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A natural product is a natural
compound Compound may refer to: Architecture and built environments * Compound (enclosure), a cluster of buildings having a shared purpose, usually inside a fence or wall ** Compound (fortification), a version of the above fortified with defensive struct ...
or
substance Substance may refer to: * Matter, anything that has mass and takes up space Chemistry * Chemical substance, a material with a definite chemical composition * Drug substance ** Substance abuse, drug-related healthcare and social policy diagnosis ...
produced by a living organism—that is, found in
nature Nature, in the broadest sense, is the physics, physical world or universe. "Nature" can refer to the phenomenon, phenomena of the physical world, and also to life in general. The study of nature is a large, if not the only, part of science. ...
. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by
chemical synthesis As a topic of chemistry, chemical synthesis (or combination) is the artificial execution of chemical reactions to obtain one or several products. This occurs by physical and chemical manipulations usually involving one or more reactions. In moder ...
(both
semisynthesis Semisynthesis, or partial chemical synthesis, is a type of chemical synthesis that uses chemical compounds isolated from natural sources (such as microbial cell cultures or plant material) as the starting materials to produce novel compounds with ...
and
total synthesis Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially-available precursors. It usually refers to a process not involving the aid of biological processes, which distinguishes ...
) and have played a central role in the development of the field of
organic chemistry Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clayden, J.; ...
by providing challenging synthetic targets. The term natural product has also been extended for commercial purposes to refer to cosmetics, dietary supplements, and foods produced from natural sources without added artificial ingredients. Within the field of
organic chemistry Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clayden, J.; ...
, the definition of natural products is usually restricted to
organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. The ...
s isolated from natural sources that are produced by the pathways of
primary Primary or primaries may refer to: Arts, entertainment, and media Music Groups and labels * Primary (band), from Australia * Primary (musician), hip hop musician and record producer from South Korea * Primary Music, Israeli record label Works * ...
or
secondary metabolism Secondary metabolism (also called specialized metabolism) is a term for pathways and small molecule products of metabolism that are involved in ecological interactions, but are not absolutely required for the survival of the organism. These molecul ...
. Within the field of
medicinal chemistry Medicinal or pharmaceutical chemistry is a scientific discipline at the intersection of chemistry and pharmacy involved with designing and developing pharmaceutical drugs. Medicinal chemistry involves the identification, synthesis and developm ...
, the definition is often further restricted to secondary metabolites. Secondary metabolites (or specialized metabolites) are not essential for survival, but nevertheless provide organisms that produce them an evolutionary advantage. Many secondary metabolites are
cytotoxic Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa''). Cell physiology Treating cells ...
and have been selected and optimized through evolution for use as "chemical warfare" agents against prey, predators, and competing organisms. Secondary or specialized metabolites are often unique to species, which is contrasted to primary metabolites which have broad use across kingdoms. Secondary metabolites are marked by chemical complexity which is why they are of such interest to chemists. Natural sources may lead to
basic research Basic research, also called pure research or fundamental research, is a type of scientific research with the aim of improving scientific theories for better understanding and prediction of natural or other phenomena. In contrast, applied resear ...
on potential bioactive components for commercial development as
lead compound A lead compound (, i.e. a "leading" compound, not to be confused with various compounds of the metallic element lead) in drug discovery is a chemical compound that has pharmacological or biological activity likely to be therapeutically useful, b ...
s in
drug discovery In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered. Historically, drugs were discovered by identifying the active ingredient from traditional remedies or by ...
. Although natural products have inspired numerous drugs,
drug development Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes preclinical research on microorganisms and animals, filing for re ...
from natural sources has received declining attention in the 21st century by pharmaceutical companies, partly due to unreliable access and supply, intellectual property, cost, and
profit Profit may refer to: Business and law * Profit (accounting), the difference between the purchase price and the costs of bringing to market * Profit (economics), normal profit and economic profit * Profit (real property), a nonpossessory intere ...
concerns, seasonal or environmental variability of composition, and loss of sources due to rising
extinction Extinction is the termination of a kind of organism or of a group of kinds (taxon), usually a species. The moment of extinction is generally considered to be the death of the last individual of the species, although the capacity to breed and ...
rates.


Classes

The broadest definition of natural product is anything that is produced by life, and includes the likes of
biotic material Biotic material or biological derived material is any material that originates from living organisms. Most such materials contain carbon and are capable of decay. The earliest life on Earth arose at least 3.5 billion years ago.Schopf, JW, Kudrya ...
s (e.g. wood, silk),
bio-based material A bio-based material is a material intentionally made from substances derived from living (or once-living) organisms. These materials are sometimes referred to as biomaterials, but this word also has another meaning. Strictly the definition could ...
s (e.g.
bioplastic Bioplastics are plastic materials produced from renewable biomass sources, such as vegetable fats and oils, corn starch, straw, woodchips, sawdust, recycled food waste, etc. Some bioplastics are obtained by processing directly from natural ...
s, cornstarch),
bodily fluid Body fluids, bodily fluids, or biofluids, sometimes body liquids, are liquids within the human body. In lean healthy adult men, the total body water is about 60% (60–67%) of the total body weight; it is usually slightly lower in women (52-55%). ...
s (e.g. milk, plant exudates), and other natural materials (e.g. soil, coal). Natural products may be classified according to their biological function, biosynthetic pathway, or source. Depending on the sources, the number of known natural product molecules ranges between 300,000 and 400,000.


Function

Following
Albrecht Kossel Ludwig Karl Martin Leonhard Albrecht Kossel (; 16 September 1853 – 5 July 1927) was a German biochemist and pioneer in the study of genetics. He was awarded the Nobel Prize for Physiology or Medicine in 1910 for his work in determining the che ...
's original proposal in 1891, natural products are often divided into two major classes, the primary and secondary metabolites. Primary metabolites have an intrinsic function that is essential to the survival of the organism that produces them. Secondary metabolites in contrast have an extrinsic function that mainly affects other organisms. Secondary metabolites are not essential to survival but do increase the competitiveness of the organism within its environment. Because of their ability to modulate biochemical and
signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
pathways, some secondary metabolites have useful medicinal properties. Natural products especially within the field of
organic chemistry Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clayden, J.; ...
are often defined as primary and secondary metabolites. A more restrictive definition limiting natural products to secondary metabolites is commonly used within the fields of
medicinal chemistry Medicinal or pharmaceutical chemistry is a scientific discipline at the intersection of chemistry and pharmacy involved with designing and developing pharmaceutical drugs. Medicinal chemistry involves the identification, synthesis and developm ...
and
pharmacognosy Pharmacognosy is the study of medicinal plants and other natural substances as sources of drugs. The American Society of Pharmacognosy defines pharmacognosy as "the study of the physical, chemical, biochemical, and biological properties of drug ...
.


Primary metabolites

Primary metabolites as defined by Kossel are components of basic metabolic pathways that are required for life. They are associated with essential cellular functions such as nutrient assimilation, energy production, and growth/development. They have a wide species distribution that span many phyla and frequently more than one
kingdom Kingdom commonly refers to: * A monarchy ruled by a king or queen * Kingdom (biology), a category in biological taxonomy Kingdom may also refer to: Arts and media Television * ''Kingdom'' (British TV series), a 2007 British television drama s ...
. Primary metabolites include the basic building blocks of life:
carbohydrate In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may or ma ...
s,
lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include ...
s,
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
s, and
nucleic acid Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main cl ...
s. Primary metabolites that are involved with energy production include
respiratory The respiratory system (also respiratory apparatus, ventilatory system) is a biological system consisting of specific organs and structures used for gas exchange in animals and plants. The anatomy and physiology that make this happen varies grea ...
and
photosynthetic Photosynthesis is a process used by plants and other organisms to convert light energy into chemical energy that, through cellular respiration, can later be released to fuel the organism's activities. Some of this chemical energy is stored in c ...
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
s. Enzymes in turn are composed of
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
s and often non-peptidic
cofactors Cofactor may also refer to: * Cofactor (biochemistry), a substance that needs to be present in addition to an enzyme for a certain reaction to be catalysed * A domain parameter in elliptic curve cryptography, defined as the ratio between the order ...
that are essential for enzyme function. The basic structure of cells and of organisms are also composed of primary metabolites. These include cell membranes (e.g.
phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...
s), cell walls (e.g.
peptidoglycan Peptidoglycan or murein is a unique large macromolecule, a polysaccharide, consisting of sugars and amino acids that forms a mesh-like peptidoglycan layer outside the plasma membrane, the rigid cell wall (murein sacculus) characteristic of most ...
,
chitin Chitin ( C8 H13 O5 N)n ( ) is a long-chain polymer of ''N''-acetylglucosamine, an amide derivative of glucose. Chitin is probably the second most abundant polysaccharide in nature (behind only cellulose); an estimated 1 billion tons of chit ...
), and
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...
s (proteins). Primary metabolite enzymatic cofactors include members of the
vitamin B B vitamins are a class of water-soluble vitamins that play important roles in cell metabolism and synthesis of red blood cells. Though these vitamins share similar names (B1, B2, B3, etc.), they are chemically distinct compounds that often coexist ...
family.
Vitamin B1 Thiamine, also known as thiamin and vitamin B1, is a vitamin, an essential micronutrient, that cannot be made in the body. It is found in food and commercially synthesized to be a dietary supplement or medication. Phosphorylated forms of thia ...
as thiamine diphosphate is a coenzyme for
pyruvate dehydrogenase Pyruvate dehydrogenase is an enzyme that catalyzes the reaction of pyruvate and a lipoamide to give the acetylated dihydrolipoamide and carbon dioxide. The conversion requires the coenzyme thiamine pyrophosphate. Pyruvate dehydrogenase is us ...
, 2-oxoglutarate dehydrogenase, and
transketolase Transketolase (abbreviated as TK) is an enzyme that is encoded by the TKT gene. It participates in both the pentose phosphate pathway in all organisms and the Calvin cycle of photosynthesis. Transketolase catalyzes two important reactions, which ...
which are all involved in carbohydrate metabolism.
Vitamin B2 Riboflavin, also known as vitamin B2, is a vitamin found in food and sold as a dietary supplement. It is essential to the formation of two major coenzymes, flavin mononucleotide and flavin adenine dinucleotide. These coenzymes are involved in e ...
(riboflavin) is a constituent of FMN and
FAD A fad or trend is any form of collective behavior that develops within a culture, a generation or social group in which a group of people enthusiastically follow an impulse for a short period. Fads are objects or behaviors that achieve short- ...
which are necessary for many redox reactions.
Vitamin B3 Vitamin B3, colloquially referred to as niacin, is a vitamin family that includes three forms or vitamers: niacin (nicotinic acid), nicotinamide (niacinamide), and nicotinamide riboside. All three forms of vitamin B3 are converted within the bo ...
(nicotinic acid or niacin), synthesized from tryptophan is a component of the coenzymes NAD and
NADP Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require NAD ...
which in turn are required for electron transport in the
Krebs cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and protein ...
,
oxidative phosphorylation Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine tri ...
, as well as many other redox reactions.
Vitamin B5 Pantothenic acid, also called vitamin B5 is a water-soluble B vitamin and therefore an essential nutrient. All animals require pantothenic acid in order to synthesize coenzyme A (CoA) – essential for fatty acid metabolism – as well as to, i ...
(pantothenic acid) is a constituent of
coenzyme A Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All genomes sequenced to date encode enzymes that use coenzyme A as a subs ...
, a basic component of carbohydrate and amino acid metabolism as well as the biosynthesis of fatty acids and polyketides.
Vitamin B6 Vitamin B6 is one of the B vitamins, and thus an essential nutrient. The term refers to a group of six chemically similar compounds, i.e., "vitamers", which can be interconverted in biological systems. Its active form, pyridoxal 5′-phosphat ...
(pyridoxol, pyridoxal, and pyridoxamine) as pyridoxal 5′-phosphate is a cofactor for many enzymes especially transaminases involve in amino acid metabolism.
Vitamin B12 Vitamin B12, also known as cobalamin, is a water-soluble vitamin involved in metabolism. It is one of eight B vitamins. It is required by animals, which use it as a cofactor in DNA synthesis, in both fatty acid and amino acid metabolism. It ...
(cobalamins) contain a
corrin Corrin is a heterocyclic compound. It is the parent macrocycle related to the substituted derivative that is found in vitamin B12. Its name reflects that it is the "core" of vitamin B12 (cobalamins).Nelson, D. L.; Cox, M. M. "Lehninger, Princ ...
ring similar in structure to
porphyrin Porphyrins ( ) are a group of heterocyclic macrocycle organic compounds, composed of four modified pyrrole subunits interconnected at their α carbon atoms via methine bridges (=CH−). The parent of porphyrin is porphine, a rare chemical com ...
and is an essential coenzyme for the catabolism of fatty acids as well for the biosynthesis of
methionine Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine plays a critical ro ...
. DNA and
RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
which store and transmit
genetic information A nucleic acid sequence is a succession of bases signified by a series of a set of five different letters that indicate the order of nucleotides forming alleles within a DNA (using GACT) or RNA (GACU) molecule. By convention, sequences are usua ...
are composed of nucleic acid primary metabolites. First messengers are signaling molecules that control
metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
or
cellular differentiation Cellular differentiation is the process in which a stem cell alters from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellular ...
. These signaling molecules include hormones and growth factors in turn are composed of peptides,
biogenic amine A biogenic amine is a biogenic substance with one or more amine groups. They are basic nitrogenous compounds formed mainly by decarboxylation of amino acids or by amination and transamination of aldehydes and ketones. Biogenic amines are organic ...
s,
steroid hormone A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be grouped into two classes: corticosteroids (typically made in the adrenal cortex, hence ''cortico-'') and sex steroids (typically made in the gonads or placenta). Wi ...
s,
auxin Auxins (plural of auxin ) are a class of plant hormones (or plant-growth regulators) with some morphogen-like characteristics. Auxins play a cardinal role in coordination of many growth and behavioral processes in plant life cycles and are essenti ...
s,
gibberellin Gibberellins (GAs) are plant hormones that regulate various developmental processes, including stem elongation, germination, dormancy, flowering, flower development, and leaf and fruit senescence. GAs are one of the longest-known classes of p ...
s etc. These first messengers interact with cellular receptors which are composed of proteins. Cellular receptors in turn activate
second messengers Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form or cell signaling, encompassing both first me ...
are used to relay the extracellular message to intracellular targets. These signaling molecules include the primary metabolites
cyclic nucleotide A cyclic nucleotide (cNMP) is a single-phosphate nucleotide with a cyclic bond arrangement between the sugar and phosphate groups. Like other nucleotides, cyclic nucleotides are composed of three functional groups: a sugar, a nitrogenous base, a ...
s,
diacyl glycerol A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols. DAGs can act as sur ...
etc.


Secondary metabolites

Secondary in contrast to primary metabolites are dispensable and not absolutely required for survival. Furthermore, secondary metabolites typically have a narrow species distribution. Secondary metabolites have a broad range of functions. These include
pheromone A pheromone () is a secreted or excreted chemical factor that triggers a social response in members of the same species. Pheromones are chemicals capable of acting like hormones outside the body of the secreting individual, to affect the behavio ...
s that act as social signaling molecules with other individuals of the same species, communication molecules that attract and activate
symbiotic Symbiosis (from Greek , , "living together", from , , "together", and , bíōsis, "living") is any type of a close and long-term biological interaction between two different biological organisms, be it mutualistic, commensalistic, or parasit ...
organisms, agents that solubilize and transport nutrients (
siderophores Siderophores (Greek: "iron carrier") are small, high-affinity iron-chelating compounds that are secreted by microorganisms such as bacteria and fungi. They help the organism accumulate iron. Although a widening range of siderophore functions is no ...
etc.), and competitive weapons ( repellants,
venoms Venom or zootoxin is a type of toxin produced by an animal that is actively delivered through a wound by means of a bite, sting, or similar action. The toxin is delivered through a specially evolved ''venom apparatus'', such as fangs or a sti ...
,
toxins A toxin is a naturally occurring organic poison produced by metabolic activities of living cells or organisms. Toxins occur especially as a protein or conjugated protein. The term toxin was first used by organic chemist Ludwig Brieger (1849–1 ...
etc.) that are used against competitors, prey, and predators. For many other secondary metabolites, the function is unknown. One hypothesis is that they confer a competitive advantage to the organism that produces them. An alternative view is that, in analogy to the
immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
, these secondary metabolites have no specific function, but having the machinery in place to produce these diverse chemical structures is important and a few secondary metabolites are therefore produced and selected for. General structural classes of secondary metabolites include
alkaloid Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar ...
s,
phenylpropanoid The phenylpropanoids are a diverse family of organic compounds that are synthesized by plants from the amino acids phenylalanine and tyrosine. Their name is derived from the six-carbon, aromatic phenyl group and the three-carbon propene tail of ...
s,
polyketide Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...
s, and
terpenoid The terpenoids, also known as isoprenoids, are a class of naturally occurring organic chemicals derived from the 5-carbon compound isoprene and its derivatives called terpenes, diterpenes, etc. While sometimes used interchangeably with "terpenes" ...
s.


Biosynthesis

The biosynthetic pathways leading to the major classes of natural products are described below. *
Photosynthesis Photosynthesis is a process used by plants and other organisms to convert light energy into chemical energy that, through cellular respiration, can later be released to fuel the organism's activities. Some of this chemical energy is stored i ...
or
gluconeogenesis Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrat ...
monosaccharide Monosaccharides (from Greek ''monos'': single, '' sacchar'': sugar), also called simple sugars, are the simplest forms of sugar and the most basic units (monomers) from which all carbohydrates are built. They are usually colorless, water-solub ...
s →
polysaccharide Polysaccharides (), or polycarbohydrates, are the most abundant carbohydrates found in food. They are long chain polymeric carbohydrates composed of monosaccharide units bound together by glycosidic linkages. This carbohydrate can react with wa ...
s (
cellulose Cellulose is an organic compound with the formula , a polysaccharide consisting of a linear chain of several hundred to many thousands of β(1→4) linked D-glucose units. Cellulose is an important structural component of the primary cell wall ...
,
chitin Chitin ( C8 H13 O5 N)n ( ) is a long-chain polymer of ''N''-acetylglucosamine, an amide derivative of glucose. Chitin is probably the second most abundant polysaccharide in nature (behind only cellulose); an estimated 1 billion tons of chit ...
,
glycogen Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. The polysaccharide structure represents the main storage form of glucose in the body. Glycogen functions as one o ...
etc.) * Acetate pathway →
fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, fr ...
s and
polyketide Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...
s *
Shikimate pathway The shikimate pathway (shikimic acid pathway) is a seven-step metabolic pathway used by bacteria, archaea, fungi, algae, some protozoans, and plants for the biosynthesis of folates and aromatic amino acids (tryptophan, phenylalanine, and tyrosine) ...
→ aromatic amino acids and
phenylpropanoid The phenylpropanoids are a diverse family of organic compounds that are synthesized by plants from the amino acids phenylalanine and tyrosine. Their name is derived from the six-carbon, aromatic phenyl group and the three-carbon propene tail of ...
s *
Mevalonate pathway The mevalonate pathway, also known as the isoprenoid pathway or HMG-CoA reductase pathway is an essential metabolic pathway present in eukaryotes, archaea, and some bacteria. The pathway produces two five-carbon building blocks called isopentenyl ...
and methyletrythritol phosphate pathway
terpenoid The terpenoids, also known as isoprenoids, are a class of naturally occurring organic chemicals derived from the 5-carbon compound isoprene and its derivatives called terpenes, diterpenes, etc. While sometimes used interchangeably with "terpenes" ...
s and
steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...
s * Amino acids →
alkaloid Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar ...
s


Carbohydrates

Carbohydrate In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may or ma ...
s are an essential energy source for most life forms. In addition,
polysaccharide Polysaccharides (), or polycarbohydrates, are the most abundant carbohydrates found in food. They are long chain polymeric carbohydrates composed of monosaccharide units bound together by glycosidic linkages. This carbohydrate can react with wa ...
s formed from simpler carbohydrates are important structural components of many organisms such the
cell wall A cell wall is a structural layer surrounding some types of cells, just outside the cell membrane. It can be tough, flexible, and sometimes rigid. It provides the cell with both structural support and protection, and also acts as a filtering mech ...
s of bacteria and plants. Carbohydrate are the products of plant
photosynthesis Photosynthesis is a process used by plants and other organisms to convert light energy into chemical energy that, through cellular respiration, can later be released to fuel the organism's activities. Some of this chemical energy is stored i ...
and animal
gluconeogenesis Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrat ...
. Photosynthesis produces initially 3-phosphoglyceraldehyde, a three carbon atom containing sugar (a
triose A triose is a monosaccharide, or simple sugar, containing three carbon atoms. There are only three possible trioses (including dihydroxyacetone): L-glyceraldehyde and D-glyceraldehyde, the two enantiomers of glyceraldehyde, which are aldotriose ...
). This triose in turn may be converted into
glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...
(a six carbon atom containing sugar) or a variety of
pentose In chemistry, a pentose is a monosaccharide (simple sugar) with five carbon atoms. The chemical formula of many pentoses is , and their molecular weight is 150.13 g/mol.Calvin cycle The Calvin cycle, light-independent reactions, bio synthetic phase, dark reactions, or photosynthetic carbon reduction (PCR) cycle of photosynthesis is a series of chemical reactions that convert carbon dioxide and hydrogen-carrier compounds into ...
. In animals, the three carbon precursors lactate or
glycerol Glycerol (), also called glycerine in British English and glycerin in American English, is a simple triol compound. It is a colorless, odorless, viscous liquid that is sweet-tasting and non-toxic. The glycerol backbone is found in lipids known ...
can be converted into
pyruvate Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell. Pyruvic aci ...
which in turn can be converted into carbohydrates in the liver.


Fatty acids and polyketides

Through the process of
glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...
sugars are broken down into
acetyl-CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized for ...
. In an ATP dependent enzymatically catalyzed reaction, acetyl-CoA is carboxylated to form
malonyl-CoA Malonyl-CoA is a coenzyme A derivative of malonic acid. Functions It plays a key role in chain elongation in fatty acid biosynthesis and polyketide biosynthesis. Fatty acid biosynthesis Malonyl-CoA provides 2-carbon units to fatty acids and commi ...
. Acetyl-CoA and malonyl-CoA undergo a
Claisen condensation The Claisen condensation is a carbon–carbon bond forming reaction that occurs between two esters or one ester and another carbonyl compound in the presence of a strong base, resulting in a β-keto ester or a β-diketone. It is named after Raine ...
with lose of carbon dioxide to form
acetoacetyl-CoA Acetoacetyl CoA is the precursor of HMG-CoA in the mevalonate pathway, which is essential for cholesterol biosynthesis. It also takes a similar role in the ketone bodies synthesis (ketogenesis) pathway of the liver. In the ketone bodies digestion ...
. Additional condensation reactions produce successively higher molecular weight poly-β-keto chains which are then converted into other
polyketide Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...
s. The polyketide class of natural products have diverse structures and functions and include
prostaglandin The prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are derive ...
s and
macrolide antibiotic The Macrolides are a class of natural products that consist of a large macrocycle, macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-memb ...
s. One molecule of acetyl-CoA (the "starter unit") and several molecules malonyl-CoA (the "extender units") are condensed by
fatty acid synthase Fatty acid synthase (FAS) is an enzyme that in humans is encoded by the ''FASN'' gene. Fatty acid synthase is a multi-enzyme protein that catalyzes fatty acid synthesis. It is not a single enzyme but a whole enzymatic system composed of two iden ...
to produce
fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, fr ...
s. Fatty acid are essential components of lipid bilayers that form cell membranes as well as fat energy stores in animals.


Sources

Natural products may be extracted from the
cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...
s, tissues, and
secretion 440px Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classical ...
s of
microorganism A microorganism, or microbe,, ''mikros'', "small") and ''organism'' from the el, ὀργανισμός, ''organismós'', "organism"). It is usually written as a single word but is sometimes hyphenated (''micro-organism''), especially in olde ...
s, plants and animals. A crude ( unfractionated) extract from any one of these sources will contain a range of structurally diverse and often novel chemical compounds. Chemical diversity in nature is based on biological diversity, so researchers collect samples from around the world to analyze and evaluate in drug discovery screens or
bioassays An assay is an investigative (analytic) procedure in laboratory medicine, mining, pharmacology, environmental biology and molecular biology for qualitatively assessing or quantitatively measuring the presence, amount, or functional activity of a ...
. This effort to search for biologically active natural products is known as
bioprospecting Bioprospecting (also known as biodiversity prospecting) is the exploration of natural sources for small molecules, macromolecules and biochemical and genetic information that could be developed into commercialization, commercially valuable prod ...
.
Pharmacognosy Pharmacognosy is the study of medicinal plants and other natural substances as sources of drugs. The American Society of Pharmacognosy defines pharmacognosy as "the study of the physical, chemical, biochemical, and biological properties of drug ...
provides the tools to detect, isolate and identify bioactive natural products that could be developed for medicinal use. When an "active principle" is isolated from a traditional medicine or other biological material, this is known as a "hit". Subsequent scientific and legal work is then performed to validate the hit (eg. elucidation of
mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targe ...
, confirmation that there is no intellectual property conflict). This is followed by the
hit to lead Hit to lead (H2L) also known as lead generation is a stage in early drug discovery where small molecule hits from a high-throughput screening, high throughput screen (HTS) are evaluated and undergo limited optimization to identify promising lead co ...
stage of drug discovery, where derivatives of the active compound are produced in an attempt to improve its
potency Potency may refer to: * Potency (pharmacology), a measure of the activity of a drug in a biological system * Virility * Cell potency, a measure of the differentiation potential of stem cells * In homeopathic dilutions, potency is a measure of how ...
and
safety Safety is the state of being "safe", the condition of being protected from harm or other danger. Safety can also refer to risk management, the control of recognized hazards in order to achieve an acceptable level of risk. Meanings There are ...
. In this and related ways, modern medicines can be developed directly from natural sources. Although traditional medicines and other biological material are considered an excellent source of novel compounds, the extraction and isolation of these compounds can be a slow, expensive and inefficient process. For large scale manufacture therefore, attempts may be made to produce the new compound by total synthesis or semisynthesis. Because natural products are generally
secondary metabolite Secondary metabolites, also called specialised metabolites, toxins, secondary products, or natural products, are organic compounds produced by any lifeform, e.g. bacteria, fungi, animals, or plants, which are not directly involved in the norm ...
s with complex
chemical structure A chemical structure determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target molecule or other solid. Molecular geometry refers to the spatial arrangement of at ...
s, their total/semisynthesis is not always commercially viable. In these cases, efforts can be made to design simpler analogues with comparable potency and safety that are amenable to total/semisynthesis.


Prokaryotic


Bacteria

The serendipitous discovery and subsequent clinical success of
penicillin Penicillins (P, PCN or PEN) are a group of β-lactam antibiotics originally obtained from ''Penicillium'' moulds, principally '' P. chrysogenum'' and '' P. rubens''. Most penicillins in clinical use are synthesised by P. chrysogenum using ...
prompted a large-scale search for other environmental
microorganisms A microorganism, or microbe,, ''mikros'', "small") and ''organism'' from the el, ὀργανισμός, ''organismós'', "organism"). It is usually written as a single word but is sometimes hyphenated (''micro-organism''), especially in olde ...
that might produce anti-infective natural products. Soil and water samples were collected from all over the world, leading to the discovery of
streptomycin Streptomycin is an antibiotic medication used to treat a number of bacterial infections, including tuberculosis, ''Mycobacterium avium'' complex, endocarditis, brucellosis, ''Burkholderia'' infection, plague, tularemia, and rat bite fever. Fo ...
(derived from ''
Streptomyces griseus ''Streptomyces griseus'' is a species of bacteria in the genus ''Streptomyces'' commonly found in soil. A few strains have been also reported from deep-sea sediments. It is a Gram-positive bacterium with high GC content. Along with most other s ...
''), and the realization that bacteria, not just fungi, represent an important source of pharmacologically active natural products. This, in turn, led to the development of an impressive arsenal of antibacterial and antifungal agents including
amphotericin B Amphotericin B is an antifungal medication used for serious fungal infections and leishmaniasis. The fungal infections it is used to treat include mucormycosis, aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, and cryptococcosis. Fo ...
,
chloramphenicol Chloramphenicol is an antibiotic useful for the treatment of a number of bacterial infections. This includes use as an eye ointment to treat conjunctivitis. By mouth or by injection into a vein, it is used to treat meningitis, plague, cholera, a ...
,
daptomycin Daptomycin, sold under the brand name Cubicin among others, is a lipopeptide antibiotic used in the treatment of systemic and life-threatening infections caused by Gram-positive organisms. Daptomycin was removed from the World Health Organiza ...
and
tetracycline Tetracycline, sold under various brand names, is an oral antibiotic in the tetracyclines family of medications, used to treat a number of infections, including Acne vulgaris, acne, cholera, brucellosis, plague (disease), plague, malaria, and sy ...
(from ''
Streptomyces ''Streptomyces'' is the largest genus of Actinomycetota and the type genus of the family Streptomycetaceae. Over 500 species of ''Streptomyces'' bacteria have been described. As with the other Actinomycetota, streptomycetes are gram-positive, ...
''
spp. In biology, a species is the basic unit of classification and a taxonomic rank of an organism, as well as a unit of biodiversity. A species is often defined as the largest group of organisms in which any two individuals of the appropriate se ...
), the
polymyxin Polymyxins are antibiotics. Polymyxins B and E (also known as colistin) are used in the treatment of Gram-negative bacterial infections. They work mostly by breaking up the bacterial cell membrane. They are part of a broader class of molecules ...
s (from ''
Paenibacillus polymyxa ''Paenibacillus polymyxa'', also known as ''Bacillus polymyxa'', is a Gram-positive bacterium capable of fixing nitrogen. It is found in soil, plant tissues, marine sediments and hot springs. It may have a role in forest ecosystems and potential ...
''), and the rifamycins (from ''
Amycolatopsis rifamycinica ''Amycolatopsis rifamycinica'' is a species of Gram-positive bacteria in the genus ''Amycolatopsis''. It produces the rifamycin antibiotics (''e.g.'', rifamycin SV), which are used to treat mycobacterial diseases such as tuberculosis and leprosy ...
''). Antiparasitic and antiviral drugs have similarly been derived from bacterial metabolites. Although most of the drugs derived from bacteria are employed as anti-infectives, some have found use in other fields of medicine.
Botulinum toxin Botulinum toxin, or botulinum neurotoxin (BoNT), is a neurotoxic protein produced by the bacterium ''Clostridium botulinum'' and related species. It prevents the release of the neurotransmitter acetylcholine from axon endings at the neuromusc ...
(from ''
Clostridium botulinum ''Clostridium botulinum'' is a Gram-positive, rod-shaped, anaerobic, spore-forming, motile bacterium with the ability to produce the neurotoxin botulinum. The botulinum toxin can cause botulism, a severe flaccid paralytic disease in humans an ...
'') and
bleomycin -13- (1''H''-imidazol-5-yl)methyl9-hydroxy-5- 1''R'')-1-hydroxyethyl8,10-dimethyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazapentadec-1-yl}-2,4'-bi-1,3-thiazol-4-yl)carbonyl]amino}propyl)(dimethyl)sulfonium , chemical_formula = , C=55 , H=84 , N=1 ...
(from ''
Streptomyces verticillus ''Streptomyces verticillus'' is a species of Gram-positive bacteria in the genus ''Streptomyces''. Whilst screening fermentation broths of this species for bioactivity in the early 1960s, Hamao Umezawa and colleagues at the Institute of Microbi ...
'') are two examples. Botulinum, the neurotoxin responsible for botulism, can be injected into specific muscles (such as those controlling the eyelid) to prevent muscle spasm. Also, the glycopeptide bleomycin is used for the treatment of several cancers including Hodgkin's lymphoma, head and neck cancer, and testicular cancer. Newer trends in the field include the metabolic profiling and isolation of natural products from novel bacterial species present in underexplored environments. Examples include symbionts or endophytes from tropical environments, subterranean bacteria found deep underground via mining/drilling, and Marine (ocean), marine bacteria.


Archaea

Because many Archaea have adapted to life in extreme environments such as polar regions, hot springs, acidic springs, alkaline springs, salt lakes, and the high pressure of deep ocean water, they possess enzymes that are functional under quite unusual conditions. These enzymes are of potential use in the food industry, food, chemical industry, chemical, and pharmaceutical industry, pharmaceutical industries, where biotechnological processes frequently involve high temperatures, extremes of pH, high salt concentrations, and / or high pressure. Examples of enzymes identified to date include amylases, pullulanases, cyclodextrin glycosyltransferases, cellulases, xylanases, chitinases, proteases, alcohol dehydrogenase, and esterases. Archaea represent a source of novel chemical compounds also, for example isoprenyl glycerol ethers 1 and 2 from ''Thermococcus'' S557 and ''Methanocaldococcus jannaschii'', respectively.


Eukaryotic


Fungi

Several anti-infective medications have been derived from fungi including
penicillin Penicillins (P, PCN or PEN) are a group of β-lactam antibiotics originally obtained from ''Penicillium'' moulds, principally '' P. chrysogenum'' and '' P. rubens''. Most penicillins in clinical use are synthesised by P. chrysogenum using ...
and the cephalosporins (antibacterial drugs from ''Penicillium rubens'' and ''Cephalosporium acremonium'', respectively) and griseofulvin (an antifungal drug from ''Penicillium griseofulvum''). Other medicinally useful fungal metabolites include lovastatin (from ''Pleurotus ostreatus''), which became a lead for a series of drugs that lower cholesterol levels, cyclosporin (from ''Tolypocladium inflatum''), which is used to suppress the immune response after organ transplant operations, and ergometrine (from ''Claviceps'' spp.), which acts as a Vasoconstriction, vasoconstrictor, and is used to prevent bleeding after childbirth. Asperlicin (from ''Aspergillus alliaceus'') is another example. Asperlicin is a novel antagonist of cholecystokinin, a neurotransmitter thought to be involved in panic attacks, and could potentially be used to treat anxiety.


Plants

Plants are a major source of complex and highly structurally diverse chemical compounds (phytochemicals), this structural diversity attributed in part to the natural selection of organisms producing wikt:potent, potent compounds to deter herbivore, herbivory (Plant defense against herbivory#Types, feeding deterrents). Major classes of phytochemical include natural phenol, phenols, polyphenols, tannins, terpenes, and
alkaloid Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar ...
s. Though the number of plants that have been extensively studied is relatively small, many pharmacologically active natural products have already been identified. Clinically useful examples include the anticancer agents paclitaxel and omacetaxine mepesuccinate (from ''Taxus brevifolia'' and ''Cephalotaxus harringtonii'', respectively), the antimalarial agent artemisinin (from ''Artemisia annua''), and the acetylcholinesterase inhibitor galantamine (from ''Galanthus'' spp.), used to treat Alzheimer's disease. Other plant-derived drugs, used medicinally and/or Recreational drug use, recreationally include morphine, cocaine, quinine, tubocurarine, muscarine, and nicotine.


Animals

Animals also represent a source of bioactive natural products. In particular, venomous animals such as snakes, spiders, scorpions, caterpillars, bees, wasps, centipedes, ants, toads, and frogs have attracted much attention. This is because venom constituents (peptides, enzymes, nucleotides, lipids, biogenic amines etc.) often have very specific interactions with a macromolecular target in the body (e.g. α-bungarotoxin from cobras). As with plant feeding deterrents, this biological activity is attributed to natural selection, organisms capable of killing or paralyzing their prey and/or defending themselves against predators being more likely to survive and reproduce. Because of these specific chemical-target interactions, venom constituents have proved important tools for studying Receptor (biochemistry), receptors, ion channels, and
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
s. In some cases, they have also served as leads in the development of novel drugs. For example, teprotide, a peptide isolated from the venom of the Brazilian pit viper ''Bothrops jararaca'', was a lead in the development of the antihypertensive agents cilazapril and captopril. Also, echistatin, a disintegrin from the venom of the saw-scaled viper ''Echis carinatus'' was a lead in the development of the antiplatelet drug tirofiban. In addition to the terrestrial animals and amphibians described above, many Marine (ocean), marine animals have been examined for pharmacologically active natural products, with corals, sea sponge, sponges, tunicates, sea snails, and bryozoans yielding chemicals with interesting analgesic, Antiviral drug, antiviral, and anticancer activities. Two examples developed for clinical use include ω-conotoxin (from the marine snail ''Conus magus'') and trabectedin, ecteinascidin 743 (from the tunicate ''Ecteinascidia turbinata''). The former, ω-conotoxin, is used to relieve severe and chronic pain, while the latter, ecteinascidin 743 is used to treat metastasis, metastatic soft tissue sarcoma. Other natural products derived from marine animals and under investigation as possible therapies include the antitumour agents discodermolide (from the sponge ''Discodermia dissoluta''), eleutherobin (from the coral ''Erythropodium caribaeorum''), and the bryostatins (from the bryozoan ''Bugula neritina'').


Medical uses

Natural products sometimes have pharmacological activity that can be of therapeutic benefit in treating diseases. Moreover, synthetic analogs of natural products with improved potency and safety can be prepared and therefore natural products are often used as starting points for
drug discovery In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered. Historically, drugs were discovered by identifying the active ingredient from traditional remedies or by ...
. Natural product constituents have inspired numerous drug discovery efforts that eventually gained approval as new drugs


Traditional medicine

Indigenous peoples and ancient civilizations experimented with various plant and animal parts to determine what effect they might have. Through trial and error in isolated cases, traditional healers or shamans found some sources to provide therapeutic effect, representing knowledge of a crude drug that was passed down through generations in such practices as traditional Chinese medicine and Ayurveda. Extracts of some natural products led to modern discovery of their active constituents and eventually to the development of new drugs.


Modern natural product-derived drugs

A large number of currently prescribed drugs have been either directly derived from or inspired by natural products. Some of the oldest natural product based drugs are analgesics. The bark of the willow tree has been known from antiquity to have pain relieving properties. This is due to presence of the natural product salicin which in turn may be hydrolyzed into salicylic acid. A synthetic derivative acetylsalicylic acid better known as aspirin is a widely used pain reliever. Its mechanism of action is inhibition of the cyclooxygenase (COX) enzyme. Another notable example is opium is extracted from the latex from ''Papaver somniferous'' (a flowering poppy plant). The most potent narcotic component of opium is the alkaloid morphine which acts as an opioid receptor agonist. A more recent example is the N-type calcium channel blocker ziconotide analgesic which is based on a cyclic peptide cone snail toxin (ω-conotoxin MVIIA) from the species ''Conus magus''. A significant number of Infection#Treatments, anti-infectives are based on natural products. The first antibiotic to be discovered,
penicillin Penicillins (P, PCN or PEN) are a group of β-lactam antibiotics originally obtained from ''Penicillium'' moulds, principally '' P. chrysogenum'' and '' P. rubens''. Most penicillins in clinical use are synthesised by P. chrysogenum using ...
, was isolated from the mold ''Penicillium''. Penicillin and related beta lactams work by inhibiting DD-transpeptidase enzyme that is required by bacteria to cross link
peptidoglycan Peptidoglycan or murein is a unique large macromolecule, a polysaccharide, consisting of sugars and amino acids that forms a mesh-like peptidoglycan layer outside the plasma membrane, the rigid cell wall (murein sacculus) characteristic of most ...
to form the cell wall. Several natural product drugs target tubulin, which is a component of the
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...
. These include the tubulin polymerization inhibitor colchicine isolated from the ''Colchicum autumnale'' (autumn crocus flowering plant), which is used to treat gout. Colchicine is biosynthesized from the amino acids phenylalanine and tryptophan. Paclitaxel, in contrast, is a tubulin polymerization stabilizer and is used as a chemotherapeutic drug. Paclitaxel is based on the terpenoid natural product taxol, which is isolated from ''Taxus brevifolia'' (the pacific yew tree). A class of drugs widely used to lower cholesterol are the HMG-CoA reductase inhibitors, for example atorvastatin. These were developed from mevastatin, a polyketide produced by the fungus ''Penicillium citrinum''. Finally, a number natural product drugs are used to treat hypertension and congestive heart failure. These include the angiotensin-converting enzyme inhibitor captopril. Captopril is based on the peptidic bradykinin potentiating factor isolated from venom of the Brazilian arrowhead viper (''Bothrops jararaca'').


Limiting and enabling factors

Numerous challenges limit the use of natural products for drug discovery, resulting in 21st century preference by pharmaceutical companies to dedicate discovery efforts toward high-throughput screening of pure synthetic compounds with shorter timelines to refinement. Natural product sources are often unreliable to access and supply, have a high probability of duplication, inherently create intellectual property concerns about patent protection, vary in composition due to sourcing season or environment, and are susceptible to rising
extinction Extinction is the termination of a kind of organism or of a group of kinds (taxon), usually a species. The moment of extinction is generally considered to be the death of the last individual of the species, although the capacity to breed and ...
rates. The biological resource for drug discovery from natural products remains abundant, with small percentages of microorganisms, plant species, and insects assessed for bioactivity. In enormous numbers, bacteria and marine microorganisms remain unexamined. As of 2008, the field of metagenomics was proposed to examine genes and their function in soil microbes, but most pharmaceutical firms have not exploited this resource fully, choosing instead to develop "diversity-oriented synthesis" from libraries of known drugs or natural sources for lead compounds with higher potential for bioactivity.


Isolation and purification

All natural products begin as mixtures with other compounds from the natural source, often very complex mixtures, from which the product of interest must be isolated and purified. The ''isolation'' of a natural product refers, depending on context, either to the isolation of sufficient quantities of pure chemical matter for chemical structure elucidation, derivitzation/degradation chemistry, biological testing, and other research needs (generally milligrams to grams, but historically, often more), or to the isolation of "analytical quantities" of the substance of interest, where the focus is on identification and quantitation of the substance (e.g. in biological tissue or fluid), and where the quantity isolated depends on the analytical method applied (but is generally always sub-microgram in scale). The ease with which the active agent can be isolated and List of purification methods in chemistry, purified depends on the structure, stability, and quantity of the natural product. The methods of isolation applied toward achieving these two distinct scales of product are likewise distinct, but generally involve extraction (chemistry), extraction, precipitation, adsorptions, chromatography, and sometimes crystallizations. In both cases, the isolated substance is purified to ''chemical homogeneity'', i.e. specific combined separation and analytical methods such as Liquid chromatography–mass spectrometry, LC-MS methods are chosen to be "orthogonal"—achieving their separations based on distinct modes of interaction between substance and isolating matrix—with the goal being repeated detection of only a single species present in the putative pure sample. Early isolation is almost inevitably followed by ''structure determination'', especially if an important pharmacologic activity is associated with the purified natural product. Structure determination refers to methods applied to determine the
chemical structure A chemical structure determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target molecule or other solid. Molecular geometry refers to the spatial arrangement of at ...
of an isolated, pure natural product, a process that involves an array of chemical and physical methods that have changed markedly over the history of natural products research; in earliest days, these focused on chemical transformation of unknown substances into known substances, and measurement of physical properties such as melting point and boiling point, and related methods for determining molecular weight. In the modern era, methods focus on mass spectrometry and NMR, nuclear magnetic resonance methods, often multidimensional, and, when feasible, small molecule crystallography. For instance, the
chemical structure A chemical structure determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target molecule or other solid. Molecular geometry refers to the spatial arrangement of at ...
of penicillin was determined by Dorothy Hodgkin, Dorothy Crowfoot Hodgkin in 1945, work for which she later received a Nobel Prize in Chemistry (1964).


Synthesis

Many natural products have very complex chemical structure, structures. The perceived complexity of a natural product is a qualitative matter, consisting of consideration of its molecular mass, the particular arrangements of substructures (functional groups, rings etc.) with respect to one another, the number and density of those functional groups, the stability of those groups and of the molecule as a whole, the number and type of chiral, stereochemical elements, the physical properties of the molecule and its intermediates (which bear on the ease of its handling and purification), all of these viewed in the context of the novelty of the structure and whether preceding related synthetic efforts have been successful (see below for details). Some natural products, especially those less complex, are easily and cost-effectively prepared via complete chemical synthesis from readily available, simpler chemical ingredients, a process referred to as
total synthesis Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially-available precursors. It usually refers to a process not involving the aid of biological processes, which distinguishes ...
(especially when the process involves no steps mediated by biological agents). Not all natural products are amenable to total synthesis, cost-effective or otherwise. In particular, those most complex often are not. Many are accessible, but the required routes are simply too expensive to allow synthesis on any practical or industrial scale. However, to be available for further study, all natural products must yield to isolation and purification. This may suffice if isolation provides appropriate quantities of the natural product for the intended purpose (e.g. as a drug to alleviate disease). Drugs such as
penicillin Penicillins (P, PCN or PEN) are a group of β-lactam antibiotics originally obtained from ''Penicillium'' moulds, principally '' P. chrysogenum'' and '' P. rubens''. Most penicillins in clinical use are synthesised by P. chrysogenum using ...
, morphine, and paclitaxel proved to be affordably acquired at needed commercial scales solely via isolation procedures (without any significant synthetic chemistry contributing). However, in other cases, needed agents are not available without synthetic chemistry manipulations.


Semisynthesis

The process of isolating a natural product from its source can be costly in terms of committed time and material expense, and it may challenge the availability of the relied upon natural resource (or have ecological consequences for the resource). For instance, it has been estimated that the bark (botany), bark of an entire Taxus brevifolia, yew tree (''Taxus brevifolia'') would have to be harvested to extract enough paclitaxel for just a single dose of therapy. Furthermore, the number of structural analogues obtainable for structure–activity relationship, structure–activity analysis (SAR) simply via harvest (if more than one structural analogue is even present) is limited by the biology at work in the organism, and so outside of the experimentalist's control. In such cases where the ultimate target is harder to come by, or limits SAR, it is sometimes possible to source a middle-to-late stage biosynthetic precursor or analogue from which the ultimate target can be prepared. This is termed
semisynthesis Semisynthesis, or partial chemical synthesis, is a type of chemical synthesis that uses chemical compounds isolated from natural sources (such as microbial cell cultures or plant material) as the starting materials to produce novel compounds with ...
or ''partial synthesis''. With this approach, the related biosynthetic intermediate is harvested and then converted to the final product by conventional procedures of
chemical synthesis As a topic of chemistry, chemical synthesis (or combination) is the artificial execution of chemical reactions to obtain one or several products. This occurs by physical and chemical manipulations usually involving one or more reactions. In moder ...
. This strategy can have two advantages. Firstly, the intermediate may be more easily extracted, and in higher yield, than the ultimate desired product. An example of this is paclitaxel, which can be manufactured by extracting 10-deacetylbaccatin III from ''T. brevifolia'' Needle (botany), needles, then carrying out a four-step synthesis. Secondly, the route designed between semisynthetic starting material and ultimate product may permit analogues of the final product to be synthesized. The newer generation semisynthetic penicillins are an illustration of the benefit of this approach.


Total synthesis

In general, the
total synthesis Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially-available precursors. It usually refers to a process not involving the aid of biological processes, which distinguishes ...
of natural products is a non-commercial research activity, aimed at deeper understanding of the synthesis of particular natural product frameworks, and the development of fundamental new synthetic methods. Even so, it is of tremendous commercial and societal importance. By providing challenging synthetic targets, for example, it has played a central role in the development of the field of
organic chemistry Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clayden, J.; ...
. Prior to the development of analytical chemistry methods in the twentieth century, the structures of natural products were affirmed by total synthesis (so-called "structure proof by synthesis"). Early efforts in total synthesis, natural products synthesis targeted complex substances such as Vitamin B12, cobalamin (vitamin B12), an essential cofactor (biochemistry), cofactor in cellular
metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
.


Symmetry

Examination of Dimer (chemistry), dimerized and Dimer (chemistry), trimerized natural products has shown that an element of bilateral symmetry is often present. Bilateral symmetry refers to a molecule or system that contains a C2, Cs, or C2v point group identity. C2 symmetry tends to be much more abundant than other types of bilateral symmetry. This finding sheds light on how these compounds might be mechanistically created, as well as providing insight into the thermodynamic properties that make these compounds more favorable. Density functional theory, Density functional theoretical (DFT), Hartree–Fock method, Hartree Fock, and Semi-empirical quantum chemistry method, semiempirical calculations also show some favorability for dimerization in natural products due to evolution of more energy per bond than the equivalent trimer or tetramer. This is proposed to be due to steric hindrance at the core of the molecule, as most natural products dimerize and trimerize in a head-to-head fashion rather than head-to-tail.


Research and teaching

Research and teaching activities related to natural products fall into a number of diverse academic areas, including
organic chemistry Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clayden, J.; ...
,
medicinal chemistry Medicinal or pharmaceutical chemistry is a scientific discipline at the intersection of chemistry and pharmacy involved with designing and developing pharmaceutical drugs. Medicinal chemistry involves the identification, synthesis and developm ...
,
pharmacognosy Pharmacognosy is the study of medicinal plants and other natural substances as sources of drugs. The American Society of Pharmacognosy defines pharmacognosy as "the study of the physical, chemical, biochemical, and biological properties of drug ...
, ethnobotany, traditional medicine, and ethnopharmacology. Other biological areas include chemical biology, chemical ecology, chemogenomics, systems biology, molecular modeling, chemometrics, and chemoinformatics.


Chemistry

Natural products chemistry is a distinct area of chemical research which was important in the development and history of chemistry. Isolating and identifying natural products has been important to source substances for early preclinical drug discovery research, to understand traditional medicine and ethnopharmacology, and to find pharmacologically useful areas of Drug discovery#Chemical diversity of natural products, chemical space. To achieve this, many technological advances have been made, such as the evolution of technology associated with Liquid chromatography–mass spectrometry, chemical separations, and the development of modern methods in chemical structure determination such as NMR. Early attempts to understand the biosynthesis of natural products, saw chemists employ first radiolabelling and more recently stable isotope labeling combined with NMR experiments. In addition, natural products are prepared by organic synthesis, to provide confirmation of their structure, or to give access to larger quantities of natural products of interest. In this process, the structure of some natural products have been revised, and the challenge of synthesising natural products has led to the development of new synthetic methodology, total synthesis, synthetic strategy, and tactics. In this regard, natural products play a central role in the training of new synthetic organic chemists, and are a principal motivation in the development of new variants of old chemical reactions (e.g., the Evans aldol reaction), as well as the discovery of completely new chemical reactions (e.g., the Woodward cis-hydroxylation, Sharpless epoxidation, and Suzuki reaction, Suzuki–Miyaura cross-coupling reactions).


History


Foundations of organic and natural product chemistry

The concept of natural products dates back to the early 19th century, when the foundations of
organic chemistry Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clayden, J.; ...
were laid. Organic chemistry was regarded at that time as the chemistry of substances that plants and animals are composed of. It was a relatively complex form of chemistry and stood in stark contrast to inorganic chemistry, the principles of which had been established in 1789 by the Frenchman Antoine Lavoisier in his work ''Traité Élémentaire de Chimie''.


Isolation

Lavoisier showed at the end of the 18th century that organic substances consisted of a limited number of elements: primarily carbon and hydrogen and supplemented by oxygen and nitrogen. He quickly focused on the isolation of these substances, often because they had an interesting pharmacological activity. Plants were the main source of such compounds, especially alkaloids and glycosides. It was long been known that opium, a sticky mixture of alkaloids (including codeine, morphine, noscapine, thebaine, and papaverine) from the opium poppy (Papaver somniferum), possessed a narcotic and at the same time mind-altering properties. By 1805, morphine had already been isolated by the German chemist Friedrich Sertürner and in the 1870s it was discovered that boiling morphine with acetic anhydride produced a substance with a strong pain suppressive effect: heroin. In 1815, Eugène Chevreul isolated cholesterol, a crystalline substance, from animal tissue that belongs to the class of steroids, and in 1819 strychnine, an alkaloid was isolated.


Synthesis

A second important step was the synthesis of organic compounds. Whereas the synthesis of inorganic substances had been known for a long time, the synthesis of organic substances was a difficult hurdle. In 1827 the Swedish chemist Jöns Jacob Berzelius held that an indispensable force of nature for the synthesis of organic compounds, called vital force or life force, was needed. This philosophical idea, vitalism, well into the 19th century had many supporters, even after the introduction of the atomic theory. The idea of vitalism especially fitted in with beliefs in medicine; the most traditional healing practices believed that disease was the result of some imbalance in the vital energies that distinguishes life from nonlife. A first attempt to break the vitalism idea in science was made in 1828, when the German chemist Friedrich Wöhler succeeded in synthesizing urea, a natural product found in urine, by heating ammonium cyanate, an inorganic substance: :\mathrm This reaction showed that there was no need for a life force in order to prepare organic substances. This idea, however, was initially met with a high degree of skepticism, and only 20 years later, with the synthesis of acetic acid from carbon by Adolph Wilhelm Hermann Kolbe, was the idea accepted. Organic chemistry has since developed into an independent area of research dedicated to the study of carbon-containing compounds, since that element in common was detected in a variety of nature-derived substances. An important factor in the characterization of organic materials was on the basis of their physical properties (such as melting point, boiling point, solubility, crystallinity, or color).


Structural theories

A third step was the structure elucidation of organic substances: although the elemental composition of pure organic substances (irrespective of whether they were of natural or synthetic origin) could be determined fairly accurately, the molecular structure was still a problem. The urge to do structural elucidation resulted from a dispute between Friedrich Wöhler and Justus von Liebig, who both studied a silver salt of the same composition but had different properties. Wöhler studied silver cyanate, a harmless substance, while von Liebig investigated silver fulminate, a salt with explosive properties. The elemental analysis shows that both salts contain equal quantities of silver, carbon, oxygen and nitrogen. According to the then prevailing ideas, both substances should possess the same properties, but this was not the case. This apparent contradiction was later solved by Berzelius's theory of isomers, whereby not only the number and type of elements are of importance to the properties and chemical reactivity, but also the position of atoms in within a compound. This was a direct cause for the development of structure theories, such as the radical theory of Jean-Baptiste Dumas and the substitution theory of Auguste Laurent. However, it took until 1858 before by August Kekulé formulated a definite structure theory. He posited that carbon is tetravalent and can bind to itself to form carbon chains as they occur in natural products.


Expanding the concept

The concept of natural product, which initially based on organic compounds that could be isolated from plants, was extended to include animal material in the middle of the 19th century by the German Justus von Liebig. Hermann Emil Fischer in 1884, turned his attention to the study of carbohydrates and purines, work for which he was awarded the Nobel Prize in 1902. He also succeeded to make synthetically in the laboratory in a variety of carbohydrates, including
glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...
and mannose. After the discovery of
penicillin Penicillins (P, PCN or PEN) are a group of β-lactam antibiotics originally obtained from ''Penicillium'' moulds, principally '' P. chrysogenum'' and '' P. rubens''. Most penicillins in clinical use are synthesised by P. chrysogenum using ...
by Alexander Fleming in 1928, fungi and other micro-organisms were added to the arsenal of sources of natural products.


Milestones

By the 1930s, several large classes of natural products were known. Important milestones included: * Terpenes, first systematically studied by Otto Wallach (Nobel Prize 1910) and later by Leopold Ružička (Nobel Prize 1939) * Dyes based on porphins (including chlorophyll and heme), studied by Richard Willstätter (Nobel Prize 1915) and Hans Fischer (Nobel Prize 1930) * Steroids, studied by Heinrich Otto Wieland (Nobel Prize 1927) and Adolf Windaus (Nobel Prize 1928) * Carotenoids, studied by Paul Karrer (Nobel Prize 1937) * Vitamins, studied among others by Paul Karrer, Adolf Windaus, Robert R. Williams, Norman Haworth (Nobel Prize 1937), Richard Kuhn (Nobel Prize 1938) and Albert Szent-Györgyi * Hormones studied by Adolf Butenandt (Nobel Prize 1939) and Edward Calvin Kendall (Nobel Prize 1950) * Alkaloids and anthocyanins, studied by, among others, Robert Robinson (organic chemist), Robert Robinson (Nobel Prize 1947)


See also

* Biogenic substance * Ethnobotany *
Pharmacognosy Pharmacognosy is the study of medicinal plants and other natural substances as sources of drugs. The American Society of Pharmacognosy defines pharmacognosy as "the study of the physical, chemical, biochemical, and biological properties of drug ...
* Phytotherapy * Secondary metabolite


Journals

* ''Chemistry of Natural Compounds'' * ''Journal of Natural Products'' * ''Natural Product Reports'' * ''Natural Product Research''


References


Further reading

* * * *


External links

* * * {{Authority control Natural products Chemistry Nature