Hello, everyone. Welcome back to my Coursera class, biochemical principles of energy metabolism. In the previous session, I clearly emphasized the importance of ATP hydrolysis. In terms of driving unfavorable reactions, which is enderrgonic reactions and they are heavily involved in synthesis of macro molecules. So I'm going to continue to the importance of ATP. Today's topic is ATP hydrolysis and mechanical work. So mechanical works obviously, I believe make you think about a muscle, right? So I'm going to give you the brief introduction of muscle, and what is muscle? So in the human body, so about 50% is composed of muscle. And there are three types of muscles available. Number one is skeletal muscle. It connects different types of bones and make a lot of contractual forces, for movement and jogging. We can think about many types of voluntary movements or made by the skeletal muscles. The second class is cardiac muscles, cardiac is heart. And in your heart, there are specialized muscles called a cardiac muscles. And it can pump your blood throughout muscular contractions. The third one is smooth muscle. Actually which is the key component to your internal organs, like stomach and bladder and intestines. And change the shape of those internal organs, and functionally facilitate their roles. So why don't we just a little bit more take a closer look at the muscular structures? So this is cross section of skeletal muscle, and there are couple of units called the fascicles, and several fascicles are making a bundle of your muscle. And each fascicle is composed of muscle fiber, each fascicle is composed of muscle fiber. And each muscle fiber contains many myofibrils. Myofibril is kind of a unit. And in this transmission electron diagram, you are looking at the myofibril cross section images, and there are many stripes. So why are they striated? All right, sarcomere is the basic unit for muscle contraction. We are looking at the overall structure of sarcomere contractual unit, and it is compose of two major filaments. One is very thin actin filaments, filaments means protein fiber, protein-based fiber. And the other one is a thick, very thick myosin filament, okay? So I can show more details by using this diagram on your left. This thin actin filament looks like this. So small globular actin proteins form a chain of fibrous actin polymer that's this thin filament. And thick filament in the middle is composed of myosin, myosin molecule polymers. This is over a structure of myosin. So myosin exhibit very unique structural feature. So long tail and some hinge region, and particular arm structure and globular head on it. And these myosin proteins, they're intertwined and they form a think filament in the middle of the sarcomere. And this head main, There are two major biochemical activities going on. First one is this a thin filament actin binding. And the other one is ATP binding and ATP hydrolysis activity. How this muscle contraction is regulated to generate a force? So simply, we first take a look at the muscle contraction. So actin-based thin filaments, they're attached to the structure and forming a z line. Upon the muscle contraction, the distance between z line can be shortened. As you can see, this diagram, the idea is very simple. A thin actin filament can slide into the middle region. And then muscle contraction occurs, and force can be generated. And when you look carefully, take a look at this slide. When this actin filament is coming along toward the middle area of sarcomere, there is molecular interaction between head domain of myosin and actin. So myosin is very interesting proteins. So ATP-dependent motor proteins. So what does that motor protein mean? So motor protein is kind of very specialized protein can utilize free energy into mechanical form of energy. So it's kind of transform the energy from the chemistry into physics. So mechanical, like transforming small molecular machine. Very interestingly, these myosins can bind to ATP and there is activity adenosine triphosphatase enzyme activity, ATP hydrolizing activity. So why is that important? So you're looking at the myosin protein structure depending on ATP phosphate bound status, and depending on the nucleotide free state. A group of scientists solved the three dimensional myosin protein structure in the absence or presence of ATP phosphate and those ATP hydrolysis products. So from this diagram, so what can you immediately sense? This is head domain, and these are sort of arm structure, right? As I said, the myosin structure are like this, head domain, the arm structure, and long tail structure, okay? This head domain ATP can be hydrolyzed into ADP and phosphate. Okay, so when myosin bound to ADP phosphate the confirmation is like this. So when nucleotide and inorganic phosphate are released, there's a huge conformational changes almost 90 degree angular transformation of this arm structure. So in this case, ATP hydrolysis can lead to huge conformational changes of the target protein, in this case myosin protein. By combining all information I explained so far, I'm going to fully present the muscle contraction cycle, the biochemical basis of muscle contraction cycle. So first, the neurons send signals, they secrete muscular muscle excitatory hormones or neural transmitters like acetylcholine, and finally muscle is activated. So when muscle is activated, the cytosolic calcium level is elevated. The primary biochemical event for muscle contraction is elevation of intracellular calcium ions, okay? When this calcium ion level is increased, that calcium binds to a thin filament, associated proteins like troponin. And finally, this calcium and a thin filament interactions, the myosin head domain can access to actin filament. So without calcium, without the reasonable amount of calcium levels inside the muscle, this myosin head domain cannot physically interact with thin actin filaments. All right, so upon this interaction, so called cross-bridge, cross-bridge between myosin and actin filaments. After that, after this cross-bridge formation, after this cross-bridge formation, The head domain, in the head domain of myosin ADP and phosphate, they can be released. They can be released from the myosin head domain. And as you saw from the previous slide, there is a huge conformational changes of myosin. And that conformational changes causes so called power stroke. The actin, myosin bound actin filament, Can slide in toward the midline of sarcomere. So around 10 nanometer of muscle contraction can be mediated by this power stroke event. The biochemical and myosin protein conformational changes upon the ADP and phosphate release is the key biochemical basis for this force-generating muscle contraction event. And then the vacant ATP, a vacant myosin head domain is now being filled back with the ATP molecules. And then later hydrolyzed by myosin head domain ATP's activity, and now ADP-bound phosphate myosin head. They are being reset back to the cocked position to make sure the next round of muscle contraction can be done. So ATP is obviously the key component of skeletal muscular. And not just the skeletal, all types of muscular contractile events and related the mechanical work, right? So I'm going to give you one more very interesting point of ATP turnover. So primary source of ATP, Primary energy source for muscle and brain is obviously ATP, primary energy source is ATP. And in a short amount of time, your muscle can consume ATP very, very rapidly. In that case, there's another backup high energy phosphate molecule called the creatine phosphate or phosphate creatine. They are working as extra back up energy in your muscle and brain. So what does that mean? So these high phosphate containing, high energy phosphate containing phosphocreatine. It's just they're just ready and just build up inside your muscle cells. When ATP level is dramatically lowered, maybe under the strenuous muscular activities, whatever. And then in a short amount of time to backup the deficit of this ATP, this phosphocreatine donate these phosphate into ADP. And ATP can be in a short amount of time can be resupplied, resynthesized. And then can be used for muscular and your neural activities. This kind of extra backup energy from another energy phosphate molecule called creatine phosphate. All right, so, the take home message of today's session is very clear. ATP hydrolysis can drive mechanical work. And that ATP hydrolysis, indeed provide free energy required for your muscular contraction. And not just for the muscular contraction. Other examples like ciliated and flagellated cells like sperms utilize ATP for driving their mechanical like a motion or work, and the first event for life, the fertilization can be made possible. And the other liquid example is chromosome segregation, your genome during the cell division. Your genome is supposed to be segregated and supposed to be moved inside your cells, right? And that mechanical process is also made possible by ATP hydrolysis.
