Research Director: Dr. Masasuke Yoshida
(Professor, Chemical Resources Laboratory, Tokyo Institute of Technology)
Research Term: 2001.10-2007.3


Through the activity of evolution, guided by natural selection, nature has produced a wide variety of organisms, organs and chemical systems. One amazing example is the way energy is stored and transported in every cell of every organism.

The dominant strategy involves a molecule called ATP, which is synthesized from ADP and phosphate through the enzymatic action of a special protein (ATP synthase). Naturally, since this process is essential for the functioning of any organism, ATP synthase has been major research subjects for many years. An analysis of the enzyme structure by Masasuke Yoshida led to a prediction by Paul Boyer that it actually rotates while converting ADP to ATP and storing energy. Rotation is not the only significant aspect, since it was also predicted that the catalysis functions like a motor with two driving units and a common shaft. This view was furthered by J. E. Walker through an X-ray crystallographic analysis. Still, firm evidence was needed. This was recently achieved by Yoshida, who attached a very long (1-3 micrometers) actin filament with a fluorescent marker to the upper motor (10 nanometer diameter) and actually made a video of the rotation.

Through the accumulated investigations, ATP synthase is now being pictured as acting like two motors connected by a common rotary shaft. The energy source is food which supplies hydrogen while discarding carbon as carbon dioxide. The hydrogens are burnt in mitochondria through respiration with pumping out hydrogen ions (protons) from mitochondria. A buildup of protons causes a proton potential difference across a biological membrane; this acts as the power source to rotate the lower motor (F0) of ATP synthase. A connecting shaft causes the upper motor (F1) to rotate While synthesizing ATP. This two-motor-like molecule, which has great likeness to an actual macroscopic motor, can also be run in reverse while changing ATP to ADP and flowing protons in the opposite direction. Some bacteria actually use this capability to transport nutrients.

There is now a very great need to understand this enzyme motor in more detail as well as the total system within which it works. Though this enzyme might be one of the most common in nature, since ATP is ubiquitous, other motor-like enzymes or motors are virtually unknown in the chemistry of organisms, except for a motor-like assembly that rotates the flagella of some bacteria. One intriguing question is that if better observational techniques can be established will this motor strategy be shown to be more common than ever imagined and involved in important biological activities.

Outline of Research

This project is interested in how ATP synthase can rotate, how the rotation transmits the energy from proton flow, the mechanism of ATP synthesis, and why the biological world has adapted this type of very complicated process for the synthesis of ATP. Research is being pursued in three interacting areas to solve these very challenging problems:

The first area concerns the detailed mechanism of the motor system. To understand the dynamics of both motors (F0 & F1), a special detection system is being developed. The main tool is a very fast video camera that can record about 8,000 frames per second. Using this camera will allow the rotational motions to be observed very exactly. The actual rotational speed of the ATP synthase without an attached actin filament is an amazing 100 revolutions per second. So far only the upper motor, which synthesizes ATP has been observed. Now the lower motor (F0), that is driven by a proton gradient and rotates a shaft connected to the second motor (F 1), needs to be analyzed. To do this it is necessary to divide the space into two and to introduce a membrane, through which protons can produce the driving force.

The second area involves an effort to find other motor-like enzymes in the biological world. Maybe the enzymes handling DNA also have this type of mechanism. One hypothesis is that as DNA moves up a central cavity of some enzyme, the DNA rotates while being wound or unwound using a screw-type motion. Another possibility is a DNA dense packing system into a bacteriophage capsid.

The third area concerns with regulation of the motor system. For instance, usually the motor should run by using a proton gradient to produce ATP, not the reverse. Work is being done to explain the mechanism that controls this in a changing environment, like for a plant with changing availability of sunshine. A subunit, called epsilon, is being studied concerning how it can sense a change in the environment. Also being studied is the power generation system mechanism.
This high-profile project is being watched by many people not only concerning the basic science involved; but also its significant possibilities concerning manmade nanotechnology, such as very small power units.


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