Metabolism

• 1. Introduction

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  Metabolism is the set of life-sustaining chemical reactions that occur inside every living organism. The word comes from the Greek metabole, meaning "change." Inside your cells right now, glucose is being torn apart, proteins are being stitched together, and waste is being flushed out. Each of these steps is steered by a specific protein called an enzyme. Without those enzymes, the reactions would not happen on their own.

  Consider one strange fact. There is only a tiny amount of the molecule ATP in your cells at any moment. Yet because it is constantly rebuilt, the human body can cycle through roughly its own weight in ATP across a single day. That relentless recycling is the engine of being alive.

  What follows is an attempt to understand how a cell breaks food down for energy, how it builds itself back up, and why the same core chemistry appears in a single bacterium and in an elephant. We will look at the molecules life is made from, the enzymes that govern the pace, the way order is wrung out of disorder, and the centuries of experiments that revealed all of it.

• 2. The Four Molecules Of Life

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  Amino acids, carbohydrates, nucleic acids, and lipids are the four basic classes of molecules that make up animals, plants, and microbes. Metabolic reactions either build these molecules during the construction of cells and tissues, or break them down to obtain energy. Joined together, they form polymers such as DNA and proteins, the essential macromolecules of life.

  Proteins are amino acids arranged in a linear chain, linked by peptide bonds. Many proteins are themselves the enzymes that drive metabolism. Others are structural, like the cytoskeleton, a scaffolding system that holds the cell's shape. Proteins also carry out cell signaling, immune responses, cell adhesion, and active transport across membranes. When glucose runs scarce, amino acids can even feed the citric acid cycle as a carbon source.

  Lipids are the most diverse group of these biochemicals. They contain a long, non-polar hydrocarbon chain with a small polar region holding oxygen, and they dissolve in organic solvents such as ethanol, benzene, or chloroform. A glycerol molecule attached to three fatty acids by ester linkages forms a triacylglyceride. Variations include backbones like sphingosine in sphingomyelin, and hydrophilic groups like phosphate in phospholipids. Steroids such as sterol form another major class.

  Carbohydrates are the most abundant biological molecules. They are aldehydes or ketones bristling with hydroxyl groups, existing as straight chains or rings. Their basic units are monosaccharides, including galactose, fructose, and most importantly glucose. Linked together they form polysaccharides such as starch, glycogen, and the cellulose in plants or chitin in animals.

  DNA and RNA, the two nucleic acids, are polymers of nucleotides. Each nucleotide pairs a phosphate with a ribose or deoxyribose sugar attached to a nitrogenous base, classified as a purine or a pyrimidine. Some viruses, like HIV, carry an RNA genome and use reverse transcription to build a DNA template from it. RNA can even act like an enzyme: ribozymes such as spliceosomes and ribosomes catalyze chemical reactions of their own.

• 3. The Cell's Currency

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  Adenosine triphosphate, known as ATP, is the energy currency of cells. This nucleotide carries chemical energy from one reaction to another, and it serves as the bridge between catabolism and anabolism. Catabolic reactions, which break molecules down, generate ATP. Anabolic reactions, which assemble molecules, consume it. ATP also carries phosphate groups in phosphorylation reactions.

  Coenzymes like ATP exist because most metabolic reactions, despite their vast number, fall into a few basic types involving the transfer of functional groups of atoms. A small set of shuttle molecules can therefore carry chemical groups between many different reactions. Each coenzyme is made by one set of enzymes and consumed by another, so it is continuously produced, used, and recycled.

  A vitamin is an organic compound needed in small amounts that the cell cannot make itself. Most vitamins become coenzymes after modification, and all water-soluble vitamins are phosphorylated or coupled to nucleotides before use. Nicotinamide adenine dinucleotide, or NAD+, derives from vitamin B3, also called niacin, and acts as a hydrogen acceptor. Hundreds of separate dehydrogenases strip electrons from their substrates and reduce NAD+ into NADH. The NAD+/NADH pair matters most in catabolism, while the related NADP+/NADPH pair drives anabolism.

  Inorganic elements matter too. About 99 percent of a human's body weight is made of carbon, nitrogen, calcium, sodium, chlorine, potassium, hydrogen, phosphorus, oxygen, and sulfur. Ions such as sodium, potassium, calcium, magnesium, chloride, phosphate, and bicarbonate act as electrolytes, holding osmotic pressure and pH steady. They cross the membrane through proteins called ion channels, and muscle contraction depends on calcium, sodium, and potassium moving through those channels and through T-tubules. Transition metals like zinc and iron appear as trace elements, bound tightly inside proteins or stored in ferritin or metallothionein when not in use.

• 4. Breaking Things Down

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  Catabolism is the set of processes that break large molecules apart, releasing the energy and components that anabolic reactions need. In animals, this falls into three stages. First, large molecules like proteins, polysaccharides, or lipids are digested into smaller pieces outside the cells. Next, those pieces are taken up and converted, usually into acetyl coenzyme A. Finally, the acetyl group is oxidized to water and carbon dioxide in the citric acid cycle and electron transport chain.

  Macromolecules cannot be used directly, so digestion comes first. Proteases break proteins into amino acids, and glycoside hydrolases split polysaccharides into monosaccharides. Microbes simply secrete these enzymes into their surroundings. Animals release them from specialized cells in the gut, including the stomach, pancreas, and salivary glands, then pump the freed sugars and amino acids into cells by active transport.

  Glucose, once inside, follows the route of glycolysis and is converted into pyruvate, generating NADH and ATP along the way. Most pyruvate becomes acetyl-CoA and enters the citric acid cycle, where oxidative phosphorylation produces more ATP, consuming oxygen and releasing water and carbon dioxide. When oxygen runs short, as in intense muscular exertion, the enzyme lactate dehydrogenase converts pyruvate to lactate. The lactate can later return to pyruvate, or be rebuilt into glucose through the Cori cycle.

  Fats are split by hydrolysis into glycerol and free fatty acids. The glycerol enters glycolysis, while the fatty acids are broken down by beta oxidation into acetyl-CoA. Fatty acids release more energy when oxidized than carbohydrates do. Some bacteria even break down steroids by a similar process, and M. tuberculosis can grow on the lipid cholesterol as its sole source of carbon.

  Amino acids meet a different fate. A transaminase removes the amino group, which is fed into the urea cycle, leaving behind a deaminated carbon skeleton in the form of a keto acid. Several of these keto acids are citric acid cycle intermediates, such as the alpha-ketoglutarate formed by deamination of glutamate. The glucogenic amino acids can also be turned into glucose through gluconeogenesis.

• 5. Turning Energy Into ATP

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  Electrons removed from organic molecules in the citric acid cycle are the starting point of oxidative phosphorylation. They are transferred to oxygen, and the energy released is captured to make ATP. In eukaryotes this happens along the electron transport chain, a series of proteins in the membranes of mitochondria. In prokaryotes the same proteins sit in the cell's inner membrane. They use energy from reduced molecules like NADH to pump protons across a membrane.

  Pumping protons out of the mitochondria builds a concentration difference and an electrochemical gradient. That force drives the protons back in through the base of an enzyme called ATP synthase. The flow makes the stalk subunit rotate, changing the shape of the active site and phosphorylating adenosine diphosphate into ATP.

  Not all energy comes from food. Chemolithotrophy, found in prokaryotes, pulls energy from the oxidation of inorganic compounds like hydrogen, reduced sulfur compounds, ferrous iron, or ammonia. These microbial processes underpin global biogeochemical cycles such as acetogenesis, nitrification, and denitrification, and they are critical for soil fertility.

  Sunlight is the other great source. Plants, cyanobacteria, purple bacteria, green sulfur bacteria, and some protists capture solar energy, often coupling it to the conversion of carbon dioxide into organic compounds. The capture works much like oxidative phosphorylation, storing energy as a proton gradient that then drives ATP synthesis. The electrons come from light-gathering proteins called photosynthetic reaction centres. In plants, algae, and cyanobacteria, photosystem II uses light to strip electrons from water, releasing oxygen as waste, before the electrons flow through the cytochrome b6f complex and photosystem I to reduce NADP+.

• 6. Building Things Up

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  Anabolism uses the energy released by catabolism to construct complex molecules from simpler precursors. It runs in three stages: producing precursors such as amino acids, monosaccharides, isoprenoids, and nucleotides; activating them into reactive forms using energy from ATP; and assembling them into proteins, polysaccharides, lipids, and nucleic acids. Autotrophs like plants build complex molecules straight from carbon dioxide and water, while heterotrophs need more complex starting substances such as monosaccharides and amino acids.

  Photosynthesis is the synthesis of carbohydrates from sunlight and carbon dioxide. In plants, cyanobacteria, and algae, oxygenic photosynthesis splits water and gives off oxygen as waste. The ATP and NADPH from the reaction centres convert carbon dioxide into glycerate 3-phosphate, which can become glucose. That carbon-fixation step is carried out by the enzyme RuBisCO as part of the Calvin-Benson cycle. Plants use three variants: C3, C4, and CAM photosynthesis, the latter two adaptations to intense sunlight and dry conditions.

  Gluconeogenesis generates glucose from compounds like pyruvate, lactate, glycerol, and amino acids, working through intermediates shared with glycolysis. It is not simply glycolysis in reverse, since several steps use non-glycolytic enzymes, which lets the cell regulate glucose buildup and breakdown separately. Vertebrates such as humans cannot convert acetyl-CoA into pyruvate, so the fatty acids in fat stores cannot become glucose. After long-term starvation, vertebrates instead make ketone bodies from fatty acids to feed tissues like the brain. Plants and bacteria sidestep the problem with the glyoxylate cycle.

  Fatty acids are made by fatty acid synthases that polymerize and reduce acetyl-CoA units, lengthening the chain through cycles of adding, reducing, dehydrating, and reducing again. In animals and fungi a single multifunctional type I protein does the whole job, while plant plastids and bacteria use separate type II enzymes for each step. Terpenes and isoprenoids, the largest class of plant natural products, are built from isoprene units. Sterol biosynthesis joins those units into squalene, folds it into rings to make lanosterol, and then converts lanosterol into sterols such as cholesterol and ergosterol.

  Proteins close the loop. Organisms differ in which amino acids they can make: most bacteria and plants build all twenty, but mammals make only eleven, so nine essential amino acids must come from food. Some parasites, like Mycoplasma pneumoniae, make none and take them from their hosts. Each amino acid is activated by attachment to a transfer RNA, and the ribosome then joins it onto the growing chain following the sequence in a messenger RNA.

• 7. Order From Disorder

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  The second law of thermodynamics states that in any isolated system, entropy, or disorder, cannot decrease. The startling complexity of living organisms seems to defy this, yet it does not. All organisms are open systems that exchange matter and energy with their surroundings. They are dissipative systems, holding their high complexity in place by driving a larger increase in the entropy of their environment. The cell achieves this by coupling the spontaneous reactions of catabolism to the non-spontaneous reactions of anabolism. In thermodynamic terms, metabolism maintains order by creating disorder.

  Because environments change constantly, metabolism must be finely tuned to keep conditions steady, a state called homeostasis. Regulation works on two linked ideas: how an enzyme's activity rises and falls in response to signals, and how much that change actually affects the flux through the whole pathway. An enzyme can be highly regulated yet barely control a pathway if its swings have little effect on the overall rate.

  Intrinsic regulation lets a pathway respond to its own substrate and product levels, often through allosteric control of several enzymes at once. Extrinsic control comes from outside the cell, carried by water-soluble messengers like hormones and growth factors and detected by surface receptors. The hormone insulin offers a clear example. Released when blood glucose rises, insulin binds its receptors and triggers a cascade of protein kinases, prompting cells to take up glucose and store it as fatty acids and glycogen. It acts on glycogen by tipping the balance between phosphorylase, which breaks glycogen down, and glycogen synthase, which builds it up.

• 8. Reading The Living Engine

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  Radioactive tracers gave early biochemists their first clear map of metabolism. By following labelled intermediates from precursor to product at the whole-organism, tissue, and cellular levels, researchers traced the paths of individual pathways, then purified the enzymes and studied their kinetics and responses to inhibitors. A parallel approach catalogues the small molecules in a cell, a complete set known as the metabolome. These reductionist methods illuminate simple pathways but fall short on the full complexity of a living cell.

  The scale of that complexity is staggering. Genome sequences can list up to around 26,500 genes, and a single cell holds thousands of different enzymes. Genomic data now lets scientists reconstruct entire networks of biochemical reactions and build mathematical models that predict their behavior, especially when combined with gene expression data from proteomic and DNA microarray studies. A model of human metabolism has been produced to guide future drug discovery, and such models are used to sort human diseases into groups sharing common proteins or metabolites. Bacterial metabolic networks show a striking bow-tie organization, taking in many nutrients and producing many products through a few common intermediate currencies.

  This knowledge has a practical edge in metabolic engineering. Organisms such as yeast, plants, or bacteria are genetically modified to aid red biotechnology and to make drugs like antibiotics or industrial chemicals such as 1,3-propanediol and shikimic acid. These modifications usually aim to cut the energy needed, raise yields, and reduce waste.

  Aristotle, in The Parts of Animals, laid out enough detail for an open flow model of metabolism to be drawn from his work. He believed food was transformed at each stage, with heat released as the classical element of fire and leftover materials excreted as urine, bile, or faeces. Centuries later, in his 1260 AD work Al-Risalah al-Kamiliyyah fil Siera al-Nabawiyyah, Ibn al-Nafis wrote that "Both the body and its parts are in a continuous state of dissolution and nourishment, so they are inevitably undergoing permanent change."

  Santorio Santorio published the first controlled experiments in human metabolism in 1614, in his book Ars de statica medicina. He weighed himself before and after eating, sleeping, working, fasting, drinking, and excreting, and found that most of the food he took in vanished through what he called "insensible perspiration." For a long time, scientists assumed a vital force animated living tissue.

  Louis Pasteur, studying the fermentation of sugar to alcohol by yeast in the 19th century, concluded that fermentation was catalyzed by substances inside the yeast cells, which he called "ferments." He wrote that "alcoholic fermentation is an act correlated with the life and organization of the yeast cells, not with the death or putrefaction of the cells." In 1828, Friedrich Wohler published the chemical synthesis of urea, the first organic compound made from wholly inorganic precursors, undercutting the vital force theory.

  Eduard Buchner's discovery of enzymes at the start of the 20th century split the chemistry of metabolism from the biology of cells and marked the beginning of biochemistry. Among the most prolific later biochemists was Hans Krebs, who discovered the urea cycle and, working with Hans Kornberg, the citric acid cycle and the glyoxylate cycle. The central pathways they helped reveal, like glycolysis and the citric acid cycle, are present in all three domains of life and were already present in the last universal common ancestor, a prokaryotic cell probably a methanogen.