‘Creating space, creating time’

When we think about the mundane things we do every day or about life-changing or earth-shaking events that happen in the world, we almost always refer to the coordinates of time and space — when and where something happened, how long it took, how often it happens, where it came from or went. In the world of the natural sciences, we also measure everything in time and space. Time was when we would simply rely on our senses and simple gadgets to measure the size, shape or speed of objects. These days, we are able to “see” molecules and know what they are doing, say in cells, through powerful instruments and sensitive experimental tools that can make measurements to a billionth of a meter or a billionth of a second and beyond.

What do we see in a cell? We see that it is very concentrated. (Imagine a chicken egg cell which really looks thick.) It is packed with biomolecules of different kinds and sizes, interacting with one another in various ways to carry out the functions of life. A cell is likened to an electrical circuit that transmits signals (information) from outside the cell to its surface, to the cytoplasm, to the subcellular organelles, including the nucleus, and back. Biomolecules, mostly proteins, behave like sensors, others like insulators, conductors, transducers, adaptors or rheostats, that are assembled to form signalling pathways and networks, and engage in cross-talking and feedback looping. These tiny cells, these tiny creatures, are jampacked not only with biomolecules but with signalling activity. (The bacterium E. coli is a unicellular organism, so a cell can be a “creature”!)

Proteins make up a large part of the cell. Proteins are of many different types and functions. (The whole set of proteins in a cell is known as the proteome.) In general, how does a protein function? In simple terms, first, it binds specifically to a partner. The partner could be a small molecule, a medium size molecule, or a big molecule like another protein. (Versatile proteins that engage in multiple protein-protein interactions are described as “promiscuous.”) The key to the binding is the specificity. How is this specific binding possible? Through the creation of specific binding sites or 3D spaces on the surface of the protein. (Promiscuous proteins have many specific binding sites.)

Proteins have evolved in such a way that, more than any other type of biomolecule, their structures can fold and refold, and so they have the flexibility to produce all sorts of shapes — niches, crevices and bumps — on their surfaces. And since proteins are made up of amino acids, each with its unique side chain, the amino acids trapped in specific locations within the crevice can form non-covalent interactions with the partner. This unique or specific 3D space (surface topology) created by the protein is recognized and filled in by the partner through a lock-and-key or an induced fit mechanism. (The partner must have the complementary surface to fit into the protein’s surface.)  Once locked in, the non-covalent interactions come into play and cause some bending, shifting, tilting or movement of the whole protein structure (known as conformational change) and this triggers effects on other proteins or other biomolecules which ultimately results in a biological effect felt by the whole cell.

We can think of a growth factor receptor protein sitting on the surface of the cell membrane waiting to receive a signal from outside the cell. The signal would be the growth factor, and once it binds to the receptor, the signal is transmitted through the membrane, to the cytoplasm, all the way to the nucleus, through a pathway composed of an assembly of proteins.

Among the proteins, enzymes, which catalyze chemical reactions, are the oldest and most highly evolved. Aside from binding a substrate specifically, an enzyme is able to speed up the conversion of the substrate to a product by a thousand to a million times faster than an uncatalyzed reaction. This is a remarkable feat that only enzymes can perform, through specialized mechanisms of chemical bond breaking and bond making, and it happens not at high temperatures but at low (body or cell) temperature! (Non-biological catalysts, such as metal catalysts used in industry, do not increase reaction rates by this much.) When we think of the many chemical reactions required for metabolism — to break down food and storage materials to release energy (catabolism) or to biosynthesize biomolecules such as nucleic acids, proteins, carbohydrates, lipids (anabolism), we can appreciate how central to life enzymes are. A many-fold increase in reaction rate or decrease in reaction time, saves cell metabolism, saves us, a lot of time.

However, the impact on time of enzymes goes beyond converting one substrate to a product at high speed. The catalytic rate includes the turnover or release of the product. Once released, another catalytic cycle begins. (Imagine the enzyme like a molecular machine being fed substrates and churning out products continuously). In the cell cytoplasm, many enzymes have substrates that are also enzymes. Kinases are enzymes that add a phosphate group to the substrate. Many signalling pathways include an assembly of kinases catalyzing the phosphorylation of other kinases. When the kinase is phosphorylated, it is converted to the active form and it starts to phosphorylate other kinases, other enzymes or proteins. Imagine the cascading, multiplier or amplifying effect of this assembly of kinases! Kinases are “creating time,” with a time management strategy that gets the job done, the effect spread out, in a very short time. The cell as a circuit has parallel pathways and networks. Signals can be transmitted simultaneously, mostly mediated by kinases, and as a whole, this makes the cell attain a very high rate of efficiency and productivity.

Biological structures have evolved to become very efficient in their own interactions and in their functions as part of a larger assembly of biological structures. Proteins are remarkably “intelligent” in the sense that they are able to create the most specific 3D binding spaces and fastest catalytic time in all of Nature. 

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GP Padilla-Concepcion is a professor of the Marine Science Institute, University of the Philippines where she team-teaches and co-leads research on bioactive compounds from marine organisms, their cellular and molecular mechanisms of action in relation to human diseases. She is an academician of the National Academy of Science and Technology. She is currently the vice president for academic affairs of the University of the Philippines System. E-mail her at [email protected].