- 1 詞源和歷史
- 2 結構
- 3 機制
- 4 輔助因子
- 5 Thermodynamics
- 6 Kinetics
- 7 Inhibition
- 8 Biological function
- 9 命名規則
- 10 各行業的應用
- 11 參見
- 12 參考
- 13 拓展閱讀
By the late 17th and early 18th centuries, the digestion of meat by stomach secretionsand the conversion of starch to sugars by plant extracts and saliva were known but the mechanisms by which these occurred had not been identified.
French chemist Anselme Payen was the first to discover an enzyme, diastase, in 1833. A few decades later, when studying the fermentation of sugar to alcohol by yeast, Louis Pasteurconcluded that this fermentation was caused by a Vitalism|vital force contained within the yeast cells called "ferments", which were thought to function only within living organisms. He wrote that "alcoholic fermentation is an act correlated with the life and organization of the yeast cells, not with the death or putrefaction of the cells."
In 1877, German physiologist Wilhelm Kühne (1837–1900) first used the term enzyme, which comes from Ancient Greek|Greek ἔνζυμον, "leavened", to describe this process. The word enzyme was used later to refer to nonliving substances such as pepsin, and the word ferment was used to refer to chemical activity produced by living organisms.
Eduard Buchner submitted his first paper on the study of yeast extracts in 1897. In a series of experiments at the Humboldt University of Berlin|University of Berlin, he found that sugar was fermented by yeast extracts even when there were no living yeast cells in the mixture. He named the enzyme that brought about the fermentation of sucrose "zymase". In 1907, he received the Nobel Prize in Chemistry for "his discovery of cell-free fermentation". Following Buchner's example, enzymes are usually named according to the reaction they carry out: the suffix -ase is combined with the name of the substrate (e.g.,lactase is the enzyme that cleaves lactose) or to the type of reaction (e.g., DNA polymerase forms DNA polymers).
The biochemical identity of enzymes was still unknown in the early 1900s. Many scientists observed that enzymatic activity was associated with proteins, but others (such as Nobel laureate Richard Willstätter) argued that proteins were merely carriers for the true enzymes and that proteins per se were incapable of catalysis. In 1926, James B. Sumner showed that the enzyme urease was a pure protein and crystallized it; he did likewise for the enzyme catalase in 1937. The conclusion that pure proteins can be enzymes was definitively demonstrated by John Howard Northropand Wendell Meredith Stanley, who worked on the digestive enzymes pepsin (1930), trypsin and chymotrypsin. These three scientists were awarded the 1946 Nobel Prize in Chemistry.
The discovery that enzymes could be crystallized eventually allowed their structures to be solved by x-ray crystallography. This was first done for lysozyme, an enzyme found in tears, saliva and egg whites that digests the coating of some bacteria; the structure was solved by a group led by David Chilton Phillips and published in 1965. This high-resolution structure of lysozyme marked the beginning of the field of structural biology and the effort to understand how enzymes work at an atomic level of detail.
酶通常比底物大得多。酶的肽鏈長度從62個氨基酸殘基的4-草酰巴豆酸異構酶的單體到長度超過2,500個氨基酸殘基的動物脂肪酸合酶。酶的結構只有一小部分（大約2-4個氨基酸）是直接與催化相關的。這部分稱爲催化位點（catalytic site）。催化位點通常與一個或多個與底物結合的結合位點（binding site）相連。催化位點與結合位點共同組成了酶的活性位點（active site）。酶的其餘部分起維持活性位點準確的方向以及動力學特性的作用。
一些酶並不需要額外的組分就能就能正常發揮作用，另外一些酶則要在和輔助因子（cofactor）結合後才能顯示出活性。輔助因子可以是無機物（如金屬離子、铁硫簇），也可以是有機物（比如黃素和血紅素）。有機輔助 因子如果在反應中會與酶分離則爲輔酶（coenzyme），如果與酶緊密結合則爲輔基（prosthetic groups）。有機的輔基可能與酶發生共價結合（丙酮酸羧化酶與生物素（biotin）之間即發生共價結合）。
As with all catalysts, enzymes do not alter the position of the chemical equilibrium of the reaction. In the presence of an enzyme, the reaction runs in the same direction as it would without the enzyme, just more quickly.:8.2.3 For example, carbonic anhydrase catalyzes its reaction in either direction depending on the concentration of its reactants:
(in Biological tissue|tissues; high CO2 concentration) (
(in lungs; low CO2 concentration) (
The rate of a reaction is dependent on the activation energy needed to form the transition state which then decays into products. Enzymes increase reaction rates by lowering the energy of the transition state. First, binding forms a low energy enzyme-substrate complex (ES). Secondly the enzyme stabilises the transition state such that it requires less energy to achieve compared to the uncatalyzed reaction (ES‡). Finally the enzyme-product complex (EP) dissociates to release the products.:8.3
Enzymes can couple two or more reactions, so that a thermodynamically favorable reaction can be used to "drive" a thermodynamically unfavourable one so that the combined energy of the products is lower than the substrates. For example, the hydrolysis of Adenosine triphosphate|ATP is often used to drive other chemical reactions.
Enzyme kinetics is the investigation of how enzymes bind substrates and turn them into products. The rate data used in kinetic analyses are commonly obtained from enzyme assays. In 1913 Leonor Michaelis and Maud Leonora Menten proposed a quantitative theory of enzyme kinetics, which is referred to as Michaelis–Menten kinetics. The major contribution of Michaelis and Menten was to think of enzyme reactions in two stages. In the first, the substrate binds reversibly to the enzyme, forming the enzyme-substrate complex. This is sometimes called the Michaelis-Menten complex in their honor. The enzyme then catalyzes the chemical step in the reaction and releases the product. This work was further developed by G. E. Briggs and J. B. S. Haldane, who derived kinetic equations that are still widely used today.
Enzyme rates depend on solution conditions and substrate concentration. To find the maximum speed of an enzymatic reaction, the substrate concentration is increased until a constant rate of product formation is seen. This is shown in the saturation curve on the right. Saturation happens because, as substrate concentration increases, more and more of the free enzyme is converted into the substrate-bound ES complex. At the maximum reaction rate (Vmax) of the enzyme, all the enzyme active sites are bound to substrate, and the amount of ES complex is the same as the total amount of enzyme.:8.4
Vmax is only one of several important kinetic parameters. The amount of substrate needed to achieve a given rate of reaction is also important. This is given by theMichaelis-Menten constant (Km), which is the substrate concentration required for an enzyme to reach one-half its maximum reaction rate; generally, each enzyme has a characteristic Km for a given substrate. Another useful constant is kcat, also called the turnover number, which is the number of substrate molecules handled by one active site per second.:8.4
The efficiency of an enzyme can be expressed in terms of kcat/Km. This is also called the specificity constant and incorporates the rate constants for all steps in the reaction up to and including the first irreversible step. Because the specificity constant reflects both affinity and catalytic ability, it is useful for comparing different enzymes against each other, or the same enzyme with different substrates. The theoretical maximum for the specificity constant is called the diffusion limit and is about 108 to 109 (M−1 s−1). At this point every collision of the enzyme with its substrate will result in catalysis, and the rate of product formation is not limited by the reaction rate but by the diffusion rate. Enzymes with this property are called catalytically perfect orkinetically perfect. Example of such enzymes are triose-phosphate isomerase, carbonic anhydrase, acetylcholinesterase, catalase,fumarase, β-lactamase, and superoxide dismutase.:8.4.2 The turnover of such enzymes can reach several million reactions per second.:9.2
Michaelis–Menten kinetics relies on the law of mass action, which is derived from the assumptions of free diffusion and thermodynamically driven random collision. Many biochemical or cellular processes deviate significantly from these conditions, because of macromolecular crowding and constrained molecular movement. More recent, complex extensions of the model attempt to correct for these effects.
Types of inhibition[编辑]
- A competitive inhibitor and substrate cannot bind to the enzyme at the same time.Often competitive inhibitors strongly resemble the real substrate of the enzyme. For example, the drug methotrexate is a competitive inhibitor of the enzyme dihydrofolate reductase, which catalyzes the reduction of folic acid|dihydrofolate to tetrahydrofolate. The similarity between the structures of dihydrofolate and this drug are shown in the accompanying figure. This type of inhibition can be overcome with high substrate concentration. In some cases, the inhibitor can bind to a site other than the binding-site of the usual substrate and exert an allosteric effect to change the shape of the usual binding-site.
- A non-competitive inhibitor binds to a site other than where the substrate binds. The substrate still binds with its usual affinity and hence Km remains the same. However the inhibitor reduces the catalytic efficiency of the enzyme so that Vmax is reduced. In contrast to competitive inhibition, non-competitive inhibition cannot be overcome with high substrate concentration.:76–78
- An uncompetitive inhibitor cannot bind to the free enzyme, only to the enzyme-substrate complex; hence, these types of inhibitors are most effective at high substrate concentration. In the presence of the inhibitor, the enzyme-substrate complex is inactive.:78 This type of inhibition is rare.
- A mixed inhibitor binds to an allosteric site and the binding of the substrate and the inhibitor affect each other. The enzyme's function is reduced but not eliminated when bound to the inhibitor. This type of inhibitor does not follow the Michaelis-Menten equation.:76–78
- An irreversible inhibitor permanently inactivates the enzyme, usually by forming a covalent bond to the protein. Penicillin and aspirin are common drugs that act in this manner.
Functions of inhibitors[编辑]
In many organisms, inhibitors may act as part of a feedback mechanism. If an enzyme produces too much of one substance in the organism, that substance may act as an inhibitor for the enzyme at the beginning of the pathway that produces it, causing production of the substance to slow down or stop when there is sufficient amount. This is a form of negative feedback. Major metabolic pathways such as the citric acid cycle make use of this mechanism.:17.2.2
Since inhibitors modulate the function of enzymes they are often used as drugs. Many such drugs are reversible competitive inhibitors that resemble the enzyme's native substrate, similar to methotrexate above; other well-known examples include statins used to treat high cholesterol, and protease inhibitor (pharmacology)|protease inhibitors used to treat retrovirus|retroviral infections such as HIV. A common example of an irreversible inhibitor that is used as a drug is aspirin, which inhibits the Cyclooxygenase|COX-1 and Cyclooxygenase|COX-2 enzymes that produce the inflammationmessenger prostaglandin. Other enzyme inhibitors are poisons. For example, the poison cyanide is an irreversible enzyme inhibitor that combines with the copper and iron in the active site of the enzyme cytochrome c oxidase and blocks cellular respiration.
Enzymes serve a wide variety of functions inside living organisms. They are indispensable for signal transduction and cell regulation, often viakinases and phosphatases. They also generate movement, withmyosin hydrolyzing ATP to generate muscle contraction, and also transport cargo around the cell as part of the cytoskeleton. Other ATPases in the cell membrane are ion pumps involved in active transport. Enzymes are also involved in more exotic functions, such as luciferase generating light in firefly|fireflies. Viruses can also contain enzymes for infecting cells, such as the HIV integrase and reverse transcriptase, or for viral release from cells, like the influenza virus neuraminidase.
An important function of enzymes is in the digestive systems of animals. Enzymes such as amylases and proteases break down large molecules (starch or proteins, respectively) into smaller ones, so they can be absorbed by the intestines. Starch molecules, for example, are too large to be absorbed from the intestine, but enzymes hydrolyze the starch chains into smaller molecules such as maltose and eventually glucose, which can then be absorbed. Different enzymes digest different food substances. In ruminants, which have herbivorous diets, microorganisms in the gut produce another enzyme, cellulase, to break down the cellulose cell walls of plant fiber.
Several enzymes can work together in a specific order, creating metabolic pathways.:30.1 In a metabolic pathway, one enzyme takes the product of another enzyme as a substrate. After the catalytic reaction, the product is then passed on to another enzyme. Sometimes more than one enzyme can catalyze the same reaction in parallel; this can allow more complex regulation: with, for example, a low constant activity provided by one enzyme but an inducible high activity from a second enzyme.
Enzymes determine what steps occur in these pathways. Without enzymes, metabolism would neither progress through the same steps and could not be regulated to serve the needs of the cell. Most central metabolic pathways are regulated at a few key steps, typically through enzymes whose activity involves the hydrolysis of Adenosine triphosphate|ATP. Because this reaction releases so much energy, other reactions that are thermodynamically unfavorable can be coupled to ATP hydrolysis, driving the overall series of linked metabolic reactions.:30.1
Control of activity[编辑]
There are five main ways that enzyme activity is controlled in the cell.:30.1.1
- Enzymes can be either enzyme activator|activated or enzyme inhibitor|inhibited by other molecules. For example, the end product(s) of a metabolic pathway are often inhibitors for one of the first enzymes of the pathway (usually the first irreversible step, called committed step), thus regulating the amount of end product made by the pathways. Such a regulatory mechanism is called a negative feedback|negative feedback mechanism, because the amount of the end product produced is regulated by its own concentration.:141–48 Negative feedback mechanism can effectively adjust the rate of synthesis of intermediate metabolites according to the demands of the cells. This helps with effective allocations of materials and energy economy, and it prevents the excess manufacture of end products. Like other homeostasis|homeostatic devices, the control of enzymatic action helps to maintain a stable internal environment in living organisms.:141
- Post-translational modification
- Examples of post-translational modification include phosphorylation, myristoylation and glycosylation.:149–69 For example, in the response to insulin, the phosphorylation of multiple enzymes, including glycogen synthase, helps control the synthesis or degradation of glycogen and allows the cell to respond to changes in blood sugar. Another example of post-translational modification is the cleavage of the polypeptide chain. Chymotrypsin, a digestive protease, is produced in inactive form as chymotrypsinogen in the pancreas and transported in this form to the stomach where it is activated. This stops the enzyme from digesting the pancreas or other tissues before it enters the gut. This type of inactive precursor to an enzyme is known as a zymogen:149–53 or proenzyme.
- Enzyme production (Transcription (genetics)|transcription and Translation (genetics)|translation of enzyme genes) can be enhanced or diminished by a cell in response to changes in the cell's environment. This form of gene regulation is called enzyme induction. For example, bacteria may becomeresistant to antibiotics such as penicillin because enzymes called beta-lactamases are induced that hydrolyse the crucial Beta-lactam|beta-lactam ring within the penicillin molecule. Another example comes from enzymes in the liver called cytochrome P450 oxidases, which are important in drug metabolism. Induction or inhibition of these enzymes can cause drug interactions. Enzyme levels can also be regulated by changing the rate of enzyme catabolism|degradation.:30.1.1
- Subcellular distribution
- Enzymes can be compartmentalized, with different metabolic pathways occurring in different cellular compartments. For example, fatty acids are synthesized by one set of enzymes in the cytosol, endoplasmic reticulum and golgi apparatus|Golgi and used by a different set of enzymes as a source of energy in themitochondrion, through β-oxidation. In addition, trafficking of the enzyme to different compartments may change the degree of protonation (cytoplasm neutral and lysosome acidic) or oxidative state [e.g., oxidized (periplasm) or reduced (cytoplasm)] which in turn affects enzyme activity.
- Organ specialization
- In multicellular eukaryotes, cells in different organ (anatomy)|organs and tissue (biology)|tissues have different patterns of gene expression and therefore have different sets of enzymes (known as isozymes) available for metabolic reactions. This provides a mechanism for regulating the overall metabolism of the organism. For example, hexokinase, the first enzyme in the glycolysis pathway, has a specialized form called glucokinase expressed in the liver andpancreas that has a lower affinity for glucose yet is more sensitive to glucose concentration. This enzyme is involved in sensing blood sugar and regulating insulinproduction.
Involvement in disease[编辑]
Since the tight control of enzyme activity is essential for homeostasis, any malfunction (mutation, overproduction, underproduction or deletion) of a single critical enzyme can lead to a genetic disease. The malfunction of just one type of enzyme out of the thousands of types present in the human body can be fatal. An example of a fatal genetic disease due to enzyme insufficiency is Tay-Sachs disease, in which patients lack the enzyme hexosaminidase.
One example of enzyme deficiency is the most common type of phenylketonuria. Many different single amino acid mutations in the enzyme phenylalanine hydroxylase, which catalyzes the first step in the degradation of phenylalanine, result in build-up of phenylalanine and related products. Some mutations are in the active site, directly disrupting binding and catalysis, but many are far from the active site and reduce activity by destabilising the protein structure, or affecting correct oligomerisation. This can lead to intellectual disability if the disease is untreated. Another example is pseudocholinesterase deficiency, in which the body's ability to break down choline ester drugs is impaired. Oral administration of enzymes can be used to treat some functional enzyme deficiencies, such as pancreatic insufficiency and lactose intolerance.
Another way enzyme malfunctions can cause disease comes from germline mutations in genes coding for DNA repair enzymes. Defects in these enzymes cause cancer because cells are less able to repair mutations in their genomes. This causes a slow accumulation of mutations and results in the carcinogenesis|development of cancers. An example of such a hereditary cancer syndrome is xeroderma pigmentosum, which causes the development of skin cancers in response to even minimal exposure to ultraviolet light.
- EC 1 氧化還原酶：催化氧化還原反應的酶類，例如乳酸去氫酶、琥珀酸去氫酶、細胞色素氧化酶、過氧化氫酶、過氧化物酶等。
- EC 2 轉移酶：轉移官能团（例如甲基或是磷酸基團）的酶類，例如甲基轉移酶、氨基轉移酶、己糖激酶、磷酸化酶等。
- EC 3 水解酶：催化受質發生水解反應的酶類，例如澱粉酶、蛋白酶、脂肪酶、磷酸酶等。
- EC 4 裂合酶：用氧化及水解反應以外的方式移去基團的酶類，例如碳酸酐酶、醛縮酶、檸檬酸合酶等。
- EC 5 異構酶：催化分子同分異構反應的酶類，例如磷酸丙糖異構酶、消旋酶等。
- EC 6 連接酶：用共价键結合二個分子的酶類，例如谷氨醯胺合成酶、丙酮酸羧化酶等。。
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