Coenzyme

Overview
Coenzymes are small organic non-protein molecules that carry chemical groups between enzymes. Coenzymes are sometimes referred to as cosubstrates. These molecules are substrates for enzymes and do not form a permanent part of the enzymes' structures. This distinguishes coenzymes from prosthetic groups, which are non-protein components that are bound tightly to enzymes - such as iron-sulfur centers, flavin or haem groups. Both coenzymes and prosthetic groups are types of the broader group of cofactors, which are any non-protein molecules (usually organic molecules or metal ions) that are required by an enzyme for its activity.

In metabolism, coenzymes are involved in both group-transfer reactions, for example coenzyme A and adenosine triphosphate (ATP), and redox reactions, such as coenzyme Q10 and nicotinamide adenine dinucleotide (NAD+). Coenzymes are consumed and recycled continuously in metabolism, with one set of enzymes adding a chemical group to the coenzyme and another set removing it. For example, enzymes such as ATP synthase continuously phosphorylate adenosine diphosphate (ADP), converting it into ATP, while enzymes such as kinases dephosphorylate the ATP and convert it back to ADP.

Coenzymes molecules are often vitamins or are made from vitamins. Many conezymes contain the nucleotide adenosine as part of their structures, such as ATP, coenzyme A and NAD+. This common structure may reflect a common evolutionary origin as part of ribozymes in an ancient RNA world.

Coenzymes 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. This common chemistry allows cells to use a small set of metabolic intermediates to carry chemical groups between different reactions. These group-transfer intermediates are the coenzymes.

Each class of group-transfer reaction is carried out by a particular coenzyme, 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 (NADH) as a cofactor. Here, hundreds of separate types of enzymes remove electrons from their substrates and reduce NAD+ to NADH. This reduced coenzyme is then a substrate for any of the reductases in the cell that need to reduce their substrates.

Coenzymes 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. This means that each ATP molecule is recycled 1000 to 1500 times daily.

Types
Coenzymes are the major role in organisms of vitamins, although vitamins do have other functions in the body. Coenzymes are also commonly made from nucleotides: such as adenosine triphosphate, the biochemical carrier of phosphate groups, or coenzyme A, the coenzyme that carries acyl groups. Most coenzymes 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 coenzymes that evolved in methanogens, which are restricted to this group of archaea.

Evolution
Coenzymes, 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. At least some of the current set of coenzymes may therefore have been present in the last universal ancestor, which lived about 4 billion years ago.

Coenzymes may have been present even earlier in the history of life on Earth. Interestingly, the nucleotide adenosine is present in coenzymes 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. Adenosine-based coenzymes are thought to have acted as interchangeable adaptors that allowed enzymes and ribozymes to bind new coenzymes through small modifications in existing adenosine-binding domains, which had originally evolved to bind a different cofactor. This process of adapting a pre-evolved structure for a novel use is referred to as exaptation.

History
The first coenzyme to be discovered was NAD+, which was identified by Arthur Harden and William Youndin 1906. 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. Other coenzymes were identified throughout the early 20th century, with ATP being isolated in 1929 by Karl Lohmann, and coenzyme A being discovered in 1945 by Fritz Albert Lipmann.

The functions of coenzymes were at first mysterious, but in 1936, Otto Heinrich Warburg identified the function of NAD+ in hydride transfer. 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. This confirmed the central role of ATP in energy transfer that had been proposed by Fritz Albert Lipmann in 1941. Later, in 1949, Morris Friedkin and Albert L. Lehninger proved that the coenzyme NAD+ linked metabolic pathways such as the citric acid cycle and the synthesis of ATP.