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 54 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 53 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. 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.

Skip to 2 minutes and 50 secondsThere 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. There are many classes of natural products that are derived from amino acids, including peptides and alkaloids.

Skip to 3 minutes and 16 secondsPenicillin 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. 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.

Skip to 4 minutes and 8 secondsTraditional 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. Another 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.

Skip to 4 minutes and 59 secondsFor example, DNA nucleosides have provided the chemical templates for numerous drugs, including azidothymidine, one of the most effective anti-HIV drugs. Manipulation 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.

Skip to 5 minutes and 50 secondsIn 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 6 minutes and 3 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. There 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.

Introduction

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

Analgesic

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.)

Anaesthetic

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

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.

Polyketide

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

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.

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This video is from the free online course:

Biochemistry: the Molecules of Life

UEA (University of East Anglia)