Adenosine triphosphate (ATP) is a coenzyme of vast importance in the transfer of chemical energy derived from biochemical oxidations. Other nucleotides (formed from uracil, cytosine, guanine, and inosine) have also been found to act as coenzymes. For example, uridine triphosphate—a derivative of uracil—has been demonstrated to be of great importance in the metabolism of carbohydrates, as in the biosynthesis of glycogen and sucrose.
Those coenzymes that have been found to be necessary in the diet are vitamins. One such compound, biotin, is a member of the B complex; it was first isolated in 1935 from dried egg yolk, and its structure was established in 1942. Biotin is usually found attached to a lysine residue in certain enzymes, where it participates in reactions involving the transfer of carboxyl (-COOH) groups; one such reaction is essential for the synthesis of fatty acids.
Another group of coenzymes is the cobalamin family; one member, cyanocobalamin (vitamin B12) is known to be essential in the diet, although its role in metabolism remains obscure. Closely related cobalamins seem to be involved in the biosynthesis of methionine and methane. The complicated cyanocobalamin molecule was reported in 1973 to have been synthesized; it was first isolated from liver some 25 years prior to that date.
Coenzyme A has been shown to participate in a variety of biochemical reactions, all involving acyl groups such as the acetyl unit; it is, for instance, associated with the pivotal first step of the Krebs cycle, in which an acetyl unit (the breakdown product of carbohydrates) is introduced into the cycle to be converted eventually into carbon dioxide, water, and chemical energy. Coenzyme A is derived from adenine, ribose, and pantothenic acid (a vitamin of the B complex).
The two flavin coenzymes, riboflavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), occur universally in living organisms and play important roles in biochemical oxidations and reductions. They are usually found tightly bound to certain enzymes (flavoproteins) and are derived from riboflavin (vitamin B2).
Glutathione, a tripeptide consisting of residues of glutamic acid, cysteine, and glycine, is known to act as a coenzyme in a few enzymatic reactions, but its importance may lie in its role as a nonspecific reducing agent within the cell. It is hypothesized that glutathione serves to maintain the biological activity of certain proteins by keeping selected cysteine sidechains in the reduced thiol form, thereby not allowing these residues to oxidize and cross-link with one another to form cystine residues. (Unnecessary cross-links often result in distortions of protein structure.)
Heme, a complicated molecule containing iron in the ferrous state, serves as a coenzyme in a variety of biochemical processes. It forms an essential part of the structure of hemoglobin and participates intimately in the uptake and release of oxygen by this protein. (In this case the use of the word coenzyme may be inappropriate in that often hemoglobin is not considered to be an enzyme, since it does not catalyze a chemical reaction.) Heme is an important part of the cytochromes, enzymes that catalyze the biochemical oxidations and reductions involved in the production of chemical energy in the form of ATP; heme is also associated with the various enzymes that catalyze the cleavage of peroxides.
Lipoic acid seems to be involved in the removal of carboxyl groups from α-keto acids and in the transfer of the remaining acyl groups to various acceptors. Lipoic acid in fact transfers the acetyl group of pyruvic acid to coenzyme A. Like biotin, lipoic acid is commonly found attached to lysine residues within certain enzymes. It was first reported to have been purified and isolated in crystalline form in 1953.
The nicotinamide nucleotides were the first coenzymes to be detected (1904) in extracts of a living organism. Nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) are derived from adenine, ribose, and nicotinic acid or niacin (a vitamin of the B complex) and are important intermediates in the biochemical oxidations and reductions that provide chemical energy within the cell. Both NAD and NADP can be reduced by accepting a hydride ion (H-, a proton with two electrons) from an appropriate donor; the resulting NADH and NADPH can then be oxidized back to their original states by transferring their hydride ions to various acceptors. In this fashion electron pairs (and protons) are shuttled about in the cell from high-energy donors to lower-energy acceptors. As a general rule, NADPH donates its hydride ions to biosynthetic processes, such as the fixing of carbon dioxide to make carbohydrates during the dark reaction of photosynthesis. NADH, on the other hand, donates its hydride ions to systems such as the cytochromes, which eventually donate them to oxygen to make (with the addition of a proton) water, producing chemical energy in the form of ATP as a byproduct; the process is not yet completely understood.
Pyridoxal phosphate is a coenzyme that is essential for many enzymatic reactions, almost all of which are associated with amino acid metabolism. It is, for example, involved in the synthesis of tryptophan, a derivative of pyridoxine (another vitamin of the B complex).
The coenzyme tetrahydrofolic acid is derived in humans from the B-complex vitamin folic acid. This coenzyme and its close relatives participate in the transfer of various carbon fragments from one molecule to another; they are, for instance, involved in the synthesis of methionine and thymine.
Thiamine pyrophosphate is derived from another B-complex vitamin, thiamine. This coenzyme often plays a role in the removal of carboxyl (-COOH) groups from organic acids, releasing the carbon and oxygen atoms as carbon dioxide (CO2). This coenzyme, for example, helps to remove a carboxyl group from pyruvic acid, leaving behind an acetyl group, which it donates to lipoic acid; the lipoic acid then transfers the acetyl group to coenzyme A, which finally inserts it into the beginning of the Krebs cycle. This important three-step enzymatic process requires the participation of three coenzymes; hundreds of other biochemical reactions require coenzymes as well, and this serves to explain the great significance of those molecules in the functioning of living organisms. In the case of human beings, it also serves to explain the importance of proper dietary intake of vitamins, which provide the only source of certain "building blocks" for several of these coenzymes.
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 coenzymes 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.
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.
|Coenzyme||Vitamin||Additional component||Chemical group(s) transferred||Distribution|
|NAD+ and NADP+||Niacin (B3)||ADP||Electrons||Bacteria, archaea and eukaryotes|
|Coenzyme A||Pantothenic acid (B5)||ADP||Acetyl group and other acyl groups||Bacteria, archaea and eukaryotes|
|Tetrahydrofolic acid||Folic acid (B9)||Glutamate residues||Methyl, formyl, methylene and formimino groups||Bacteria, archaea and eukaryotes|
|Menaquinone||Vitamin K||None||Carbonyl group and electrons||Bacteria, archaea and eukaryotes|
|Ascorbic acid||Vitamin C||None||Electrons||Bacteria, archaea and eukaryotes|
|Coenzyme F420||Riboflavin (B2)||Amino acids||Electrons||Methanogens and some bacteria|
|Coenzyme||Chemical group(s) transferred||Distribution|
|Adenosine triphosphate||Phosphate group||Bacteria, archaea and eukaryotes|
|S-Adenosyl methionine||Methyl group||Bacteria, archaea and eukaryotes|
|3'-Phosphoadenosine-5'-phosphosulfate||Sulfate group||Bacteria, archaea and eukaryotes|
|Coenzyme Q||Electrons||Bacteria, archaea and eukaryotes|
|Tetrahydrobiopterin||Oxygen atom and electrons||Bacteria, archaea and eukaryotes|
|Cytidine triphosphate||Diacylglycerols and lipid head groups||Bacteria, archaea and eukaryotes|
|Nucleotide sugars||Monosaccharides||Bacteria, archaea and eukaryotes|
|Glutathione||Electrons||Some bacteria and most eukaryotes|
|Coenzyme M||Methyl group||Methanogens|
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.
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.