Diffusion-limited enzyme

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The distribution of known enzyme catalytic rates (kcat/KM). Most enzymes have a rate around 10 s M . The fastest enzymes in the dark box on the right (>10 s M ) are constrained by the diffusion limit. (Data adapted from reference ) Activity distribution graph.png
The distribution of known enzyme catalytic rates (kcat/KM). Most enzymes have a rate around 10 s M . The fastest enzymes in the dark box on the right (>10 s M ) are constrained by the diffusion limit. (Data adapted from reference )

A diffusion-limited enzyme catalyses a reaction so efficiently that the rate limiting step is that of substrate diffusion into the active site, or product diffusion out. [2] This is also known as kinetic perfection or catalytic perfection. Since the rate of catalysis of such enzymes is set by the diffusion-controlled reaction, it therefore represents an intrinsic, physical constraint on evolution (a maximum peak height in the fitness landscape). Diffusion limited perfect enzymes are very rare. Most enzymes catalyse their reactions to a rate that is 1,000-10,000 times slower than this limit. This is due to both the chemical limitations of difficult reactions, and the evolutionary limitations that such high reaction rates do not confer any extra fitness. [1]

Contents

History

An illustration to show (a) Alberty-Hammes-Eigen model, and (b) Chou's model, where E denotes the enzyme whose active site is colored in red, while the substrate S in blue. Enzyme-substrate difusion-controlled reaction.jpg
An illustration to show (a) Alberty-Hammes-Eigen model, and (b) Chou's model, where E denotes the enzyme whose active site is colored in red, while the substrate S in blue.

The theory of diffusion-controlled reaction was originally utilized by R.A. Alberty, Gordon Hammes, and Manfred Eigen to estimate the upper limit of enzyme-substrate reaction. [3] [4] According to their estimation, [3] [4] the upper limit of enzyme-substrate reaction was 109 M−1 s−1.

In 1972, it was observed that in the dehydration of H2CO3 catalyzed by carbonic anhydrase, the second-order rate constant obtained experimentally was about 1.5 × 1010 M−1 s−1, [5] which was one order of magnitude higher than the upper limit estimated by Alberty, Hammes, and Eigen based on a simplified model. [3] [4]

To address such a paradox, Kuo-Chen Chou and his co-workers proposed a model by taking into account the spatial factor and force field factor between the enzyme and its substrate and found that the upper limit could reach 1010 M−1 s−1, [6] [7] [8] and can be used to explain some surprisingly high reaction rates in molecular biology. [5] [9] [10]

The new upper limit found by Chou et al. for enzyme-substrate reaction was further discussed and analyzed by a series of follow-up studies. [11] [12] [13]

A detailed comparison between the simplified Alberty-Hammes-Eigen's model (a) and the Chou's model (b) in calculating the diffusion-controlled reaction rate of enzyme with its substrate, or the upper limit of enzyme-substrate reaction, was elaborated in the paper. [14]

Mechanism

Kinetically perfect enzymes have a specificity constant, kcat/Km, on the order of 108 to 109 M−1 s−1. The rate of the enzyme-catalysed reaction is limited by diffusion and so the enzyme 'processes' the substrate well before it encounters another molecule. [1]

Some enzymes operate with kinetics which are faster than diffusion rates, which would seem to be impossible. Several mechanisms have been invoked to explain this phenomenon. Some proteins are believed to accelerate catalysis by drawing their substrate in and preorienting them by using dipolar electric fields. Some invoke a quantum-mechanical tunneling explanation whereby a proton or an electron can tunnel through activation barriers. If the proton tunneling theory remained a controversial idea, [15] [16] it has been proven to be the only possible mechanism in the case of the soybean lipoxygenase. [17]

Evolution

It is worth noting that there are not many kinetically perfect enzymes. This can be explained in terms of natural selection. An increase in catalytic speed may be favoured as it could confer some advantage to the organism. However, when the catalytic speed outstrips diffusion speed (i.e. substrates entering and leaving the active site, and also encountering substrates) there is no more advantage to increase the speed even further. The diffusion limit represents an absolute physical constraint on evolution. [1] Increasing the catalytic speed past the diffusion speed will not aid the organism in any way and so represents a global maximum in a fitness landscape. Therefore, these perfect enzymes must have come about by 'lucky' random mutation which happened to spread, or because the faster speed was once useful as part of a different reaction in the enzyme's ancestry.[ citation needed ]

Examples

See also

Related Research Articles

Enzyme Large biological molecule that acts as a catalyst

Enzymes are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. Almost all metabolic processes in the cell need enzyme catalysis in order to occur at rates fast enough to sustain life. Metabolic pathways depend upon enzymes to catalyze individual steps. The study of enzymes is called enzymology and the field of pseudoenzyme analysis recognizes that during evolution, some enzymes have lost the ability to carry out biological catalysis, which is often reflected in their amino acid sequences and unusual 'pseudocatalytic' properties.

Michaelis–Menten kinetics Model of enzyme kinetics

In biochemistry, Michaelis–Menten kinetics is one of the best-known models of enzyme kinetics. It is named after German biochemist Leonor Michaelis and Canadian physician Maud Menten. The model takes the form of an equation describing the rate of enzymatic reactions, by relating reaction rate to , the concentration of a substrate S. Its formula is given by

Lineweaver–Burk plot Graph of enzyme kinetics

In biochemistry, the Lineweaver–Burk plot is a graphical representation of the Lineweaver–Burk equation of enzyme kinetics, described by Hans Lineweaver and Dean Burk in 1934. The Lineweaver–Burk plot for inhibited enzymes can be compared to no inhibitor to determine how the inhibitor is competing with the enzyme.

Malate dehydrogenase

Malate dehydrogenase (EC 1.1.1.37) (MDH) is an enzyme that reversibly catalyzes the oxidation of malate to oxaloacetate using the reduction of NAD+ to NADH. This reaction is part of many metabolic pathways, including the citric acid cycle. Other malate dehydrogenases, which have other EC numbers and catalyze other reactions oxidizing malate, have qualified names like malate dehydrogenase (NADP+).

Triosephosphate isomerase Enzyme involved in glycolysis

Triose-phosphate isomerase is an enzyme that catalyzes the reversible interconversion of the triose phosphate isomers dihydroxyacetone phosphate and D-glyceraldehyde 3-phosphate.

Enzyme assay

Enzyme assays are laboratory methods for measuring enzymatic activity. They are vital for the study of enzyme kinetics and enzyme inhibition.

Lipoxygenase

Lipoxygenases are a family of (non-heme) iron-containing enzymes most of which catalyze the dioxygenation of polyunsaturated fatty acids in lipids containing a cis,cis-1,4- pentadiene into cell signaling agents that serve diverse roles as autocrine signals that regulate the function of their parent cells, paracrine signals that regulate the function of nearby cells, and endocrine signals that regulate the function of distant cells.

Turnover number has two different meanings:

Enzyme kinetics Study of biochemical reaction rates catalysed by an enzyme

Enzyme kinetics is the study of the rates of enzyme-catalysed chemical reactions. In enzyme kinetics, the reaction rate is measured and the effects of varying the conditions of the reaction are investigated. Studying an enzyme's kinetics in this way can reveal the catalytic mechanism of this enzyme, its role in metabolism, how its activity is controlled, and how a drug or a modifier might affect the rate.

Robert A. Alberty American chemist

Robert Arnold Alberty (1921-2014) was an American biophysical chemist, Professor Emeritus at the Massachusetts Institute of Technology, and a member of the National Academy of Sciences.

Enzyme inhibitor Molecule that binds to an enzyme and decreases its activity

An enzyme inhibitor is a molecule that binds to an enzyme and decreases its activity. By binding to enzymes' active sites, inhibitors reduce the compatibility of substrate and enzyme and this leads to the inhibition of Enzyme-Substrate complexes' formation, preventing the catalysis of reactions and decreasing the amount of product produced by a reaction. It can be said that as the concentration of enzyme inhibitors increases, the rate of enzyme activity decreases, and thus, the amount of product produced is inversely proportional to the concentration of inhibitor molecules. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used in pesticides. Not all molecules that bind to enzymes are inhibitors; enzyme activators bind to enzymes and increase their enzymatic activity, while enzyme substrates bind and are converted to products in the normal catalytic cycle of the enzyme.

Enzyme catalysis Catalysis of chemical reactions by specialized proteins known as enzymes

Enzyme catalysis is the increase in the rate of a process by a biological molecule, an "enzyme". Most enzymes are proteins, and most such processes are chemical reactions. Within the enzyme, generally catalysis occurs at a localized site, called the active site.

Aldose reductase

In enzymology, aldose reductase is a cytosolic NADPH-dependent oxidoreductase that catalyzes the reduction of a variety of aldehydes and carbonyls, including monosaccharides. It is primarily known for catalyzing the reduction of glucose to sorbitol, the first step in polyol pathway of glucose metabolism.

W. Wallace Cleland

William Wallace Cleland (January 6, 1930 – March 6, 2013, often cited as W. W. Cleland, and known almost universally as "Mo Cleland", was a University of Wisconsin-Madison biochemistry professor. His research was concerned with enzyme reaction mechanism and enzyme kinetics, especially multiple-substrate enzymes. He was elected to the National Academy of Sciences in 1985.

In the field of biochemistry, the specificity constant, is a measure of how efficiently an enzyme converts substrates into products. A comparison of specificity constants can also be used as a measure of the preference of an enzyme for different substrates. The higher the specificity constant, the more the enzyme "prefers" that substrate.

Gordon G. Hammes is a distinguished service professor of biochemistry, emeritus, at Duke University, professor emeritus at Cornell University, and member of United States National Academy of Sciences. Hammes' research involves the study of enzyme mechanisms and enzyme regulation.

Enzyme promiscuity is the ability of an enzyme to catalyse a fortuitous side reaction in addition to its main reaction. Although enzymes are remarkably specific catalysts, they can often perform side reactions in addition to their main, native catalytic activity. These promiscuous activities are usually slow relative to the main activity and are under neutral selection. Despite ordinarily being physiologically irrelevant, under new selective pressures these activities may confer a fitness benefit therefore prompting the evolution of the formerly promiscuous activity to become the new main activity. An example of this is the atrazine chlorohydrolase from Pseudomonas sp. ADP that evolved from melamine deaminase, which has very small promiscuous activity toward atrazine, a man-made chemical.

Sharon Hammes-Schiffer is a physical chemist who has contributed to theoretical and computational chemistry. She is currently a Sterling Professor of Chemistry at Yale University. She has served as senior editor and deputy editor of the Journal of Physical Chemistry and advisory editor for Theoretical Chemistry Accounts. Since As of 1 January 2015 she is editor-in-chief of Chemical Reviews.

Carbonic anhydrase Class of enzymes

The carbonic anhydrases form a family of enzymes that catalyze the interconversion between carbon dioxide and water and the dissociated ions of carbonic acid. The active site of most carbonic anhydrases contains a zinc ion. They are therefore classified as metalloenzymes. The enzyme maintains acid-base balance and helps transport carbon dioxide.

Kuo-Chen Chou Chinese-American biophysicist

Kuo-Chen Chou is a Chinese-American biophysicist and bioinformatician who founded and is currently affiliated with the Gordon Life Science Institute, a non-profit research organization in Boston, Massachusetts. Among other contributions, he is the developer of pseudo amino acid composition (PseAAC), used in computational biology for proteomics analysis and pseudo K-tuple nucleotide composition (PseKNC) for genome analysis. He is the father of James Chou.

References

  1. 1 2 3 4 Bar-Even, Arren; Noor, Elad; Savir, Yonatan; Liebermeister, Wolfram; Davidi, Dan; Tawfik, Dan S; Milo, Ron (2011). "The Moderately Efficient Enzyme: Evolutionary and Physicochemical Trends Shaping Enzyme Parameters". Biochemistry. 50 (21): 4402–10. doi:10.1021/bi2002289. PMID   21506553.
  2. ↑ Berg, Jeremy M.; Tymoczko, J. L.; Stryer, L. (2006). "Oxidative phosphorylation". Biochemistry (5 ed.). pp. 491–526. ISBN   978-0716787242.
  3. 1 2 3 Alberty, Robert A.; Hammes, Gordon G. (1958). "Application of the Theory of Diffusion-controlled Reactions to Enzyme Kinetics". Journal of Physical Chemistry. 62 (2): 154–9. doi:10.1021/j150560a005.
  4. 1 2 3 Eigen, Manfred; Hammes, Gordon G. (2006). "Elementary Steps in Enzyme Reactions (as Studied by Relaxation Spectrometry)". In Nord, F. F. (ed.). Advances in Enzymology and Related Areas of Molecular Biology. Advances in Enzymology and Related Subjects of Biochemistry. 25. pp. 1–38. doi:10.1002/9780470122709.ch1. ISBN   978-0-470-12270-9. OCLC   777630506. PMID   14149678.
  5. 1 2 Koenig, Seymour H.; Brown, Rodney D. (1972). "H2CO3 as Substrate for Carbonic Anhydrase in the Dehydration of HCO3−". Proceedings of the National Academy of Sciences of the United States of America. 69 (9): 2422–5. Bibcode:1972PNAS...69.2422K. doi: 10.1073/pnas.69.9.2422 . JSTOR   61783. PMC   426955 . PMID   4627028.
  6. ↑ Chou, Kuo-Chen; Jiang, Shou-Ping (1974). "Studies on the rate of diffusion-controlled reactions of enzymes. Spatial factor and force field factor". Scientia Sinica. 27 (5): 664–80. PMID   4219062.
  7. ↑ Chou, Kuo-Chen (1976). "The kinetics of the combination reaction between enzyme and substrate". Scientia Sinica. 19 (4): 505–28. PMID   824728.
  8. ↑ Li, TT; Chou, KC (1976). "The quantitative relations between diffusion-controlled reaction rate and characteristic parameters in enzyme-substrate reaction systems. I. Neutral substrates". Scientia Sinica. 19 (1): 117–36. PMID   1273571.
  9. ↑ Riggs, Arthur D; Bourgeois, Suzanne; Cohn, Melvin (1970). "The lac represser-operator interaction". Journal of Molecular Biology. 53 (3): 401–17. doi:10.1016/0022-2836(70)90074-4. PMID   4924006.
  10. ↑ Kirschner, Kasper; Gallego, Ernesto; Schuster, Inge; Goodall, David (1971). "Co-operative binding of nicotinamide-adenine dinucleotide to yeast glyceraldehyde-3-phosphate dehydrogenase". Journal of Molecular Biology. 58 (1): 29–50. doi:10.1016/0022-2836(71)90230-0. PMID   4326080.
  11. ↑ Chou, Kuo Chen; Zhou, Guo Ping (1982). "Role of the protein outside active site on the diffusion-controlled reaction of enzymes". Journal of the American Chemical Society. 104 (5): 1409–1413. doi:10.1021/ja00369a043.
  12. ↑ Payens, T.A.J (1983). "Why are enzymes so large?". Trends in Biochemical Sciences. 8 (2): 46. doi:10.1016/0968-0004(83)90382-1.
  13. ↑ Zhou, Guozhi; Wong, Ming-Tat; Zhou, Guo-Qiang (1983). "Diffusion-controlled reactions of enzymes". Biophysical Chemistry. 18 (2): 125–32. doi:10.1016/0301-4622(83)85006-6. PMID   6626685.
  14. ↑ Zhou, Guo-Qiang; Zhong, Wei-Zhu (1982). "Diffusion-Controlled Reactions of Enzymes". European Journal of Biochemistry. 128 (2–3): 383–7. doi:10.1111/j.1432-1033.1982.tb06976.x. PMID   7151785.
  15. ↑ Garcia-Viloca, M; Gao, Jiali; Karplus, Martin; Truhlar, Donald G (2004). "How Enzymes Work: Analysis by Modern Rate Theory and Computer Simulations". Science. 303 (5655): 186–95. Bibcode:2004Sci...303..186G. doi:10.1126/science.1088172. PMID   14716003. S2CID   17498715.
  16. ↑ Olsson, Mats H. M.; Siegbahn, Per E. M.; Warshel, Arieh (2004). "Simulations of the Large Kinetic Isotope Effect and the Temperature Dependence of the Hydrogen Atom Transfer in Lipoxygenase". Journal of the American Chemical Society. 126 (9): 2820–8. doi:10.1021/ja037233l. PMID   14995199.
  17. ↑ Jevtic, S; Anders, J (2017). "A qualitative quantum rate model for hydrogen transfer in soybean lipoxygenase". The Journal of Chemical Physics. 147 (11): 114108. arXiv: 1612.03773 . Bibcode:2017JChPh.147k4108J. doi:10.1063/1.4998941. PMID   28938801. S2CID   11202267.
  18. ↑ Domnik, Lilith; Merrouch, Meriem; Goetzl, Sebastian; Jeoung, Jae-Hun; Léger, Christophe; Dementin, Sébastien; Fourmond, Vincent; Dobbek, Holger (2017-11-27). "CODH-IV: A High-Efficiency CO-Scavenging CO Dehydrogenase with Resistance to O2" (PDF). Angewandte Chemie International Edition. 56 (48): 15466–15469. doi:10.1002/anie.201709261. ISSN   1521-3773. PMID   29024326.
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