Molecule of the Month: Vitamins

A healthy diet must include all the nutrients we need to keep our cells growing normally. This includes proteins, nucleic acids, carbohydrates, and fats that are all broken apart and used to build our own molecules and provide the energy we need to live. We need many minerals, such as iron for hemoglobin in our blood and calcium to build our bones. We also require small quantities of thirteen essential vitamins. Vitamins are small, unusual molecules that are used for critical tasks in our cells. These molecules are required for healthy life, but our cells are not able to make them. So, we need to get them from the food we eat or in vitamin supplements.

This poses a question: if these molecules are so important, why can’t we make them? The answer is found, as with most things related to biology, in evolution. Throughout the evolution of our distant ancestors, these molecules were freely available in the typical diet, so there wasn’t strong pressure to make them from scratch. Also, many of these molecules are chemically difficult to construct, so there is selective pressure against expending resources to build them. So somewhere in our distant family tree, the security of being able to make the molecules wasn’t enough to cover the cost, and the ability to make them was lost forever.

The enzyme that builds vitamin B1 (thiamine) is a good example of this evolutionary trade-off. In plants and yeast cells, the unusual thiazole ring is created by the enzyme thiamine thiazole synthase. When researchers looked at the structure of this enzyme (PDB ID 3fpz), they discovered that one cysteine amino acid, number 205 in the chain, was missing its sulfur atom. Further study revealed that this enzyme donates this sulfur atom during the reaction, using it to build the thiazole ring. Thus, thiamine thiazole synthase is a “suicide enzyme” that can only work one time. For this reason, building thiamine is very costly, and yeast cells must build large quantities of the protein. Since we (and other animals) eat plants that have plenty of thiamine, we don’t need to cover the cost of building this single-use enzyme and making our own thiamine.

Vitamins were discovered through their connections to historical diseases that are caused when people don’t have a dietary source for the molecule. For example, centuries ago, sailors on long sea voyages succumbed to scurvy, a disease caused by the inability to build collagen. The culprit was the lack of vitamin C (ascorbic acid) in their diet, and the problem was eventually solved by packing plenty of citrus fruits for a voyage. Today we can look at the molecular details of this disease. The enzyme collagen prolyl 4-hydroxylase, shown here from PDB IDs 7zsc and 4bta, converts proline into hydroxyproline, which is essential for tight packing and interactions of collagen fibrils in healthy connective tissue. The enzyme uses an iron-sulfur cluster in this reaction, and an unwanted side reaction occasionally inactivates the cluster. Here is where vitamin C steps in: it is a powerful antioxidant that restores the proper oxidation state of the iron atoms, reviving the enzyme.

We get most of our vitamins from foods in our diet, and in our modern world, many processed foods are enriched with vitamins to help ensure that we always have enough. In many cases we get these vitamins directly from food, because the plants and animals that we eat are using the vitamins for the same thing in their own cells. In other cases, we can build a vitamin from a molecule that is used for another function. For example, plants have colorful beta-carotene molecules, which are brightly colored because they absorb certain wavelengths of light. Carrots are a classic source of beta-carotene, which gives them their orange color. Our cells use the enzyme carotene oxygenase to split beta-carotene into two pieces, each a functional molecule of vitamin A (retinal). Retinal also absorbs light, and is used in our eyes in the receptor protein rhodopsin. A similar retinal-forming enzyme from cyanobacteria is shown here, from PDB ID 2biw, and you can view a predicted model of the human enzyme in AF_AFQ9HAY6F1.

Vitamins have useful chemical properties. Vitamin A is a specialist: it senses light in our eyes. B vitamins are generalists: they excel at delivering chemical groups (or single electrons) to wherever they are needed and are used by many different enzymes. Vitamins C and E are antioxidants that protect our molecules from damage and vitamin D is used as a hormone to deliver messages. Vitamin K is used by enzymes that modify glutamate amino acids in proteins involved in blood clotting, such as Factor X, making them able to bind strongly to cell surfaces. PDB ID 6wv5 shows an enzyme that assists with this reaction, which is a target of the powerful anticoagulant warfarin. Vitamin K wears many hats: under the name “phylloquinone,” it has a very different function in plants. There, it helps manage transfer of electrons in proteins such as photosystem I.

B vitamins are used to carry chemical groups or electrons, and thus need to be positioned very carefully by the enzymes that use them. However, several of the B vitamins are small molecules that are difficult to manage, so cells add convenient chemical handles to them. For example, a nucleotide is added to riboflavin (vitamin B2) to form FAD (flavin adenine dinucleotide), and a similar handle is added to niacin (vitamin B3) to form NAD. Two enzymes prepare riboflavin for use: first, riboflavin kinase (PDB ID 1p4m) adds a phosphate, then FAD synthetase (PDB ID 2wsi) adds the nucleotide.

Two vitamins have an honorary place in the list: our cells are able to make them, but sometimes not quite enough. Niacin (vitamin B3) is used to make our central carrier of electrons, NADH, which is used in all manner of biosynthetic and energy-producing pathways. For example, it carries electrons from enzymes in glycolysis and the citric acid cycle to the huge NADH dehydrogenase complex. Our cells can make niacin from the amino acid tryptophan, but the process is inefficient and we rely largely on dietary sources of it. Vitamin D is created in our skin when a form of cholesterol is chemically rearranged by exposure to sunlight. This is perfectly fine if you live in a sunny climate, but if not, you may need to get it from a dose of cod liver oil or another dietary supplement.

In some cases, our bodies need to put extra effort into getting vitamins to the places they are needed. For example, vitamin E (tocopherol), is a fat-soluble antioxidant that protects our membranes. It is not very soluble in water, so we make a tocopherol transfer protein that delivers it through the bloodstream to where it is needed. A structure of this protein, PDB ID 3w67, shows that the vitamin is protected inside the protein, and when it gets to its target cell, binding of a lipid in a nearby groove may help open the protein and release the vitamin.