S1C4: Biomolecules & Cells

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a) Proteins

On the back of Chapters 1 and 2 we understand a fair bit about how macromolecules form and Chapter 3 explained why, for anything more complex, key drivers such as function and natural selection overlay the microscopic-level workings of fundamental interactions and chemistry. We also appreciate the central concept of information, how it is stored in complex organisms and how it is leveraged to create useful macromolecules, the topic we will now focus on. If you have not already read the previous chapters, I am inviting you to do so in order to get a good handle on some of the underlying concepts that will be referred to going forward.

First among macromolecules are proteins. First because they are the workhorses, through their various functions, of cell development and homeostasis, which is the maintenance of a steady internal physical and chemical state, also known as staying alive. So, what is a protein and what makes them functionally superior to other types of biomolecules, the molecules produced by living organisms?

A protein is a series of monomers called amino acids consisting of compounds containing nitrogen, carbon, oxygen and hydrogen in various formations. On Earth it seems proteins are concatenations of 22 possible types of amino acids and, if you recall the comment in Section 3.d about the codons within the DNA potentially coding for 64 types of amino acids, this means there is some redundancy and a few of these codons will end up being translated into similar amino acids. Protein biosynthesis can be broken down in two steps: the transcription of the DNA codons into messenger RNA (mRNA) and the use of this template to carry out translation within a macromolecular assembly line called the ribosome.

The superior efficiency of proteins compared to other macromolecules stems from their ability to bind tightly and accurately to other molecules through non-covalent bonds like hydrogen or ionic bonds and van der Waals interactions. In turn, this property is a consequence of their chemical composition and their shape, in particular the way they fold to create very specific binding sites which effectively select the type of molecule that can be bound. If you have followed some of the artificial intelligence developments in the world of chemistry, AlphaFold is excellent at predicting the spatial structure of proteins and therefore their interactions.

To give you a sense of numbers, a human cell contains in excess of 1 billion proteins. The key types of functions they specialize in include signalling, acting as chemical reaction catalysts, transporting other molecules and providing structure in fluid environments. We’ll quickly run through those to provide a sense of the mechanisms employed and how pervasive the use of proteins is within living organisms.

Perhaps we can start with enzymes, a term referring to proteins catalysing chemical reactions. The acceleration of the reaction rate, which can reach thousand-fold, million-fold or even many orders of magnitude more, permits the effective transformation of certain kinds of molecules into other types of molecules within the span of a few milliseconds. Applications for this stunning skill include DNA repair or replication, and of course many aspects of metabolism such as the breakdown of food and its conversion into lipids, carbohydrates and… proteins.

As for structural proteins, they can polymerize to make up the cells’ cytoskeleton, allowing those cells to retain their shape and size, they can form wire-like chains used to form muscle fibre and connective tissue such as cartilage, and they can be part of or interact with biological membranes, as receptors for instance. Biological membranes will be discussed in the upcoming section d).

When acting as receptor, the role of a structural protein is to trigger a biochemical response within the cell upon binding with a specific molecule. Together, these three aspects form the sell signalling process. The activation of the receptor can be the result of chemical binding, or of a differential in electric charges between the interior and the exterior of the cell called membrane potential, or even of pressure and temperature – all of these triggers can ultimately be decomposed into physical phenomena at the molecular level. For example, the neurons in our brain rely on both chemical and electrical signalling to transmit information across synapses. The conveying of a signal is seldom a one-step process however, and it generally involves a series of chemical interactions called the signalling pathway.

Proteins within the membrane can also facilitate the movement of molecules and ions across the biological membranes, typically on the basis of differential in electrochemical gradients but those involved in what is termed active transport can also carry out this task against concentration gradients. The most famous of this second kind would be the sodium-potassium pump, which every cycle pumps out three sodium ions and then pumps in two potassium ions. Neurotransmitter transporters are another type of transport protein located within cellular membranes, they ferry neurotransmitters across neuron membranes and to their intracellular destinations. This intracellular movement is done along the cytoskeleton network and facilitated by protein-based structures called “molecular motors” that convert one form of energy into mechanical work, a form of propulsion into a liquid environment. I have included a link to the Wikipedia entry for molecular motor in the last section of this chapter.

b) Carbohydrates

If proteins are all about function and doing things, then carbohydrates are the commodities that power those functions or act as the key building blocks of biological structures such as RNA, DNA or the cellulose found in dietary fibre and the cell walls of plants.

In biochemistry, carbohydrates are also called saccharides and include sugars, starch and cellulose. They consist of carbon and hydrogen atoms and, given the propensity of those three chemical elements to form bonds, they come in various arrangements and proportions. The most common empirical formula for this type of macromolecules is C_m(H₂O)_n where the bond of one of the hydrogen atoms is with C rather than a covalent bond with O – hence we are not dealing with water despite the H₂O formation.

The main avenue for manufacturing monomeric carbohydrates is by photosynthesis in plants and gluconeogenesis in animals – sounds technical, and it is, but it isn’t that hard to remember since “photo” refers to light from the sun and the etymology of gluconeogenesis is “gluco” for glucose, “neo” for new and “genesis” for creation. These monomer building blocks can then be bound together through glycosylation. All these processes are complex and I will not detail them here since they do not impact the understanding of the main concepts exposed in this chapter or their relationships. What we need to note however, is that the formation of those carbohydrates is endothermic, meaning it requires external energy such as that provided by sunlight in the case of photosynthesis (details on this process will be provided in Section 7.f). Consequently, as some of the bonds forming those carbohydrates are broken down to form various chemical compounds, they release energy that can be used to carry out other tasks. Hence carbohydrates often serve as energy sources and storage.

The simplest carbohydrate compounds are called monosaccharides and consist of one monomer. Among these are glucose (C₆H₁₂O₆) and fructose, a name which may sound familiar since it is the sugar contained in fruits. Plants and algae produce glucose by photosynthesis and make use of it either as a source of energy (this is the blood sugar and it is also extensively used by our brain ), or as a precursor for the synthesis of substances involved in energy storage such as glycogen, or for building more complex structures, cellulose for instance.

When two monosaccharides are joined together (the technical term is glycosidic bond), they form a disaccharide such as lactose, the sugar present in milk. This carbohydrate is consumed by infant mammals who rely on the enzyme lactase to digest this biomolecule by splitting it in two monomeric subunits: glucose and galactose. Typically, the production of lactase reduces after weaning and into adulthood, hence the difficulty of certain individuals in digesting it.

Then there are intermediate polymers made of 3 to 9 monomeric units called oligosaccharides – the etymology of “oligo” means “few”. These intermediate polymers are often used between cells for recognition or adhesion and linked to lipids or proteins. One example among them is (digestible) maltodextrin, which is often used as a food additive or in sports nutrition due to its rapid digestion into glucose units. The energetic density of such molecules is 4 calories per gram.

Lastly, the long-chain versions fall under the category of polysaccharides – the etymology of “poly” means “many”. This category of long polymers comprises of starches and non-starch compounds such as cellulose and glycogen. Starches are produced by green plants as energy storage and will for instance accumulate in fruits, tubers and seeds to power young plants through germination. This is what we consume when eating staple foods such as potatoes or cereal grains including rice, wheat and maize. Cellulose on the other hand is manufactured by plants from glucose units and is the main substrate in their cell walls, making it the most ubiquitous organic polymer on the planet. As for glycogen, it is mostly used by organisms for fuel storage before being broken down into its glucose units. In humans, glycogen is stored in muscles and liver and its depletion during long-distance athletic events is what causes bonking or “hitting the wall”.

c) ATP

This run down of the carbohydrates and their role as energy source would not be complete without talking about the key mediating molecule called ATP, which stands for adenosine triphosphate. As always, the actual energy is provided during chemical reactions, in this case the breaking of chemical bonds by a water molecule, a process called hydrolyzation. This splits ATP into inorganic phosphate and ADP (adenosine diphosphate).

In turn, the production of ATP uses ADP or AMP (adenosine monophosphate) and although there are several pathways, the main one involves the oxidizing of glucose to carbon dioxide – hence the essential role of glucose in energy generation. And yes, you read correctly, ATP is turned into ADP or AMP and those are converted back into ATP, the gaining of a phosphate group is called phosphorylation and the opposite is dephosphorylation. More importantly, the function of this cycle is to store energy in the form of ATP, transport this molecule where energy is required, and then release chemical energy by breaking down the molecule. No wonder ATP is nicknamed the energy currency of cells.

The intensity of ATP requirements in the human body is staggering: the macromolecule is recycled between 1,000 and 1,500 times per day (that’s 40 to 60 times per hour). If we run the maths, we get to a range close to our own body weight in ATP being synthesized on a daily basis.

d) Lipids and membranes

Like most other biomolecules we have seen so far, lipids are primarily made of hydrogen, oxygen and carbon atoms. Other elements such as phosphorus or nitrogen are also often involved to form a wide range of organic compounds; so much so that lipids are arranged in 8 different categories, each with different propensities to bind, behave and degrade when interacting with other compounds. By now this should not surprise us, it all comes down to structure and forces.

Arguably the most salient aspect of several lipid categories is their behaviour towards water molecules and other lipids. In fatty acids, a key building block for larger lipid compounds, the head is a carboxylic acid (R−COOH, R Group + carboxyl group) that tends to be attracted to water molecules because it is also polar. This means it has a negatively-charged end and a positively-charged one, and this uneven distribution of electrical charges favours the forming of polar bonds. This water-loving behaviour is called hydrophilic and the opposite water-fearing one is called hydrophobic. As the non-polar carbon chain extending from the head of the fatty acids grows, it becomes increasingly hydrophobic. In the absence of glucose, fatty acids can also be used as fuel through oxidation and release about 9 kcal/g, more than twice the energy intensity of carbohydrates, which you may recall from earlier stands at about 4 kcal/g.

The preferred type of lipid for energy storage within animal tissues is called triglycerides, what we commonly call “fat”. They belong to the category of glycerolipids and upon hydrolysis they break down into fatty acids and glycerol so, in that sense, triglycerides are to lipids what glycogen is to carbohydrates. Interestingly, through a cascade of chemical reactions, excess carbohydrate can be converted into triglycerides; this explains why excess carbs in our diet can find its way into our adipose tissue and liver, where most of the conversion of fatty acids and glycerol into fats takes place, a process called lipogenesis.

Even more important in the history of the evolution of complex organisms on Earth is the creation of biological membranes permitting an effective separation between each side of a membrane, or when this membrane closes on itself in a spherical shape, a compartmentalization between the inside and the outside of the membrane. The first type is achieved by phospholipids, a category of lipids with a side attracted to water and the other to lipids; in the jargon this behaviour is called amphiphilic and it allows a lipid bilayer to form with the lipophilic heads facing each other and the opposite hydrophilic heads facing the outside aqueous environment. This structure is notably impermeable to ions so it can regulate their concentration in specific areas and allow them to cross via proteins called ion pumps (we talked about these in section a).

When the bilayer sheet curves on itself it can form a circle in 2D and close to form two spheres of hydrophilic heads, a small one with an aqueous solution contained within the larger one formed by the bilayer sheet – as represented in figure 4 below. This is called a vesicle and this natural method of transporting material is nowadays used for targeted drug or nutrient delivery. The monolayer variation of liposomes where the hydrophobic tails are stacked together is called micelle; because they consist of amphipathic molecules, they tend to decrease surface tension between a liquid and another liquid, gas or solid, which is why they are called surfactants – short for “surface active agent”, hence their use in detergents for the lowering of surface tension, which facilitates the removal of unwanted materials on the surface of a solid. In turn, this provides them with emulsifying properties, thus improving the solubility of a compound.

Figure 4: lipid-based biological membranes

Credit: by Mariana Ruiz Villarreal, in the Public Domain

The fourth category of lipids I will mention in this section is sterol and I will focus on cholesterol, the principal variety found in animals. This compound is used within biological membranes alongside phospholipids, they both reinforce the structure and increase its elasticity, thereby improving its functionality. In addition, cholesterol is a precursor to other substances such as vitamin D or steroid hormones (hormones will be discussed in the next chapter) and, like some other types of lipids, it is also used for signalling. As always, information drives function and order.

e) The cell

Once biological membranes were available in the toolkit, evolution eventually chanced on an incredibly powerful innovation: the cell. We should not think of this entity as the end result of a long evolutionary process towards complex organisms but rather as one of its facilitators since cells emerged on our planet about 4 billion years ago. Of course, the primordial versions did not look very much like those of an animal today. However, as their content and properties developed, so did the capabilities and complexity of the broader organisms they are part of.

Let’s not rush to the deep end immediately though and rewind a little. The most basic cells are prokaryotic, they are single-celled organisms and do not possess a nucleus. As mentioned in Section 3.d, this accounts for two out of the three domains of life’s taxonomy: bacteria and archaea, regardless of whether this is the best way to arrange the grand family tree of life on Earth. This represents the unseen majority, by a long shot, and they are prevalent in the oceans and soil – often in concentration of millions per gramme of soil. Their boundary takes the form of an organic membrane and their interior is filled with cytoplasm, a gel-like substance composed mostly of water, and their DNA is freely floating inside, although condensed in a particular region called nucleoid.

In contrast, eukaryotic cells have a nucleus harbouring most of the cell’s genome. Its content is shielded by two lipid bilayer membranes at the periphery and since the gene translation occurs in the cytoplasm, it doesn’t interfere with the DNA replication and gene regulation taking place within the nucleus. In a spirit similar to the ion pumps of the cell membrane, the nucleus membrane can let some macromolecules move from the cytoplasm into the nucleus or vice versa, as is the case for RNA, thanks to dedicated proteins conveniently called importins and exportins, respectively.

Out in the cytoplasm are the cytoskeleton providing some transport infrastructure and several specialized sub-units often designated with the catch-all name of organelles, meaning small organs. The main organelles, besides the nucleus, are the Golgi apparatus, the ribosomes, and the mitochondria. The ribosome is where the messenger RNA translation takes place, leading to protein synthesis following the information embedded in the codons. Interestingly, it is itself made of a type of RNA and it doesn’t possess a membrane layer, unlike the Golgi apparatus, also called Golgi complex, an organelle that serves as the packaging and triage station for the proteins produced by the ribosome, making use of vesicles as vehicles. As for mitochondria, we generally use the plural form because there can be much more than one mitochondrion in a cell. Their primary function is to generate ATP via oxidation (this is the aerobic pathway that requires oxygen) but they are also involved in signalling and cell regulation aspects such as their differentiation, growth, and death.

With such a list of skills, it should not be surprising the cell is often dubbed the fundamental unit of life. Does this seem right though, or is it a misrepresentation, or perhaps just an exaggeration? After all, cells are made of lipid membranes, proteins, etc. and those structures and macromolecules are ultimately a congregation of atoms, themselves a human-made concept with elementary particles at the core that in turn may well be composite entities. In that sense the answer would be no, but clearly that would be ignoring the notion of life that expressly qualifies the question. Life will be discussed in Section 5.e and I do not want to pre-empt it, nonetheless since all the information is stored, read and acted upon at the level of the cell and ultimately this information is what makes the sustenance of life possible, there is a strong argument in favour of the central role of the cell. Take away some cells and an organisms may still live, take away parts of its cells and it won’t. This irreducibility in complexity favours the view of the cells as the smallest common denominator of life.

Tellingly, viruses have no cells and there is an ongoing debate on whether they are alive or not. They obviously exist on one side of our conceptual threshold of life marked by the absence or presence of cell.

f) Trivia – The Mitochondria

Mitochondria have their own DNA and one of the hypotheses regarding their origin is that they used to be bacteria that entered into a symbiotic relationship with eukaryotic cells and were ultimately engulfed by them – this type of symbiosis is called endosymbiosis (“endo” means “within”). Mitochondria are not the only organelle with such a relationship and the chloroplasts involved in the photosynthesis within plant cells (as well as algae) also exhibit the same dynamic.

Intriguingly, because in most animals the mitochondria supplied by the male gamete during sexual reproduction is rapidly destroyed after fertilization, all the mitochondrial genetic information within human cells is inherited through the female gamete so that mitochondrial DNA can be traced back to a matrilineal most-recent-common-ancestor: the “Mitochondrial Eve”. This however doesn’t suggest she was the first “human”, only that there is an unbroken line between each of us and her – and this common ancestor is about mitochondria only. Trivia aside, this mode of inheritance comes in useful in evolutionary biology, in particular when building evolutionary trees.