A team of scientists from the University of Washington, Seattle, and the Weizmann Institute of Science, Israel, has succeeded in creating a new type of enzyme for a reaction for which no naturally occurring enzyme has evolved, by using a combination of novel computational methodologies and molecular in vitro evolution. This achievement opens the door to the development of a variety of potential applications in medicine and industry.
Mankind triumphed in a recent 'competition' against nature when scientists succeeded in creating a new type of enzyme for a reaction for which no naturally occurring enzyme has evolved. This achievement opens the door to the development of a variety of potential applications in medicine and industry.
Enzymes are, without a doubt, a valuable model for understanding the intricate works of nature. These molecular machines - which without them, life would not exist - are responsible for initiating chemical reactions within the body. Millions of years of natural selection have fine-tuned the activity of such enzymes, allowing chemical reactions to take place millions of times faster. In order to create artificial enzymes, a comprehensive understanding of the structure of natural enzymes, their mode of action, as well as advanced protein engineering techniques is needed. A team of scientists from the University of Washington, Seattle, and the Weizmann Institute of Science, Israel, made a crucial breakthrough toward this endeavor. Their findings have recently been published in the scientific journal Nature.
Enzymes are biological catalysts that are made from a string of amino acids, which fold into specific three-dimensional protein structures. The scientists' aim was to create an enzyme for a specific chemical reaction whereby a proton (a positively charged hydrogen atom) is removed from carbon - a highly demanding reaction and rate-determining step in numerous processes for which no enzymes currently exist, but which would be beneficial in helping to speed up the reaction. During the first heat of the 'competition,' the research team designed the 'heart' of the enzymatic machine - the active site - where the chemical reactions take place.
The second heat of the competition was to design the backbone of the enzyme, i.e., to determine the sequence of the 200 amino acids that make up the structure of the protein. This was no easy feat seeing as there is an infinite number of ways to arrange 20 different types of amino acids into strings of 200. But in practice, only a limited number of possibilities are available as the sequence of amino acids determines the structure of the enzyme, which in turn, determines its specific activity. Prof. David Baker of the University of Washington, Seattle, used novel computational methodologies to scan tens of thousands of sequence possibilities, identifying about 60 computationally designed enzymes that had the potential to carry out the intended activity. Of these 60 sequences tested, eight advanced to the next 'round' having showed biological activity. Of these remaining eight, three sequences got through to the 'final stage,' which proved to be the most active. Drs. Orly Dym and Shira Albeck of the Weizmann Institute's Structural Biology Department solved the structure of one of the final contestants, and confirmed that the enzymes created were almost identical to the predicted computational design.
But the efficiency of the new enzymes could not compare to that of naturally-occurring enzymes that have evolved over millions of years. This is where 'mankind' was on the verge of losing the competition to nature, until Prof. Dan Tawfik and research student Olga Khersonsky of the Weizmann Institute's Biological Chemistry Department stepped in, whereby they developed a method allowing the synthetic enzymes to undergo 'evolution in a test tube' that mimics natural evolution. Their method is based on repeated rounds of random mutations followed by scanning the mutant enzymes to find the ones who showed the most improvement in efficiency. These enzymes then underwent further rounds of mutation and screening. Results show that it takes only seven rounds of evolution in a test tube to improve the enzymes' efficiency 200-fold compared with the efficiency of the computer-designed template, resulting in a million-fold increase in reaction rates compared with those that take place in the absence of an enzyme.
The scientists found that the mutations occurring in the area surrounding the enzyme's active site caused minor structural changes, which in turn, resulted in an increased chemical reaction rate. These mutations therefore seem to correct shortcomings in the computational design, by shedding light on what might be lacking in the original designs. Other mutations increased the flexibility of the enzymes, which helped to increase the speed of substrate release from the active site.
'Reproducing the breathtaking performances of natural enzymes is a daunting task, but the combination of computational design and molecular in vitro evolution opens up new horizons in the creation of synthetic enzymes,' says Tawfik. 'Thanks to this research, we have gained a better understanding of the structure of enzymes as well as their mode of action. This, in turn, will allow us to design and create enzymes that nature itself had not 'thought' of, which could be used in various processes, such as neutralizing poisons, developing medicines, as well as for many further potential applications.'
Prof. Dan Tawfik's research is supported by the J & R Center for Scientific Research; the Jack Wolgin Prize for Scientific Excellence; Mr. and Mrs. Yossie Hollander, Israel; Mr. Rowland Schaefer, New York, NY; and the estate of Fannie Sherr, New York, NY. Prof. Tawfik is the incumbent of the Elaine Blond Career Development Chair.
The Weizmann Institute of Science in Rehovot, Israel, is one of the world's top-ranking multidisciplinary research institutions. Noted for its wide-ranging exploration of the natural and exact sciences, the Institute is home to 2,600 scientists, students, technicians and supporting staff. Institute research efforts include the search for new ways of fighting disease and hunger, examining leading questions in mathematics and computer science, probing the physics of matter and the universe, creating novel materials and developing new strategies for protecting the environment.Weizmann Institute news releases are posted on the World Wide Web at
Yivsam Azgad | idw
The hidden structure of the periodic system
17.06.2019 | Max-Planck-Institut für Mathematik in den Naturwissenschaften (MPIMIS)
Tiny probe that senses deep in the lung set to shed light on disease
17.06.2019 | University of Edinburgh
The well-known representation of chemical elements is just one example of how objects can be arranged and classified
The periodic table of elements that most chemistry books depict is only one special case. This tabular overview of the chemical elements, which goes back to...
Light can be used not only to measure materials’ properties, but also to change them. Especially interesting are those cases in which the function of a material can be modified, such as its ability to conduct electricity or to store information in its magnetic state. A team led by Andrea Cavalleri from the Max Planck Institute for the Structure and Dynamics of Matter in Hamburg used terahertz frequency light pulses to transform a non-ferroelectric material into a ferroelectric one.
Ferroelectricity is a state in which the constituent lattice “looks” in one specific direction, forming a macroscopic electrical polarisation. The ability to...
Researchers at TU Graz calculate the most accurate gravity field determination of the Earth using 1.16 billion satellite measurements. This yields valuable knowledge for climate research.
The Earth’s gravity fluctuates from place to place. Geodesists use this phenomenon to observe geodynamic and climatological processes. Using...
Discovery by Brazilian and US researchers could change the classification of two species, which appear more akin to jellyfish than was thought.
The tube anemone Isarachnanthus nocturnus is only 15 cm long but has the largest mitochondrial genome of any animal sequenced to date, with 80,923 base pairs....
Researchers at Chalmers University of Technology, Sweden, have discovered a completely new way of capturing, amplifying and linking light to matter at the nanolevel. Using a tiny box, built from stacked atomically thin material, they have succeeded in creating a type of feedback loop in which light and matter become one. The discovery, which was recently published in Nature Nanotechnology, opens up new possibilities in the world of nanophotonics.
Photonics is concerned with various means of using light. Fibre-optic communication is an example of photonics, as is the technology behind photodetectors and...
29.04.2019 | Event News
17.04.2019 | Event News
15.04.2019 | Event News
17.06.2019 | Information Technology
17.06.2019 | Earth Sciences
17.06.2019 | Ecology, The Environment and Conservation