在步骤 B、C 和 E 中成倍增加,导致数千个酶被激活。GTP,三磷酸鸟苷。
FIGURE 1.9 MOLECULAR FEEDBACK LOOPS. A, Control of the synthesis of aromatic amino acids. An intermediate and the 区nal products of this biochemical pathway inhibit three of nine enzymes (Enz) in a concentration-dependent fashion, automatically turning down the reactions that produced them. This maintains constant levels of the 『nal products, two amino acids essential for protein synthesis. , Control of the cell cycle. The cycle consists of four stages. During the phase, the cell grows in size. During the phase, the cell duplicates the DNA of its chromosomes. During the phase, the cell checks for completion of DNA replication. In the M phase, chromosomes condense and attach to the mitotic spindle, which separates the duplicated pairs in preparation for the division of the cell by cytokinesis. Biochemical feedback loops called checkpoints halt the cycle (blunt bars) at several points until the successful completion of key preceding events.
图 1.9 分子反馈回路。A,控制芳香族氨基酸的合成。这一生化途径的中间产物和最终产物以浓度依赖的方式抑制九种酶(Enz)中的三种,自动降低产生这些产物的反应。这就保持了『最终产物』(蛋白质合成所必需的两种氨基酸)的恒定水平。 , 细胞周期的控制。细胞周期由四个阶段组成。在 阶段,细胞不断增大。在 阶段,细胞复制染色体的 DNA。在 阶段,细胞检查 DNA 复制是否完成。在 M 期,染色体凝结并附着在有丝分裂纺锤体上,纺锤体分离复制的染色体对,为细胞分裂做准备。被称为检查点的生化反馈回路会在几个点上停止循环(钝杠),直到前面的关键事件成功完成。
availability, and internal signals. The most dramatic example is the regulation of each step in the cell cycle. Feedback loops assure that the conditions are suitable for each transition such as the onset of DNA synthesis and the decision to begin mitosis. Similarly, cells carefully balance the production and degradation of their constituent molecules. Cells produce "housekeeping" molecules for basic functions, such as intermediary metabolism, and subsets of other proteins and RNAs for specialized functions. A hierarchy of mechanisms controls the supply of each protein and RNA: epigenetic mechanisms designate whether a particular region of a chromosome is active or not; regulatory proteins turn specific genes on and off and modulate the rates of translation of mRNAs into protein; synthesis balanced by the rates of degradation determines the abundance of specific RNAs and proteins; phosphorylation (covalent modification of certain amino acids with a charged phosphate group) regulates protein interactions and activities; and other mechanisms regulate of the distribution of each molecule within the cell. Feedback loops also regulate enzymes that synthesize and degrade proteins, nucleic acids, sugars, and lipids to ensure the proper levels of each cellular constituent.
细胞周期的每一个步骤都是由细胞的可利用性和内部信号调节的。最显著的例子就是细胞周期中每一步的调节。反馈回路确保每个过渡阶段(如开始 DNA 合成和决定开始有丝分裂)都有合适的条件。同样,细胞也会仔细平衡其组成分子的生产和降解。细胞为中间代谢等基本功能生产 "管家 "分子,为特殊功能生产其他蛋白质和 RNA 子集。控制每种蛋白质和 RNA 供应的机制层次分明:表观遗传机制指定染色体的特定区域是否活跃;调节蛋白开启或关闭特定基因,并调节 mRNA 翻译成蛋白质的速率;合成与降解速率的平衡决定了特定 RNA 和蛋白质的丰度;磷酸化(用带电的磷酸基团对某些氨基酸进行共价修饰)调节蛋白质的相互作用和活性;其他机制调节每种分子在细胞内的分布。反馈回路还对合成和降解蛋白质、核酸、糖类和脂类的酶进行调节,以确保每种细胞成分的适当水平。
A practical consequence of these common biochemical mechanisms is that general principles may be discovered by studying any cell that is favorable for experimentation. This text cites many examples of research on bacteria, insects, protozoa, or fungi that revealed fundamental mechanisms shared by human cells. For example, humans and baker's yeast use similar mechanisms to control the cell cycle, guide protein secretion, and segregate chromosomes at mitosis. Indeed, particular proteins are often functionally interchangeable between human and yeast cells.

Features That Distinguish Eukaryotic and Prokaryotic Cells

Although sharing a common origin and basic biochemistry, cells vary considerably in their structure and organization (Fig. 1.2). Bacteria and Archaea have much in common, including chromosomes in the cytoplasm, cell membranes with similar families of pumps, carriers and channels, basic metabolic pathways, gene expression, motility powered by rotary flagella, and lack of membranebound organelles. On the other hand, these prokaryotes are wonderfully diverse in terms of morphology and their use of a wide range of energy sources.
虽然细胞具有共同的起源和基本的生物化学特性,但它们的结构和组织却有很大的不同(图 1.2)。细菌和古细菌有许多共同点,包括细胞质中的染色体、具有类似泵、载体和通道家族的细胞膜、基本的新陈代谢途径、基因表达、由旋转鞭毛驱动的运动以及缺乏膜结合的细胞器。另一方面,这些原核生物在形态和利用各种能源方面却有着奇妙的多样性。
Eukaryotes comprise a multitude of unicellular organisms, algae, plants, amoebas, fungi, and animals that differ from prokaryotes in having a compartmentalized cytoplasm with membrane-bounded organelles including a nucleus. The basic features of eukaryotic cells were refined more than 1.5 billion years ago, before the major groups of eukaryotes diverged. The nuclear envelope separates the two major compartments: nucleoplasm and cytoplasm. Chromosomes carrying the cell's genes and the machinery to express those genes reside inside the nucleus. Most eukaryotic cells have ER (the site of protein and phospholipid synthesis), a Golgi apparatus (adds sugars to membrane proteins, lysosomal proteins, and secretory proteins), lysosomes (compartments containing digestive enzymes), and peroxisomes (containers for enzymes involved in oxidative reactions). Most also have mitochondria that convert energy stored in the chemical bonds of nutrients into ATP. Cilia (and flagella) are ancient eukaryotic specializations used for motility or sensing the environment.
真核生物包括多种单细胞生物、藻类、植物、变形虫、真菌和动物,与原核生物不同的是,真核生物的细胞质是分隔的,具有包括细胞核在内的膜质细胞器。真核细胞的基本特征是在 15 亿多年前,即真核生物主要类群分化之前形成的。核膜将核质和细胞质两大区块分隔开来。携带细胞基因的染色体和表达这些基因的机器位于细胞核内。大多数真核细胞都有 ER(合成蛋白质和磷脂的场所)、高尔基体(将糖添加到膜蛋白、溶酶体蛋白和分泌蛋白中)、溶酶体(含有消化酶的隔室)和过氧物酶体(参与氧化反应的酶的容器)。大多数生物还具有线粒体,可将营养物质化学键中储存的能量转化为 ATP。纤毛(和鞭毛)是真核生物的古老特化现象,用于运动或感知环境。
Membrane-bounded compartments give eukaryotic cells a number of advantages. Membranes provide a barrier that allows each type of organelle to maintain novel ionic and enzymatic interior environments. Each

of these special environments favors a subset of the biochemical reactions required for life as illustrated by the following examples. The nuclear envelope separates the synthesis and processing of RNA in the nucleus from the translation of mature mRNAs into proteins in the cytoplasm. Segregation of digestive enzymes in lysosomes prevents them from destroying other cellular components. ATP synthesis depends on the impermeable membrane around mitochondria; energy-releasing reactions produce a proton gradient across the membrane that drives enzymes in the membrane to synthesize ATP.
这些特殊环境有利于生命所需的一部分生化反应,下面的例子就说明了这一点。核膜将细胞核中 RNA 的合成和处理与细胞质中成熟 mRNA 翻译成蛋白质的过程分隔开来。消化酶被隔离在溶酶体中,防止它们破坏其他细胞成分。ATP 的合成取决于线粒体周围的不透膜;能量释放反应在膜上产生质子梯度,推动膜上的酶合成 ATP。

Overview of Eukaryotic Cellular Organization and Functions

This section previews the major constituents and processes of eukaryotic cells. With this background the reader will be able to appreciate cross-references to chapters later in the book.

Plasma Membrane 等离子膜

The plasma membrane is the interface of the cell with its environment (Fig. 1.2). Owing to the hydrophobic interior of its lipid bilayer, the plasma membrane is impermeable to ions and most water-soluble molecules. Consequently, they cross the membrane only through transmembrane channels, carriers, and pumps (Fig. 1.10). These transmembrane proteins provide the cell with nutrients, control internal ion concentrations, and establish a transmembrane electrical potential. A single amino acid change in one plasma membrane pump and channel causes the human disease cystic fibrosis.
质膜是细胞与其环境的界面(图 1.2)。由于其脂质双分子层内部疏水,质膜对离子和大多数水溶性分子都是不渗透的。因此,它们只能通过跨膜通道、载体和泵(图 1.10)穿过膜。这些跨膜蛋白为细胞提供营养,控制内部离子浓度,并建立跨膜电位。质膜泵和 通道中一个氨基酸的改变就会导致人类疾病囊性纤维化。
Other plasma membrane proteins mediate interactions of cells with their immediate environment. Transmembrane receptors convert the binding of extracellular signaling molecules, such as hormones and growth factors into chemical or electrical signals that influence the activity of the cell. Genetic defects in signaling proteins, which mistakenly turn on signals for growth in the absence of appropriate extracellular stimuli, contribute to human cancers.
Plasma membrane adhesion proteins allow cells to bind specifically to each other or to the extracellular matrix (Fig. 1.10). These selective interactions allow cells to form multicellular associations, such as epithelia (sheets of cells that separate the interior of the body from the outside world). Similar interactions allow white blood cells to bind bacteria so that they can be ingested and killed. In cells that are subjected to mechanical forces, such as muscle and epithelia, cytoskeletal filaments inside the cell reinforce the plasma membrane adhesion proteins. In skin, defects in these attachments cause blistering diseases.
质膜粘附蛋白可使细胞相互之间或与细胞外基质特异性结合(图 1.10)。这些选择性的相互作用使细胞形成多细胞联合体,如上皮(将人体内部与外界隔开的细胞片)。类似的相互作用还能让白细胞与细菌结合,从而将其吞噬并杀死。在肌肉和上皮细胞等受到机械力作用的细胞中,细胞内的细胞骨架丝会加强质膜粘附蛋白。在皮肤中,这些附着物的缺陷会导致水疱病。
FIGURE 1.10 STRUCTURE AND FUNCTIONS OF AN ANIMAL CELL PLASMA MEMBRANE. The lipid bilayer is a permeability barrier between the cytoplasm and the extracellular environment. Transmembrane adhesion proteins anchor the membrane to the extracellular matrix (A) or to like receptors on other cells (B) and transmit forces to the cytoskeleton (C). Adenosine triphosphate (ATP)-driven enzymes (D) pump out of and into the cell (E) to establish concentration gradients across the lipid bilayer. Transmembrane carrier proteins (F) use these ion concentration gradients to transport of nutrients into the cell. Selective ion channels regulate the electrical potential across the membrane. A large variety of receptors bind speci『c extracellular ligands and send signals across the membrane to the cytoplasm.
图 1.10 动物细胞质膜的结构和功能。脂质双分子层是细胞质与细胞外环境之间的渗透屏障。跨膜粘附蛋白将膜固定到细胞外基质(A)或其他细胞上的同类受体(B)上,并将力传递到细胞骨架(C)。三磷酸腺苷(ATP)驱动的酶(D)将 泵出细胞,将 泵入细胞(E),在脂质双分子层上建立浓度梯度。跨膜载体蛋白(F)利用这些离子浓度梯度将营养物质输送到细胞内。选择性离子通道 可调节膜上的电位。各种受体 与特定的细胞外配体结合,并向细胞质发送跨膜信号。
FIGURE 1.11 ELECTRON MICROGRAPH OF A THIN SECTION OF A NUCLEUS. (Courtesy Don Fawcett, Harvard Medical School, Boston, MA.)
图 1.11 细胞核薄片的电子显微照片。(马萨诸塞州波士顿哈佛医学院 Don Fawcett 提供)。

Nucleus 核心

The nuclear envelope is a double membrane that separates the nucleus from the cytoplasm (Fig. 1.11). All traffic into and out of the nucleus passes through nuclear pores that bridge the double membranes. Inbound traffic includes all nuclear proteins and ribosomal proteins destined for the nucleolus. Outbound traffic includes mRNAs and ribosomal subunits.
核膜是将细胞核与细胞质隔开的双层膜(图 1.11)。所有进出细胞核的物质都要通过桥接双层膜的核孔。进入细胞核的物质包括所有核蛋白和核糖体蛋白。外向运输包括 mRNA 和核糖体亚基。
The nucleus stores genetic information in extraordinarily long DNA molecules called chromosomes. Remarkably, portions of genes encoding proteins and structural RNAs make up only a small fraction ( ) of the 3 billion nucleotide pairs in human DNA, but more than of the 97 million nucleotide pairs in a nematode worm. Regions of DNA called telomeres stabilize the ends of chromosomes, and other DNA sequences organize centromeres that direct the distribution of chromosomes to daughter cells when cells divide. Much of the DNA encodes a myriad of RNAs with regulatory activities.
细胞核将遗传信息储存在称为染色体的超长 DNA 分子中。值得注意的是,在人类 DNA 的 30 亿个核苷酸对中,编码蛋白质和结构 RNA 的基因部分只占一小部分( ),但在线虫的 9700 万个核苷酸对中,却有超过 。被称为端粒的 DNA 区域稳定着染色体的末端,其他 DNA 序列组织着中心粒,在细胞分裂时引导染色体向子细胞的分配。大部分 DNA 都编码了大量具有调节功能的 RNA。
The DNA and its associated proteins are called chromatin (Fig. 1.5). Interactions with histones and other proteins fold each chromosome compactly enough to fit into discrete territories inside the nucleus. During mitosis, chromosomes condense and reorganize into separate structural units suitable for sorting into daughter cells (Fig. 1.5).
DNA 及其相关蛋白质被称为染色质(图 1.5)。染色质与组蛋白和其他蛋白质相互作用,将每条染色体折叠得足够紧凑,以适应细胞核内不连续的区域。在有丝分裂过程中,染色体凝集并重组为适合分选到子细胞中的独立结构单元(图 1.5)。
Regulatory proteins called transcription factors turn specific genes on and off in response to genetic, developmental, and environmental signals. Enzymes called polymerases make RNA copies of active genes, a process called transcription. mRNAs specify the amino acid sequences of proteins. Other RNAs have structural, regulatory, or catalytic functions. Most newly synthesized RNAs are processed extensively before they are ready for use. Processing involves removal of intervening sequences, alteration of bases, or addition of specific chemical groups at both ends. For cytoplasmic RNAs, this processing occurs before RNA molecules are exported from the nucleus through nuclear pores. The nucleolus assembles ribosomes from more than 50 different proteins and 3 RNA molecules. Genetic errors resulting in altered RNA and protein products cause or predispose individuals to many inherited human diseases.
称为转录因子的调控蛋白会根据遗传、发育和环境信号打开或关闭特定基因。mRNA 指定了蛋白质的氨基酸序列。其他 RNA 具有结构、调节或催化功能。大多数新合成的 RNA 都要经过大量加工才能使用。加工过程包括去除中间序列、改变碱基或在两端添加特定化学基团。对于细胞质 RNA 来说,这种加工过程发生在 RNA 分子通过核孔从细胞核输出之前。核仁由 50 多种不同的蛋白质和 3 种 RNA 分子组装成核糖体。导致 RNA 和蛋白质产物改变的遗传错误会导致或易导致许多遗传性人类疾病。

Ribosomes and Protein Synthesis

Ribosomes catalyze the synthesis of proteins, using the nucleotide sequences of mRNA molecules to specify the sequence of amino acids (Fig. 1.4). Ribosomes free in the cytoplasm synthesize proteins that are released for routing to various intracellular destinations (Fig. 1.6).
核糖体利用 mRNA 分子的核苷酸序列指定氨基酸的序列,催化蛋白质的合成(图 1.4)。游离在细胞质中的核糖体合成的蛋白质被释放出来,然后被输送到细胞内的各个目的地(图 1.6)。

Endoplasmic Reticulum 内质网

Ribosomes synthesizing proteins destined for insertion into cellular membranes or for export from the cell associate with the ER, a continuous system of flattened membrane sacks and tubules (Fig. 1.12). Proteins produced on these ribosomes carry signal sequences of amino acids that target their ribosomes to receptors on the ER (Fig. 1.6). These regions of the ER are called rough ER owing to the attached ribosomes. As a polypeptide chain grows, its sequence determines whether the protein folds up in the lipid bilayer or translocates across the membrane into the lumen of the ER. Enzymes add sugar
合成蛋白质的核糖体将插入细胞膜或从细胞中输出,这些核糖体与 ER 结合,ER 是一个由扁平膜袋和膜管组成的连续系统(图 1.12)。这些核糖体上产生的蛋白质带有氨基酸信号序列,可将其核糖体定向到 ER 上的受体(图 1.6)。由于核糖体附着,ER 的这些区域被称为粗糙 ER。随着多肽链的生长,其序列决定了蛋白质是在脂质双分子层中折叠起来,还是穿过膜转运到 ER 腔中。酶添加糖
图 1.12 显示细胞器的肝细胞薄片电子显微照片。(马萨诸塞州波士顿哈佛医学院 Don Fawcett 提供)。
polymers to some proteins exposed in the lumen. Some proteins are retained in the ER, but most move on to other parts of the cell.
一些蛋白质的聚合物暴露在内腔中。有些蛋白质被保留在 ER 中,但大多数会转移到细胞的其他部分。
ER is very dynamic. Motor proteins move along microtubules to pull the ER membranes into a branching network spread throughout the cytoplasm. Continuous bidirectional traffic moves small vesicles between the ER and the Golgi apparatus. These vesicles carry soluble proteins in their lumens, in addition to transporting membrane lipids and proteins. Proteins on the cytoplasmic surface of the membranes catalyze each membrane budding and fusion event. The use of specialized proteins for budding and fusion of membranes at different sites in the cell organizes this membrane traffic and prevents the membrane components from getting mixed up.
ER 非常活跃。运动蛋白沿着微管运动,将 ER 膜拉成一个遍布细胞质的分支网络。持续不断的双向交流使小囊泡在 ER 和高尔基体之间移动。这些囊泡除了运输膜脂和蛋白质外,还在其腔内携带可溶性蛋白质。膜的细胞质表面上的蛋白质催化着每一次膜的萌发和融合。在细胞的不同部位使用专门的蛋白质进行膜的萌发和融合,可以组织这种膜运输,防止膜成分混淆。
The ER also serves as the outer membrane of the nuclear envelope, which can have attached ribosomes. ER enzymes synthesize many cellular lipids and metabolize drugs, while ER pumps and channels regulate the cytoplasmic concentration.
ER 还是核膜的外膜,核膜上可能附着核糖体。ER酶合成许多细胞脂质并代谢药物,而ER泵和通道则调节细胞质 浓度。

Golgi Apparatus 高尔基体

The Golgi apparatus processes the sugar side chains on transmembrane and secreted proteins. It consists of a stack of flattened, membrane-bound sacks with many associated vesicles. The Golgi apparatus is characteristically located in the middle of the cell near the nucleus and the centrosome (Figs. 1.2 and 1.12). Proteins to be processed come in vesicles that detach from the ER and fuse with Golgi apparatus membranes (Fig. 1.6). As proteins pass through the stacked Golgi membranes from one side to the other, enzymes in specific stacks modify the sugar side chains of secretory and membrane proteins.
高尔基体处理跨膜蛋白质和分泌蛋白质上的糖侧链。高尔基体由一堆扁平的膜袋和许多相关囊泡组成。高尔基体通常位于细胞中部,靠近细胞核和中心体(图 1.2 和 1.12)。待处理的蛋白质以囊泡的形式从细胞内质网分离出来,并与高尔基体膜融合(图 1.6)。当蛋白质从一侧通过堆积的高尔基体膜到另一侧时,特定堆积中的酶会改变分泌蛋白和膜蛋白的糖侧链。

On the downstream side of the Golgi apparatus, processed proteins segregate into different vesicles destined for lysosomes or the plasma membrane (Fig. 1.6). Many components of the plasma membrane including receptors for extracellular molecules recycle from the plasma membrane to endosomes and back to the cell surface many times before they are degraded. Defects in this process can cause arteriosclerosis.
在高尔基体的下游一侧,处理过的蛋白质分离成不同的囊泡,进入溶酶体或质膜(图 1.6)。包括细胞外分子受体在内的许多质膜成分在降解前都会从质膜循环到内体,然后再返回细胞表面多次。这一过程中的缺陷可导致动脉硬化。

Lysosomes 溶酶体

An impermeable membrane separates degradative enzymes inside lysosomes from other cellular components (Fig. 1.12). After synthesis by rough ER, lysosomal proteins move through the Golgi apparatus, where enzymes add the modified sugar, phosphorylated mannose (Fig. 1.6). Vesicular transport, guided by phosphomannose receptors, delivers lysosomal proteins to the lumen of lysosomes.
一层防渗膜将溶酶体内的降解酶与其他细胞成分隔开(图 1.12)。溶酶体蛋白质由粗糙ER合成后,通过高尔基体移动,酶在高尔基体中添加修饰糖--磷酸甘露糖(图 1.6)。在磷甘露糖受体的引导下,囊泡运输将溶酶体蛋白运送到溶酶体腔内。
Cells ingest microorganisms and other materials in membrane vesicles derived from the plasma membrane. The contents of these endosomes and phagosomes are delivered to lysosomes for degradation by lysosomal enzymes. Deficiencies of lysosomal enzymes cause many severe congenital diseases where substrates of the enzyme accumulate in quantities that can impair the function of the brain, liver, or other organs.

Mitochondria 线粒体

Mitochondrial enzymes use most of the energy released from the breakdown of nutrients to synthesize ATP, the common currency for most energy-requiring reactions in cells (Fig. 1.12). This efficient process uses molecular oxygen to complete the oxidation of fats, proteins, and sugars to carbon dioxide and water. A less-efficient glycolytic system in the cytoplasm extracts energy from the
线粒体酶利用营养物质分解释放的大部分能量来合成 ATP,ATP 是细胞中大多数能量需求反应的通用货币(图 1.12)。这一高效过程利用分子氧将脂肪、蛋白质和糖氧化成二氧化碳和水。细胞质中的糖酵解系统效率较低,它从细胞质中提取能量(图 1.12)。

partial breakdown of glucose to make ATP. Mitochondria cluster near sites of ATP utilization, such as membranes engaged in active transport, nerve terminals, and the contractile apparatus of muscle cells.
部分分解葡萄糖以产生 ATP。线粒体聚集在利用 ATP 的部位附近,如从事主动运输的膜、神经末梢和肌肉细胞的收缩装置。
Mitochondria also respond to toxic stimuli from the environment including drugs used in cancer chemotherapy by activating controlled cell death called apoptosis. A toxic cocktail of enzymes degrades proteins and nucleic acids as the cell breaks into membrane-bound fragments. Defects in this form of cellular suicide lead to autoimmune disorders, cancer, and some neurodegenerative diseases.
Mitochondria form in a fundamentally different way from the ER, Golgi apparatus, and lysosomes (Fig. 1.6). Cytoplasmic ribosomes synthesize most mitochondrial proteins. Signal sequences on these mitochondrial proteins bind receptors on the surface of mitochondria. The proteins are then transported into the mitochondrial interior or inserted into the outer or inner mitochondrial membranes.
线粒体的形成方式与 ER、高尔基体和溶酶体有本质区别(图 1.6)。细胞质核糖体合成大多数线粒体蛋白质。这些线粒体蛋白质上的信号序列与线粒体表面的受体结合。然后,这些蛋白质被运输到线粒体内部或插入线粒体外膜或内膜。
Mitochondria arose from symbiotic Bacteria (Fig. 1.1) and most of the bacterial genes subsequently moved to the nucleus. However, mitochondrial DNA, ribosomes, and mRNAs still produce a few essential proteins for the organelle. Defects in the maternally inherited mitochondrial genome cause several diseases, including deafness, diabetes, and ocular myopathy.
线粒体产生于共生细菌(图 1.1),大部分细菌基因随后转移到细胞核中。不过,线粒体 DNA、核糖体和 mRNA 仍能产生一些细胞器必需的蛋白质。母体遗传的线粒体基因组缺陷会导致多种疾病,包括耳聋、糖尿病和眼肌病。

Peroxisomes 过氧物酶体

Peroxisomes are membrane-bound organelles containing enzymes that participate in oxidative reactions. Like mitochondria, peroxisomal enzymes oxidize fatty acids, but the energy is not used to synthesize ATP. Peroxisomes are particularly abundant in plants. Peroxisomal proteins are synthesized in the cytoplasm and imported into the organelle using the same strategy as mitochondria but with different targeting sequences and transport machinery (Fig. 1.6). Genetic defects in peroxisomal biogenesis cause several forms of mental retardation.
过氧物酶体是一种膜结合细胞器,内含参与氧化反应的酶。与线粒体一样,过氧物酶体的酶也氧化脂肪酸,但能量不用于合成 ATP。过氧物酶体在植物中特别丰富。过氧化物酶体蛋白质在细胞质中合成,并通过与线粒体相同的策略输入细胞器,但具有不同的靶向序列和转运机制(图 1.6)。过氧化物酶体生物发生过程中的遗传缺陷会导致几种形式的智力迟钝。

Cytoskeleton and Motility Apparatus

A cytoplasmic network of three protein polymers-actin filaments, intermediate filaments, and microtubules (Fig. 1.13)-maintains the shape of most cells. Each polymer has distinctive properties and dynamics. Actin filaments and microtubules provide tracks for the ATP-powered motor proteins that produce most cellular movements (Fig. 1.14), including locomotion, muscle contraction, transport of organelles through the cytoplasm, mitosis, and the beating of cilia and flagella. The proteins are also used for highly specialized motile processes, such as muscle contraction and sperm motility.
由三种蛋白质聚合物组成的细胞质网络--肌动蛋白丝、中间丝和微管(图 1.13)--维持着大多数细胞的形状。每种聚合物都具有独特的性质和动态特性。肌动蛋白丝和微管为以 ATP 为动力的运动蛋白提供轨道,这些蛋白可产生大多数细胞运动(图 1.14),包括运动、肌肉收缩、细胞器在细胞质中的运输、有丝分裂以及纤毛和鞭毛的跳动。这些蛋白质还用于高度特化的运动过程,如肌肉收缩和精子运动。
Networks of crosslinked actin filaments anchored to the plasma membrane (Fig. 1.10) reinforce the surface of the cell. In many cells, tightly packed bundles of actin
锚定在质膜上的交联肌动蛋白丝网络(图 1.10)加固了细胞表面。在许多细胞中,紧密排列的肌动蛋白束
FIGURE 1.13 ELECTRON MICROGRAPH OF THE CYTOPLAS MIC MATRIX. A Øbroblast cell was prepared by detergent extraction of soluble components, rapid freezing, sublimation of ice, and coating with metal. IF, intermediate 『laments; MT, microtubules (shaded red). (Courtesy J. Heuser, Washington University, St. Louis, MO.)
图 1.13 细胞质基质的电子显微镜照片。通过洗涤剂提取可溶性成分、快速冷冻、冰升华和金属涂层制备Øbroblast细胞。IF,中间『丝』;MT,微管(红色阴影)。(由密苏里州圣路易斯市华盛顿大学的 J. Heuser 提供)。
filaments support finger-like projections of the plasma membrane (Fig. 1.5). These filopodia or microvilli increase the surface area of the plasma membrane for transporting nutrients and other processes, including sensory transduction in the ear. Genetic defects in a membrane-associated, actin-binding protein called dystrophin cause the most common form of muscular dystrophy.
细丝支撑着质膜的指状突起(图 1.5)。这些丝状突起或微绒毛增加了质膜的表面积,有利于营养物质的运输和其他过程,包括耳朵的感觉传导。一种名为肌营养不良蛋白(dystrophin)的膜相关肌动蛋白结合蛋白的基因缺陷会导致最常见的肌肉营养不良症。
Actin filaments participate in movements in two ways. Assembly of actin filaments produces some movements, such as the protrusion of pseudopods. Other movements result from force generated by myosin motor proteins that use the energy from ATP hydrolysis to produce movements along actin filaments. Muscles use a highly organized assembly of actin and myosin filaments to drive forceful, rapid, one-dimensional contractions. Myosin also drives the contraction of the cleavage furrow during cell division. External signals, such as chemotactic molecules, can influence both actin filament organization and the direction of motility. Genetic defects in myosin cause enlargement of the heart and sudden death.
肌动蛋白丝以两种方式参与运动。肌动蛋白丝的组装会产生一些运动,如假足的突出。其他运动则是由肌球蛋白运动蛋白产生的力量导致的,肌球蛋白运动蛋白利用 ATP 水解产生的能量沿着肌动蛋白丝产生运动。肌肉利用高度组织化的肌动蛋白和肌球蛋白丝来驱动有力、快速的一维收缩。肌球蛋白还能在细胞分裂过程中驱动裂沟收缩。外部信号,如趋化分子,可影响肌动蛋白丝的组织和运动方向。肌球蛋白的基因缺陷会导致心脏扩大和猝死。
Intermediate filaments are flexible but strong intracellular tendons that reinforce epithelial cells of the skin and other cells subjected to substantial physical stresses. All intermediate filament proteins are related to the keratin molecules found in hair. Intermediate filaments characteristically form bundles that link the plasma membrane to the nucleus. Lamin intermediate filaments reinforce the nuclear envelope. Intermediate filament networks are disassembled during mitosis and cell movements as a result of specific reversible phosphorylation events. Genetic defects in keratin intermediate filaments cause blistering diseases of the skin. Defects in nuclear lamins are associated with some types of muscular dystrophy and premature aging.
Microtubules are rigid cylindrical polymers that resist compression better than actin or intermediate filaments.
FIGURE 1.14 TRANSPORT OF CYTOPLASMIC PARTICLES ALONG ACTIN FILAMENTS AND MICROTUBULES BY MOTOR PROTEINS. A, Overview of organelle movements in a neuron and छbroblast. B, Details of the molecular motors. The microtubule-based motors, dynein and kinesin, move in opposite directions. The actinbased motor, myosin, moves in one direction along actin ₪aments. (Modi®ed from Atkinson SJ, Doberstein SK, Pollard TD. Moving off the beaten track. Curr Biol. 1992;2:326-328.)
图 1.14 运动蛋白沿肌动蛋白丝和微管运输细胞质颗粒。A, 神经元和छ成纤维细胞中细胞器运动的概况。B,分子马达的细节。基于微管的马达--动力蛋白和驱动蛋白--朝相反的方向运动。基于肌动蛋白的马达肌球蛋白沿肌动蛋白₪束单向运动。(Modi®ed from Atkinson SJ, Doberstein SK, Pollard TD.不走寻常路。Curr Biol. 1992; 2:326-328.)
The molecular polarity of the microtubule polymer gives the two ends different properties and determines the direction of movement of motor proteins. Most microtubules in cells have the same polarity relative to the organizing centers that initiate their growth (eg, the centrosome) (Fig. 1.2). Their rapidly growing ends are oriented toward the periphery of the cell. Individual cytoplasmic microtubules are remarkably dynamic, growing and shrinking on a time scale of minutes.
微管聚合物的分子极性赋予微管两端不同的特性,并决定了运动蛋白的运动方向。细胞中的大多数微管相对于启动其生长的组织中心(如中心体)具有相同的极性(图 1.2)。它们快速生长的末端朝向细胞外围。单个细胞质微管具有显著的动态性,可在几分钟的时间内生长和收缩。
Microtubules serve as mechanical reinforcing rods for the cytoskeleton and the tracks for two classes of motor proteins that use the energy liberated by ATP hydrolysis to move along the microtubules. Kinesin moves its associated cargo (vesicles and RNA-protein particles) along the microtubule network radiating away from the centrosome, whereas dynein moves its cargo toward the centrosome. Together, they form a two-way transport system that is particularly well developed in the axons and dendrites of nerve cells. Toxins can impair this transport system and cause nerve malfunctions.
微管是细胞骨架的机械加固杆,也是两类运动蛋白的轨道,它们利用 ATP 水解释放的能量沿微管运动。驱动蛋白沿着从中心体辐射开来的微管网络移动其相关货物(囊泡和 RNA 蛋白颗粒),而动力蛋白则向中心体移动其货物。它们共同构成了一个双向运输系统,在神经细胞的轴突和树突中尤为发达。毒素会损害这种运输系统,导致神经功能失调。
During mitosis, the cell assembles a mitotic apparatus of highly dynamic microtubules and uses microtubule motor proteins to distribute the replicated chromosomes into the daughter cells. The motile apparatus of cilia and flagella is built from a complex array of stable microtubules that bends when dynein slides the microtubules past each other. A genetic absence of dynein immobilizes these appendages, causing male infertility and lung infections.
Microtubules, intermediate filaments, and actin filaments each provide mechanical support for the cell. Interactions of microtubules with intermediate filaments and actin filaments unify the cytoskeleton into a continuous mechanical structure. These polymers also provide a scaffold for some cellular enzyme systems.

Cell Cycle 细胞周期

Cells carefully control their growth and division using an integrated regulatory system consisting of protein kinases (enzymes that add phosphate to the side chains of proteins), specific kinase inhibitors, transcription factors, and highly specific protein degradation. When conditions inside and outside a cell are appropriate for cell division (Fig. 1.9B), specific cell cycle kinases are activated to trigger a chain of events leading to DNA replication and cell division. Once DNA replication is complete, activation of cell cycle kinases such as Cdk1 pushes the cell into mitosis, the process that separates chromosomes into two daughter cells. Four controls sequentially activate Cdk1 through a positive feedback loop: (a) synthesis of a regulatory subunit, (b) transport into the nucleus, (c) removal and addition of inhibitory and stimulatory phosphate groups, and (d) repression of phosphatases (enzymes that remove the phosphate groups Cdk1 puts on its protein targets).
细胞利用由蛋白激酶(在蛋白质侧链上添加磷酸盐的酶)、特异性激酶抑制剂、转录因子和高度特异性蛋白质降解组成的综合调控系统,小心翼翼地控制着自身的生长和分裂。当细胞内外的条件适合细胞分裂时(图 1.9B),特异性细胞周期激酶被激活,引发一连串事件,导致 DNA 复制和细胞分裂。DNA 复制完成后,细胞周期激酶(如 Cdk1)的激活会推动细胞进入有丝分裂,即染色体分离成两个子细胞的过程。通过正反馈回路,四个控制环节依次激活 Cdk1:(a) 合成调节亚基,(b) 运输到细胞核,(c) 去除和添加抑制性和刺激性磷酸基团,(d) 抑制磷酸酶(去除 Cdk1 加到其蛋白质目标上的磷酸基团的酶)。
Phosphorylation of proteins by Cdk1 leads directly or indirectly to disassembly of the nuclear envelope (in most but not all eukaryotic cells), condensation of mitotic chromosomes, and assembly of the mitotic spindle composed of microtubules. Selective proteolysis of regulatory subunits of Cdk1 and key chromosomal proteins then allows the mitotic spindle to separate the previously duplicated identical copies of each chromosome. As cells exit mitosis, the nuclear envelope reassembles on the surface of the chromosomes to reform the daughter nuclei. Then the process of cytokinesis cleaves the daughter cells.
Cdk1 对蛋白质的磷酸化会直接或间接导致核包膜的解体(在大多数真核细胞中,但并非在所有真核细胞中)、有丝分裂染色体的凝集以及由微管组成的有丝分裂纺锤体的组装。然后,Cdk1 的调控亚基和关键染色体蛋白的选择性蛋白水解可使有丝分裂纺锤体分离先前复制的每条染色体的相同拷贝。当细胞退出有丝分裂时,核膜在染色体表面重新组合,形成子核。然后,细胞分裂过程将分裂出子细胞。
A key feature of the cell cycle is a series of built-in quality controls, called checkpoints (Fig. 1.9), which ensure that each stage of the cycle is completed successfully before the process continues to the next step. These checkpoints also detect damage to cellular constituents and block cell-cycle progression so that the damage may be repaired. Misregulation of checkpoints and other cell-cycle controls predisposes to cancer. Remarkably, the entire cycle of DNA replication, chromosomal condensation, nuclear envelope breakdown, and reformation, including the modulation of these events by checkpoints, can be carried out in cell-free extracts in a test tube.
细胞周期的一个主要特征是一系列内置的质量控制,称为检查点(图 1.9),它们确保周期的每个阶段都顺利完成,然后才继续下一步。这些检查点还能检测细胞成分的损伤,并阻止细胞周期的进行,以便修复损伤。检查点和其他细胞周期控制的失调容易导致癌症。值得注意的是,DNA 复制、染色体凝结、核膜破裂和重组的整个周期,包括检查点对这些事件的调节,都可以在试管中的无细胞提取物中进行。

Welcome to the Rest of the Book

This overview should prepare the reader to embark on the following chapters, which explain our current understanding of the molecular basis of life at the cellular level. This journey starts with the evolution of the cell and introduction to the molecules of life. The following sections cover membrane structure and function, chromosomes and the nucleus, gene expression and protein synthesis, organelles and membrane traffic, signaling mechanisms, cellular adhesion and the extracellular matrix, cytoskeleton and cellular motility, and the cell cycle. Enjoy the adventure of exploring all of these topics. As you read, appreciate that cell biology is a living field that is constantly growing and identifying new horizons. The book will prepare you to understand these new insights as they unfold in the future.


Evolution of Life on Earth

o one is certain how life began, but the common ancestor of all living things populated the earth more than 3 billion years ago, not long (geologically speaking) after the planet formed 4.5 billion years ago (Fig. 2.1). Biochemical features shared by all existing cells suggest that this primitive microscopic cell had about 600 genes encoded in DNA, ribosomes to synthesize proteins from messenger RNA templates, basic metabolic pathways, and a plasma membrane with pumps, carriers, and channels. Over time, mutations in the DNA created progeny that diverged genetically into a myriad of distinctive species, most of which have become extinct. Approximately 1.7 million living species are known to science. Extrapolations predict approximately 9 million eukaryotic species and 10 times more prokaryotic organisms living on the earth today. On the basis of evolutionary histories preserved in their genomes, living organisms are divided into three primary domains: Bacteria, Archaea, and Eucarya.
没有人能够确定生命是如何起源的,但所有生物的共同祖先是在 30 多亿年前,也就是地球在 45 亿年前形成后不久(从地质学角度来说)就开始繁衍生息的(图 2.1)。所有现存细胞都具有的生化特征表明,这种原始的微小细胞有大约 600 个 DNA 编码基因、从信使 RNA 模板合成蛋白质的核糖体、基本的代谢途径以及带有泵、载体和通道的质膜。随着时间的推移,DNA的突变产生了后代,这些后代在基因上分化成无数不同的物种,其中大部分已经灭绝。科学界已知的生物物种约有 170 万种。据推断,目前地球上大约有 900 万个真核生物物种和 10 倍于此的原核生物物种。根据保存在基因组中的进化史,生物被分为三个主要领域:细菌、古细菌和真核生物。
FIGURE 2.1 SIMPLE PHYLOGENETIC TREE WITH THE THREE DOMAINS OF LIFE-BACTERIA, ARCHAEA, AND EUCARYA (EUKARYOTES)-AND A FEW REPRESENTATIVE ORGANISMS. The origin of eukaryotes with a mitochondrion about 2 billion years ago is depicted as a fusion of an -proteobacterium with an Archaeon. Chloroplasts arose from the fusion of a cyanobacterium with the precursor of algae and plants.
图 2.1 包含三个生命领域--细菌、古细菌和真核生物--以及一些代表性生物的简单系统树。大约 20 亿年前,具有线粒体的真核生物的起源被描绘成 - 蛋白细菌与古细菌的融合。叶绿体产生于蓝细菌与藻类和植物前身的融合。

This chapter explains our current understanding of the origin of the first self-replicating cell followed by divergence of its progeny into the two diverse groups of prokaryotes, Bacteria and Archaea. It goes on to consider the origin of Eucarya and their diversification over the past 2 billion years.
Evolution is the great unifying principle in biology. Research on evolution is both exciting and challenging because this ultimate detective story involves piecing together fragmentary evidence spread over 3.5 billion years. Data include fossils of ancient organisms and/or chemical traces of their metabolic activities preserved in stone, ancient DNA from historical specimens (going back more than 500,000 years), and especially DNA of living organisms.
进化是生物学中最伟大的统一原理。对进化的研究既令人兴奋,又充满挑战,因为这个终极侦探故事需要将 35 亿年来的零散证据拼凑在一起。这些数据包括保存在石头中的远古生物化石和/或其新陈代谢活动的化学痕迹、来自历史标本的远古 DNA(可追溯到 50 多万年前),尤其是生物的 DNA。

Prebiotic Chemistry Leading to an RNA World
通向 RNA 世界的前生物化学

Where did the common ancestor come from? A wide range of evidence supports the idea that life began with self-replicating RNA polymers sheltered inside lipid vesicles even before the invention of protein synthesis (Fig. 2.2). This hypothetical early stage of evolution is called the RNA World. This attractive postulate solves the chicken-and-egg problem of how to build a system of self-replicating molecules without having to invent either DNA or proteins on their own. RNA has an advantage, because it provides a way to store information in a type of molecule that can also have catalytic activity. Proteins excel in catalysis but do not store self-replicating genetic information. Today, proteins have largely superseded RNAs as cellular catalysts. DNA excels for storing genetic information, since the absence of the hydroxyl makes it less reactive and therefore more stable than RNA. Readers unfamiliar with the structure of nucleic acids should consult Chapter 3 at this point.
共同祖先从何而来?大量证据支持这样一种观点,即在蛋白质合成技术发明之前,生命就已经从隐藏在脂质囊泡中的可自我复制的 RNA 聚合物开始了(图 2.2)。这种假设的进化早期阶段被称为 RNA 世界。这个诱人的假设解决了一个鸡生蛋、蛋生鸡的问题,即如何建立一个自我复制分子系统,而无需自己发明 DNA 或蛋白质。RNA 有一个优势,因为它提供了一种在分子类型中存储信息的方法,同时还具有催化活性。蛋白质擅长催化,但不能存储自我复制的遗传信息。如今,蛋白质已在很大程度上取代 RNA 成为细胞催化剂。DNA 擅长于储存遗传信息,因为它不含 羟基,反应性较低,因此比 RNA 更稳定。不熟悉核酸结构的读者此时应参阅第 3 章。
Experts agree that the early steps toward life involved the "prebiotic" synthesis of organic molecules that became the building blocks of macromolecules. To use
专家们一致认为,生命的早期步骤包括有机分子的 "前生物 "合成,这些有机分子成为大分子的组成部分。利用
FIGURE 2.2 HYPOTHESES FOR PREBIOTIC EVOLUTION TO LAST COMMON ANCESTOR. Simple chemical reactions are postulated to have given rise to ever more complicated RNA molecules to store genetic information and catalyze chemical reactions, including self-replication, in a prebiotic "RNA world." Eventually, genetic information was stored in more stable DNA molecules, and proteins replaced RNAs as the primary catalysts in primitive cells bounded by a lipid membrane.
图 2.2 从前生物进化到最后共同祖先的假设。据推测,在前生物 "RNA 世界 "中,简单的化学反应产生了越来越复杂的 RNA 分子,用于存储遗传信息和催化化学反应,包括自我复制。最终,遗传信息被储存在更稳定的 DNA 分子中,蛋白质取代了 RNA,成为以脂膜为界的原始细胞中的主要催化剂。
RNA as an example, mixtures of chemicals likely to have been present on the early earth can react to form ribose, nucleic acid bases, and ribonucleotides. Minerals can catalyze formation of simple sugars from formaldehyde, and hydrogen cyanide (HCN) and cyanoacetylene or formamide can react to make nucleic acid bases. One problem was the lack of plausible mechanisms to conjugate ribose with a base to make a nucleoside or add phosphate to make a nucleotide without the aid of a preexisting biochemical catalyst. However, new work revealed a pathway to make ribonucleotides directly from cyanamide, cyanoacetylene, glycolaldehyde, glyceraldehyde, and inorganic phosphate. Nucleotides do not polymerize spontaneously into polynucleotides in water, but can do so on the surface of clay called montmorillonite. While attached to clay, single strands of RNA can act as a template for synthesis of a complementary strand to make a double-stranded RNA.
以核糖核酸(RNA)为例,早期地球上可能存在的化学物质混合物可以反应生成核糖、核酸碱基和核糖核苷酸。矿物质可以催化甲醛形成单糖,氰化氢(HCN)和氰乙炔或甲酰胺可以反应生成核酸碱基。问题之一是缺乏合理的机制,无法在不借助已有生化催化剂的情况下,将核糖与碱基共轭生成核苷,或添加磷酸生成核苷酸。然而,新的研究发现了一条直接从氰酰胺、氰乙炔、乙醛、甘油醛和无机磷酸盐制造核糖核苷酸的途径。核苷酸不会在水中自发聚合成多核苷酸,但可以在名为蒙脱石的粘土表面聚合成多核苷酸。附着在粘土上时,RNA 的单链可以作为合成互补链的模板,从而形成双链 RNA。
Given a supply of nucleotides, these reactions could have created a heterogeneous pool of small RNAs in special environments such as cracks in rocks heated by hydrothermal vents. These RNAs set in motion the process of natural selection at the molecular level. The idea is that random sequences of RNA were selected for replication on the basis of useful attributes such as the ability to catalyze biochemical reactions. These RNA enzymes are called ribozymes.
如果有核苷酸供应,这些反应可能会在特殊环境中(如被热液喷口加热的岩石裂缝中)产生异质的小 RNA。这些 RNA 启动了分子水平上的自然选择过程。这种观点认为,RNA 的随机序列是在有用属性(如催化生化反应的能力)的基础上被选择复制的。这些 RNA 酶被称为核酶。
One can reproduce this process of molecular evolution in the laboratory. Starting with a pool of random initial RNA sequences, multiple rounds of error-prone replication can produce variants that can be tested for a particular biochemical function.
人们可以在实验室中重现这种分子进化过程。从一组随机的初始 RNA 序列开始,多轮容易出错的复制可以产生变体,并对其进行特定生化功能的测试。
In nature random events would rarely produce useful ribozymes, but once they appeared, natural selection could enrich for RNAs with catalytic activities that sustain a self-replicating system, including synthesis of RNA from a complementary RNA strand. Over millions of years, a ribozyme eventually evolved with the ability to catalyze the formation of peptide bonds and to synthesize proteins. This most complicated of all known ribozymes is the ribosome (see Fig. 12.6) that catalyzes the synthesis of proteins. Proteins eventually supplanted ribozymes as catalysts for most other biochemical reactions. Owing to its greater chemical stability, DNA proved to be superior to RNA for storing the genetic blueprint over time.
在自然界中,随机事件很少会产生有用的核糖酶,但一旦它们出现,自然选择就会富集具有催化活性的核糖核酸,以维持自我复制系统,包括从互补核糖核酸链合成核糖核酸。经过数百万年的进化,一种核糖酶最终进化出了催化肽键形成和合成蛋白质的能力。所有已知核糖酶中最复杂的就是核糖体(见图 12.6),它能催化蛋白质的合成。蛋白质最终取代核糖酶成为大多数其他生化反应的催化剂。由于 DNA 具有更高的化学稳定性,它在长期储存遗传蓝图方面优于 RNA。
Each of these events is improbable, and their combined probability is exceedingly remote, even with a vast number of chemical "experiments" over hundreds of millions of years. Encapsulation of these prebiotic reactions may have enhanced their probability. In addition to catalyzing RNA synthesis, clay minerals can also promote formation of lipid vesicles, which can corral reactants to avoid dilution and loss of valuable constituents. This process might have started with fragile bilayers of fatty acids that were later supplanted by more robust phosphoglyceride bilayers (see Fig. 13.5). In laboratory experiments, RNAs inside lipid vesicles can create osmotic pressure that favors expansion of the bilayer at the expense of vesicles lacking RNAs.
这些事件中的每一个都是不可能发生的,即使在数亿年的时间里进行了大量的化学 "实验",它们的综合概率也是极其微小的。这些前生物反应的封装可能会提高它们的概率。除了催化 RNA 合成外,粘土矿物还能促进脂质囊泡的形成,这种囊泡能围住反应物,避免稀释和损失有价值的成分。这一过程可能始于脆弱的脂肪酸双分子层,后来被更坚固的磷酸甘油双分子层所取代(见图 13.5)。在实验室实验中,脂质囊泡内的 RNA 可产生渗透压,从而有利于双分子层的扩张,但会损害缺乏 RNA 的囊泡。
No one knows where these prebiotic events took place. Some steps in prebiotic evolution might have occurred in thermal vents deep in the ocean or in hot springs on volcanic islands where conditions were favorable for some of the reactions. Carbon-containing meteorites have useful molecules, including amino acids. Conditions for prebiotic synthesis were probably favorable beginning approximately 4 billion years ago, but the geologic record has not preserved convincing microscopic fossils or traces of biosynthesis older than 3.5 billion years.
没有人知道这些前生物事件发生在哪里。前生物进化的某些步骤可能发生在海洋深处的热喷口或火山岛上的温泉中,那里的条件有利于某些反应的发生。含碳陨石中有有用的分子,包括氨基酸。大约从 40 亿年前开始,进行前生物合成的条件可能是有利的,但地质记录并没有保存令人信服的微观化石或 35 亿年前的生物合成痕迹。
Another mystery is how L-amino acids and D-sugars (see Chapter 3) were selected over their stereoisomers for biological macromolecules. These were pivotal
另一个谜团是,L-氨基酸和 D-糖(见第 3 章)是如何被选为生物大分子的立体异构体的。这些是关键的