A cofactor is a non-protein Proteins are organic compounds made of amino acids arranged in a linear chain and folded into a globular form. The amino acids in a polymer are joined together by the peptide bonds between the carboxyl and amino groups of adjacent amino acid residues. The sequence of amino acids in a protein is defined by the sequence of a gene, which is encoded chemical compound A chemical compound is a pure chemical substance consisting of two or more different chemical elements that can be separated into simpler substances by chemical reactions. Chemical compounds have a unique and defined chemical structure; they consist of a fixed ratio of atoms that are held together in a defined spatial arrangement by chemical bonds that is bound Molecular binding is an attractive interaction between two molecules which results in a stable association in which the molecules are in close proximity to each other. The result of molecular binding is formation of a molecular complex to a protein Proteins are organic compounds made of amino acids arranged in a linear chain and folded into a globular form. The amino acids in a polymer are joined together by the peptide bonds between the carboxyl and amino groups of adjacent amino acid residues. The sequence of amino acids in a protein is defined by the sequence of a gene, which is encoded and is required for the protein's biological activity. These proteins are commonly enzymes Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, called the products. Almost all processes in a biological cell need enzymes to occur at significant rates. Since enzymes are selective for their, and cofactors can be considered "helper molecules" that assist in biochemical transformations. Cofactors can also be classified depending on how tightly they bind to an enzyme, with loosely-bound cofactors termed coenzymes and tightly-bound cofactors termed prosthetic groups. Some sources also limit the use of the term "cofactor" to inorganic substances.^[1][2] An inactive enzyme, without the cofactor is called an apoenzyme Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, called the products. Almost all processes in a biological cell need enzymes to occur at significant rates. Since enzymes are selective for their, while the complete enzyme with cofactor is the holoenzyme.^[3]

Some enzymes or enzyme complexes require several cofactors, for example the multienzyme complex pyruvate dehydrogenase Pyruvate dehydrogenase is the first component enzyme of pyruvate dehydrogenase complex (PDC). The pyruvate dehydrogenase complex contributes to transforming pyruvate into acetyl-CoA by a process called pyruvate decarboxylation. Acetyl-CoA may then be used in the citric acid cycle to carry out cellular respiration, so pyruvate dehydrogenase.^[4] This enzyme complex at the junction of glycolysis Glycolysis is the metabolic pathway that converts glucose, C6H12O6, into pyruvate, CH3COCOO− + H+. The free energy released in this process is used to form the high energy compounds, ATP (adenosine triphosphate) and NADH (reduced nicotinamide adenine dinucleotide) and the citric acid cycle The citric acid cycle — also known as the tricarboxylic acid cycle , the Krebs cycle, or the Szent-Györgyi-Krebs cycle, — is a series of enzyme-catalysed chemical reactions, which is of central importance in all living cells that use oxygen as part of cellular respiration. In eukaryotic cells, the citric acid cycle occurs in the matrix of the requires five organic cofactors and one metal ion: loosely bound thiamine pyrophosphate Thiamine pyrophosphate , or thiamine diphosphate (ThDP), is a thiamine (vitamin B1) derivative which is produced by the enzyme thiamine pyrophosphatase. Thiamine pyrophosphate is a coenzyme that is present in all living systems, in which it catalyzes several biochemical reactions. It was first discovered as an essential nutrient (vitamin) in (TPP), covalently bound lipoamide Lipoamide is a trivial name for 6,8-dithiooctanoic amide. It is 6,8-dithiooctanoic acid's functional form where the carboxyl group is attached to protein by an amide linkage (containing -NH2) and flavin adenine dinucleotide In biochemistry, flavin adenine dinucleotide is a redox cofactor involved in several important reactions in metabolism. FAD can exist in two different redox states and its biochemical role usually involves changing between these two states. Many oxidoreductases, called flavoenzymes or flavoproteins, require FAD as a prosthetic group which (FAD), and the cosubstrates nicotinamide adenine dinucleotide Nicotinamide adenine dinucleotide, abbreviated NAD+, is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups, with one nucleotide containing an adenine base and the other containing nicotinamide (NAD⁺) and coenzyme A Coenzyme A 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 sequenced genomes encode enzymes that use coenzyme A as a substrate and around 4% of cellular enzymes use it (or a thioester, such as acetyl-CoA) as a substrate. It is adapted from cysteamine, (CoA) and a metal ion (Mg²⁺).

Organic cofactors are often vitamins A vitamin is an organic compound required as a nutrient in tiny amounts by an organism. In other words, an organic chemical compound is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on the circumstances and the particular organism. For or are made from vitamins. Many contain the nucleotide Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides play central roles in metabolism. In that capacity, they serve as sources of chemical energy , participate in cellular signaling (cyclic guanosine monophosphate and cyclic adenosine monophosphate), and are incorporated into adenosine monophosphate Adenosine monophosphate , also known as 5'-adenylic acid, is a nucleotide that is found in RNA. It is an ester of phosphoric acid and the nucleoside adenosine. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine (AMP) as part of their structures, such as ATP Adenosine-5'-triphosphate is a multifunctional nucleotide used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism. It is produced by photophosphorylation and cellular respiration and used by enzymes and structural, coenzyme A Coenzyme A 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 sequenced genomes encode enzymes that use coenzyme A as a substrate and around 4% of cellular enzymes use it (or a thioester, such as acetyl-CoA) as a substrate. It is adapted from cysteamine,, FAD A fad, sometimes called a trend, meme or a craze, is any form of behavior that develops among a large population and is collectively followed with enthusiasm for some period, generally as a result of the behavior's being perceived as novel in some way. A fad is said to "catch on" when the number of people adopting it begins to increase and NAD⁺. This common structure may reflect a common evolutionary origin as part of ribozymes A ribozyme is an RNA molecule possessing a well defined tertiary structure that enables it to catalyze a chemical reaction. Many natural ribozymes catalyze either the hydrolysis of one of their own phosphodiester bonds, or the hydrolysis of bonds in other RNAs, but they have also been found to catalyze the aminotransferase activity of the ribosome in an ancient RNA world The RNA world hypothesis proposes that a world filled with life based on ribonucleic acid predates the current world of life based on deoxyribonucleic acid (DNA). RNA, which can both store information like DNA and act as an enzyme, may have supported cellular or pre-cellular life. Some hypotheses as to the origin of life present RNA-based. It has been suggested that the AMP part of the molecule can be considered a kind a "handle" by which the enzyme can "grasp" the coenzyme to switch it between different catalytic centers.^[5]

Classification

Cofactors can be divided into two broad groups: organic cofactors, such as flavin or heme A heme or haem (British English) is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic group; these are known as hemoproteins. Hemes are, and inorganic cofactors: such as the metal ions Mg²⁺, Cu⁺, Mn²⁺ or iron-sulfur clusters Iron-sulfur proteins are proteins characterized by the presence of iron-sulfur clusters containing sulfide-linked di-, tri-, and tetrairon centers in variable oxidation states. Iron-sulfur clusters are found in a variety of metalloproteins, such as the ferredoxins, as well as NADH dehydrogenase, hydrogenases, Coenzyme Q - cytochrome c reductase,.

Organic cofactors are sometimes further divided into coenzymes and prosthetic groups. The term coenzyme refers specifically to enzymes and as such to the functional properties of a protein. On the other hand "prosthetic group", emphasizes the nature of the binding of a cofactor to a protein (tight or covalent) and thus refers to a structural property. Different sources give slightly different definitions of coenzymes, cofactors and prosthetic groups. Some consider tightly-bound organic molecules as prosthetic groups and not as coenzymes, while others define all non-protein organic molecules needed for enzyme activity as coenzymes, and classify those that are tightly bound as coenzyme prosthetic groups. Unsurprisingly, these terms are often used loosely.

A 1979 letter in Trends in Biochemical Sciences noted the confusion in the literature and the essentially arbitrary distinction made between prosthetic groups and coenzymes and proposed the following scheme. Here, cofactors were defined as an additional substance apart from protein and substrate In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or more products, which are then released from the that is required for enzyme activity and a prosthetic group as a substance that undergoes its whole catalytic cycle A catalytic cycle in chemistry is a term for a multistep reaction mechanism that involves a catalyst . The catalytic cycle is the main method for describing the role of catalysts in biochemistry, organometallic chemistry, materials science, etc. Often such cycles show the conversion of a precatalyst to the catalyst. Since catalysts are regenerated, attached to a single enzyme molecule. However, the author could not arrive at a single all-encompassing definition of a "coenzyme" and proposed that this term be dropped from use in the literature.^[6]

Inorganic

Metal ions

Metal A metal is a chemical element that is a good conductor of both electricity and heat and forms cations and ionic bonds with non-metals. In chemistry, a metal is an element, compound, or alloy characterized by high electrical conductivity. In a metal, atoms readily lose electrons to form positive ions (cations). Those ions are surrounded by ions An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. An anion , from the Greek word ἀνω (anο), meaning "up", is an ion with more electrons than protons, giving it a net negative charge (since electrons are negatively are common cofactors.^[7] The study of these cofactors falls under the area of bioinorganic chemistry Bioinorganic chemistry is a field that examines the role of metals in biology. Bioinorganic chemistry includes the study of both natural phenomena such as the behavior of metalloproteins as well artificially introduced metals, including those that are non-essential, in medicine and toxicology. Many biological processes such as respiration depend. In nutrition Nutrition is the provision, to cells and organisms, of the materials necessary (in the form of food) to support life. Many common health problems can be prevented or alleviated with a healthy diet, the list of essential trace elements In analytical chemistry, a trace element is an element in a sample that has an average concentration of less than 100 parts per million measured in atomic count, or less than 100 micrograms per gram reflects their role as cofactors. In humans this list commonly includes iron Iron is the most common element in the earth as a whole, and the fourth most common in the Earth's crust. It is produced as a result of stellar fusion in high-mass stars, and it is the heaviest stable element produced by stellar fusion because the fusion of iron is the last nuclear fusion reaction that is exothermic. Iron is the most widely used, manganese Manganese is a chemical element, designated by the symbol Mn. It has the atomic number 25. It is found as a free element in nature (often in combination with iron), and in many minerals. As a free element, manganese is a metal with important industrial metal alloy uses, particularly in stainless steels, cobalt Cobalt is a hard, lustrous, gray metal, a chemical element with symbol Co and atomic number 27. Cobalt-based colors and pigments have been used since ancient times for jewelry and paints, and miners have long used the name kobold ore for some minerals, copper Copper is a chemical element with the symbol Cu (Latin: cuprum) and atomic number 29. It is a ductile metal with very high thermal and electrical conductivity. Pure copper is rather soft and malleable, and a freshly exposed surface has a pinkish or peachy color. It is used as a thermal conductor, an electrical conductor, a building material, and a, zinc Zinc , also known as spelter, is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2. Zinc is the 24th most abundant element in the, selenium Selenium is a chemical element with the atomic number 34, represented by the chemical symbol Se, an atomic mass of 78.96. It is a nonmetal, chemically related to sulfur and tellurium, and rarely occurs in its elemental state in nature, and molybdenum Molybdenum , is a Group 6 chemical element with the symbol Mo and atomic number 42. The name is from Neo-Latin Molybdaenum, from Ancient Greek Μόλυβδος molybdos, meaning lead, since its ores were confused with lead ores. The free element, which is a silvery metal, has the sixth-highest melting point of any element. It readily forms hard,.^[8] Although chromium Chromium is a chemical element which has the symbol Cr and atomic number 24, first element in Group 6. It is a steely-gray, lustrous, hard metal that takes a high polish and has a high melting point. It is also odorless, tasteless, and malleable. The name of the element is derived from the Greek word "chrōma" (χρώμα), meaning color, deficiency causes impaired glucose tolerance Impaired glucose tolerance is a pre-diabetic state of dysglycemia, that is associated with insulin resistance and increased risk of cardiovascular pathology. IGT may precede type 2 diabetes mellitus by many years. IGT is also a risk factor for mortality, no human enzyme that uses this metal as a cofactor has been identified.^[9][10] Iodine Iodine , from Greek: ιώδης iodes, meaning violet or purple, is a chemical element that has the symbol I and the atomic number 53 is also an essential trace element, but this element is used as part of the structure of thyroid hormones The thyroid hormones, thyroxine and triiodothyronine (T3), are tyrosine-based hormones produced by the thyroid gland primarily responsible for regulation of metabolism. An important component in the synthesis of thyroid hormones is iodine. The major form of thyroid hormone in the blood is thyroxine (T4), which has a longer half life than T3. The rather than as an enzyme cofactor.^[11] Calcium Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth most abundant element by mass in the Earth's crust. Calcium is also the fifth most abundant dissolved ion in seawater by both molarity and mass, after sodium, chloride, is another special case, in that it is required as a component of the human diet, and it is needed for the full activity of many enzymes: such as nitric oxide synthase Nitric oxide synthases (NOSs) are a family of eukaryotic enzymes that catalyze the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule, having a vital role in many biological processes. NOSs can be dimeric, calmodulin-dependent or calmodulin-containing gascytochrome p450-like hemoprotein that combine, protein phosphatases A phosphatase is an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group . This action is directly opposite to that of phosphorylases and kinases, which attach phosphate groups to their substrates by using energetic molecules like ATP. A or adenylate kinase Adenylate kinase is a phosphotransferase enzyme that catalyzes the interconversion of adenine nucleotides, and plays an important role in cellular energy homeostasis (see the "Biological homeostasis" section of "Homeostasis"). The reaction catalyzed is:, but calcium activates these enzymes in allosteric regulation In biochemistry, allosteric regulation is the regulation of an enzyme or other protein by binding an effector molecule at the protein's allosteric site . Effectors that enhance the protein's activity are referred to as allosteric activators, whereas those that decrease the protein's activity are called allosteric inhibitors. The term allostery, often binding to these enzymes in a complex with calmodulin Calmodulin (an abbreviation for CALcium MODULated proteIN) is a calcium-binding protein expressed in all eukaryotic cells. It can bind to and regulate a number of different protein targets, thereby affecting many different cellular functions.^[12] Calcium is therefore a cell signaling Cell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue homeostasis. Errors in cellular information processing molecule, and not usually considered as a cofactor of the enzymes it regulates.^[13]

Other organisms require additional metals as enzyme cofactors, such as vanadium in the nitrogenase of the nitrogen-fixing bacteria of the genus Azotobacter,^[14] tungsten in the aldehyde ferredoxin oxidoreductase of the thermophilic archaean Pyrococcus furiosus,^[15] and even cadmium in the carbonic anhydrase from the marine diatom Thalassiosira weissflogii.^[16][17]

In many cases, the cofactor includes both an inorganic and organic component. One diverse set of examples are the haem proteins, which consists of a porphyrin ring coordinated to iron.

Iron-sulfur clusters

Iron-sulfur clusters are complexes of iron and sulfur atoms held within proteins by cysteinyl residues. They play both structural and functional roles, including electron transfer, redox sensing, and as structural modules.^[18]

Organic

Organic cofactors are small organic molecules (typically a molecular mass less than 1000 Da) that can be either loosely or tightly bound to the enzyme and directly participate in the reaction.^{[3][19][20][21]} In the latter case, when it is difficult to remove without denaturing the enzyme, it can be called a prosthetic group. It is important to emphasize that there is no sharp division between loosely and tightly bound cofactors.^[3] Indeed, many, such as NAD⁺ can be tightly bound in some enzymes, while it is loosely bound in others.^[3] Another example is thiamine pyrophosphate (TPP) is tightly bound in transketolase or pyruvate decarboxylase, while it is less tightly bound in pyruvate dehydrogenase. Other coenzymes, flavin adenine dinucleotide (FAD), biotin or lipoamide for instance, are covalently bound. Tightly-bound cofactors are generally regenerated during the same reaction cycle, while loosely-bound cofactors can be regenerated in a subsequent reaction catalyzed by a different enzyme. In the latter case, the cofactor can also be considered a substrate or cosubstrate.

Vitamins can serve as precursors to many organic cofactors (e.g. vitamins B₁, B₂, B₆, B₁₂, niacin, folic acid) or as coenzymes themselves (e.g. vitamin C). However, vitamins do have other functions in the body.^[22] Many organic cofactors also contain a nucleotide: such as the electron carriers NAD and FAD, or coenzyme A, which carries acyl groups. Most of these cofactors are found in a huge variety of species, and some are universal to all forms of life. An exception to this wide distribution is a group of unique cofactors that evolved in methanogens, which are restricted to this group of archaea.^[23]

Vitamins and derivatives

Non-vitamins

Cofactors as metabolic intermediates

Metabolism involves a vast array of chemical reactions, but most fall under a few basic types of reactions that involve the transfer of functional groups.^[53] This common chemistry allows cells to use a small set of metabolic intermediates to carry chemical groups between different reactions.^[54] These group-transfer intermediates are the loosely-bound organic cofactors, often called coenzymes.

Each class of group-transfer reaction is carried out by a particular cofactor, which is the substrate for a set of enzymes that produce it, and a set of enzymes that consume it. An example of this are the dehydrogenases that use nicotinamide adenine dinucleotide (NAD⁺) as a cofactor. Here, hundreds of separate types of enzymes remove electrons from their substrates and reduce NAD⁺ to NADH. This reduced cofactor is then a substrate for any of the reductases in the cell that require electrons to reduce their substrates.^[25]

These cofactors are therefore continuously recycled as part of metabolism. As an example, the total quantity of ATP in the human body is about 0.1 mole. This ATP is constantly being broken down into ADP, and then converted back into ATP. Thus, at any given time, the total amount of ATP + ADP remains fairly constant. The energy used by human cells requires the hydrolysis of 100 to 150 moles of ATP daily which is around 50 to 75 kg. Typically, a human will use up their body weight of ATP over the course of the day.^[55] This means that each ATP molecule is recycled 1000 to 1500 times daily.

Evolution

Organic cofactors, such as ATP and NADH, are present in all known forms of life and form a core part of metabolism. Such universal conservation indicates that these molecules evolved very early in the development of living things.^[56] At least some of the current set of cofactors may therefore have been present in the last universal ancestor, which lived about 4 billion years ago.^[57][58]

Organic cofactors may have been present even earlier in the history of life on Earth.^[59] Interestingly, the nucleotide adenosine is present in cofactors that catalyse many basic metabolic reactions such as methyl, acyl, and phosphoryl group transfer, as well as redox reactions. This ubiquitous chemical scaffold has therefore been proposed to be a remnant of the RNA world, with early ribozymes evolving to bind a restricted set of nucleotides and related compounds.^[60][61] Adenosine-based cofactors are thought to have acted as interchangeable adaptors that allowed enzymes and ribozymes to bind new cofactors through small modifications in existing adenosine-binding domains, which had originally evolved to bind a different cofactor.^[5] This process of adapting a pre-evolved structure for a novel use is referred to as exaptation.

History

The first organic cofactor to be discovered was NAD⁺, which was identified by Arthur Harden and William Youndin 1906.^[62] They noticed that adding boiled and filtered yeast extract greatly accelerated alcoholic fermentation in unboiled yeast extracts. They called the unidentified factor responsible for this effect a coferment. Through a long and difficult purification from yeast extracts, this heat-stable factor was identified as a nucleotide sugar phosphate by Hans von Euler-Chelpin.^[63] Other cofactors were identified throughout the early 20th century, with ATP being isolated in 1929 by Karl Lohmann,^[64] and coenzyme A being discovered in 1945 by Fritz Albert Lipmann.^[65]

The functions of these molecules were at first mysterious, but in 1936, Otto Heinrich Warburg identified the function of NAD⁺ in hydride transfer.^[66] This discovery was followed in the early 1940s by the work of Herman Kalckar, who established the link between the oxidation of sugars and the generation of ATP.^[67] This confirmed the central role of ATP in energy transfer that had been proposed by Fritz Albert Lipmann in 1941.^[68] Later, in 1949, Morris Friedkin and Albert L. Lehninger proved that NAD⁺ linked metabolic pathways such as the citric acid cycle and the synthesis of ATP.^[69]

Non-enzymatic cofactors

The term is used in other areas of biology to refer more broadly to non-protein (or even protein) molecules that either activate, inhibit or are required for the protein to function. For example, ligands such as hormones that bind to and activate receptor proteins are termed cofactors or coactivators, while molecules that inhibit receptor proteins are termed corepressors.

See also

• Enzyme catalysis
• Inorganic chemistry

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Further reading

• Bugg, Tim (1997). An introduction to enzyme and coenzyme chemistry. Oxford: Blackwell Science. ISBN 0-86542-793-3.

External links

• Cofactors lecture (Powerpoint file)
• Cofactor at eMedicine Dictionary
• MeSH Enzyme+cofactors

Categories: Enzymes | Cofactors

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