Skip to 0 minutes and 1 secondLast week we introduced the biochemical concept of metabolism as the sum of all the chemical reactions that occur in the cell, each organised into a set of metabolic pathways. Primary metabolism comprises the chemistry responsible for the synthesis of the building blocks of life, known as primary metabolites; these include amino acids, carbohydrates, nucleotides and their precursors. These products are essential for the normal growth, development and reproduction of an organism and thus the pathways are largely conserved throughout all species. However, some specific organisms, or in some cases groups of organisms, have evolved with metabolic pathways that produce non-essential chemicals known as secondary metabolites, or natural products. The chemistry concerning the synthesis of natural products is known as secondary metabolism.
Skip to 0 minutes and 52 secondsThese chemicals often provide additional, ecological functions for the organism, such as defensive mechanisms against stress, predators or pathogens, an advantage in interspecies competition or reproductive processes. Many secondary metabolites have proven invaluable as herbicides, diagnostics, and tools for research. Most critically, many induce powerful physiological effects in humans, making them a crucial source of lead compounds for drugs that can treat all kinds of diseases. The vast majority of secondary metabolites are organic molecules that have carbon atoms as their central components. Some organisms, including plants and some bacteria, are able to synthesise their own organic substances from simple inorganic precursors, such as carbon dioxide, through the process of carbon fixation. These organisms are known as autotrophs.
Skip to 1 minute and 49 secondsHeterotrophs, such as humans, have to obtain organic matter and metabolic energy from the content of their diet. Carbon fixation by plants is achieved in the second phase of photosynthesis, a metabolic pathway known as the Calvin cycle, which takes its name from its discoverer, Melvin Calvin, who was awarded the Nobel Prize in Chemistry for this research in 1961. In this cycle the enzyme ribulose bisphosphate carboxylase-oxygenase catalyses the combination of carbon dioxide with a five-carbon sugar, ribulose 1,5-biphosphate. The resulting sugar breaks down into two glycerate 3-phosphate molecules, some of which are removed from the cycle to produce amino acids and fatty acids. The rest can then be reduced by NADPH and phosphorylated by ATP to produce triose phosphate.
Skip to 2 minutes and 53 secondsMost molecules of triose phosphate are recycled back to ribulose 1,5-biphosphate, but a small amount can be used to synthesise hexose sugars and glycerol. The intermediate products of other primary metabolic pathways, including glycolysis and the citric acid cycle that were covered last week, are used both as sources of metabolic energy and as chemical precursors for the biosynthesis of natural products. For example, the synthesis of the amino acids glutamate, glutamine, and proline begins with α-ketoglutarate, an intermediate in the citric acid cycle. There are nine amino acids that can’t be synthesised in humans, including the aromatic phenylalanine, tyrosine, and tryptophan, and these are described as “essential” because they must be provided by the diet.
Skip to 3 minutes and 48 secondsOrganisms such as bacteria, fungi and plants make these three amino acids via the shikimate pathway, a seven step metabolic process that begins with phosphoenolpyruvate, an intermediate from glycolysis. There are many classes of natural products that are derived from amino acids, including peptides and alkaloids. Penicillin was the first naturally-produced antibiotic to be developed for commercial use and its characterisation led to the awarding of the Nobel Prize in Physiology or Medicine in 1945 to Fleming, Chain and Florey. Penicillin is a peptide antibiotic and is naturally produced in some fungi in order to kill surrounding bacteria that would be competing for nutrients. It is derived from three amino acids, including valine and cysteine, which form the bioactive β-lactam ring.
Skip to 4 minutes and 50 secondsUnlike most proteins that are synthesised by the process of translation of mRNA on the ribosomes, penicillin is formed in the cytosol of some microorganisms in three steps, each catalysed by a specialised synthetase enzyme. A medically important alkaloid drug is morphine, a strong analgesic and anaesthetic. Its biosynthesis is achieved through stepwise chemical modifications to the amino acid tyrosine. It is naturally found in the opium poppy plant. Indeed, plants are a well-established source of therapeutically valuable natural products. Traditional medicine has relied upon plants and their extracts for hundreds of years, and today more than half of all clinically used therapeutics are derived from plant natural products.
Skip to 5 minutes and 38 secondsAnother class of natural products that represent the structural diversity and versatility of metabolites are the polyketides, which have been isolated from many sources, including bacteria, fungi, plants, and animals. Polyketide derivatives such as erythromycin are important antibiotics, while others such as doxorubicin are anti-cancer drugs used in chemotherapy. We are familiar with the fact that DNA and RNA molecules are fundamental to all cellular life on earth. Nucleic acids and their precursors are also finding many applied uses in biotechnology and biomedicine. For example, DNA nucleosides have provided the chemical templates for numerous drugs, including azidothymidine, one of the most effective anti-HIV drugs.
Skip to 6 minutes and 32 secondsManipulation of DNA and nucleotides has been crucial to the successful development of molecular biology and genetic engineering techniques since the 1950s. Recently, there has been massive progress in improving the methods, and through the developing field of Synthetic Biology these have the potential to find useful applications in overcoming some of the grand challenges that society faces. During this week we will look into the future potential of these techniques. It is also clear that increased knowledge about metabolic pathways that involve DNA will improve our understanding of some human diseases, including many forms of cancer. In recognition of this, the 2015 Nobel Prize in Chemistry was awarded to Lindahl, Modrich and Sancar for their studies of DNA repair pathways.
Skip to 7 minutes and 20 secondsHuge varieties of natural products are also consumed by humans in many everyday foods, and have important implications for our sustained health. A diet that is rich in plant-based foods will naturally contain a variety of classes of secondary metabolites, including carotenoids, flavonoids and phytosterols. Each type can exert various health benefits, from protecting cells from free radicals, lowering cholesterol levels and preventing cancers and heart attacks. This week Superfood Siobhan will explore the biochemistry behind natural products that are essential for healthy living, and we will see how we can use this knowledge to make informed choices about what we eat.
Skip to 8 minutes and 5 secondsThere are still huge numbers of natural products from various sources that have yet to be discovered, and continued biochemical research is key to unlocking the potential of these compounds to be useful for human societies.
Watch the video to find out about the syntheses and separation of organic molecules plus the range of products used as medicines, particularly those developed from natural sources.
Technical terms in simplified form
An analgesic (or painkiller) is any member of the group of drugs used to achieve relief from pain. Usually, they relieve pain without eliminating sensation. (Note the contrast with anaesthetics, which cause a reversible loss of sensation.)
An anaesthetic is any member of the group of drugs that cause anaesthesia, which is a reversible loss of sensation. (Note the contrast with analgesics, which relieve pain without eliminating sensation.) These drugs are generally administered to facilitate surgery.
Genetic engineering - also called genetic modification - is the direct manipulation of DNA within a cell using biotechnology. It is a set of technologies used to change the genetic makeup of cells, including the transfer of genes within and across species boundaries to produce improved or novel organisms. An organism generated using genetic engineering is considered to be a genetically modified organism (GMO). Genetic engineering techniques have been applied in numerous fields including research, agriculture, industrial biotechnology, and medicine.
Polyketides are a class of secondary metabolites produced by some organisms. They are complex organic compounds that have a wide range of chemical structures and often have high biological activities. Many pharmaceuticals are derived from or inspired by polyketides.
Synthetic biology is an interdisciplinary branch of biology and engineering. It involves a wide range of methods, often combining different disciplines, such as biotechnology, evolutionary biology, molecular biology, computer engineering, and genetic engineering. Taking account of the involvement of interdisciplinary subjects, synthetic biology has been defined as the artificial design and engineering of biological systems and living organisms for the purposes of improving applications for applied or basic biological research.
Translation of mRNA
Translation involves the assembly of amino acids to synthesise new proteins. The sequence of amino acids in the protein is defined by the sequence of nucleotides in the messenger RNA (mRNA) that is generated upon transcription of a gene. Ribosomes are complex macromolecules that coordinate the process of translation.